Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment.

Mild cognitive impairment (MCI) during aging is often a harbinger of Alzheimer's disease, and, therefore, early intervention to preserve cognitive abilities before the MCI symptoms become medically refractory is particularly critical. Functional MRI­guided transcranial magnetic stimulation is a promising approach for modulating hippocampal functional connectivity and enhancing memory in healthy adults. Here, we extend these previous findings to individuals with MCI and leverage theta burst stimulation (TBS) and white matter tractography derived from diffusion-weighted MRI to target the hippocampus. Our preliminary findings suggested that TBS could be used to improve associative memory performance and increase resting-state functional connectivity of the hippocampus and other brain regions, including the occipital fusiform, frontal orbital cortex, putamen, posterior parahippocampal gyrus, and temporal pole, along the inferior longitudinal fasciculus in MCI. Although the sample size is small, these results shed light on how TBS propagates from the superficial cortex around the parietal lobe to the hippocampus.

Carotid Revascularization is Associated with Improved Mood in Patients with Advanced Carotid Disease.

OBJECTIVE: To investigate the impact of carotid interventions on patients' mental condition in patients with carotid stenosis. SUMMARY BACKGROUND DATA: Ongoing research highlights the impact of carotid interventions on neurocognitive function in patients with advanced carotid atherosclerosis. However, data regarding the impact of carotid revascularization on mood is scarce. METHODS: A total of 157 patients undergoing carotid revascularization were prospectively recruited. The primary outcome was depression, evaluated pre-operatively, and at 1-,6- and 12-month post-intervention using the long form of the geriatric depression scale (GDS-30) questionnaire. Other tests were also used to assess cognition at the respective timepoints. Statistical analyses were performed to assess the postoperative outcomes compared to baseline. RESULTS: Baseline depression (GDS>9) was observed in 49(31%) subjects, whereas 108(69%) patients were not depressed (GDS≤9). The average pre-operative GDS score was 15.42 ± 4.40(14.2-16.7) and 4.28 ±2.9(3.7-4.8) in the depressed and non-depressed groups, respectively. We observed a significant improvement in GDS scores within the depressed group at 1-month (P=0.002), 6-months (P=0.027), and 1-year (P<0.001) post-intervention compared to preop, whereas the non-depressed group had similar post-op GDS scores at all time points compared to baseline. Significant improvement in measures of executive function was seen in non-depressed patients at all three timepoints whereas depressed patients showed an improvement at 1-year follow-up. CONCLUSIONS: Our study highlights improvement in mood among patients with advanced carotid disease who screened positive for depression at baseline. Further studies with larger sample sizes are warranted to investigate the association between depression, carotid disease, and carotid intervention.

Transcranial Magnetic Stimulation for the Treatment of Chemo Brain.

This pilot feasibility study aimed to evaluate the effects of transcranial magnetic stimulation (TMS) on chemotherapy-related cognitive impairment (CRCI), and we report here on the first patient. BACKGROUND: Deleterious cognitive changes due to chemotherapy or CRCI are commonly referred to as "chemo brain". With the increasing survival of cancer patients, this poorly understood and inadequately treated condition will likewise have an increasing toll on individuals and society. Since there is no approved treatment for chemo brain, we have initiated a therapeutic trial using transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique approved in many countries for the treatment of neurologic and psychiatric conditions like migraine and depression. CASE PRESENTATION: A 58-year-old woman, diagnosed 7 years prior with left breast cancer, underwent partial mastectomy with sentinel lymph node biopsy. She then received four cycles of adjuvant chemotherapy followed by radiation therapy. Afterwards, she was on tamoxifen for 4 years and then switched to aromatase inhibitors. The patient's CRCI started during chemotherapy and severely impaired her quality of life for an additional two years. In the third year after chemotherapy, the CRCI partially cleared to stabilize to the level at the time of presentation for this trial. The patient continues to have memory difficulties and decreased concentration, which makes multi-tasking very difficult to impossible. She is reliant on memory aids at work and at home. The participant underwent 10 consecutive sessions of TMS during weekdays for 2 weeks. Stimulation was directed to the left dorsolateral prefrontal cortex. After TMS, the participant significantly improved in memory function on neuropsychological testing. While she reported no subjective differences in concentration or memory, she did report an improvement in her sleep. Functional magnetic resonance imaging of the brain before and after TMS showed increased resting-state functional connectivity between the stimulation site and several brain regions. Remarkably, after 6 years of chemo brain and remaining in the same position at work due to her inability to concentrate and multi-task, she applied for and received a promotion 5-6 months after her TMS treatments. CONCLUSIONS: This first patient in the phase 1 clinical trial testing of TMS for the treatment of "chemo brain" provided important lessons for feasibility and insights into mechanisms of potential benefit.

Carotid Intervention Improves Cognitive Function in Patients With Severe Atherosclerotic Carotid Disease.

INTRODUCTION: Carotid revascularization procedures are effective in stroke prevention in appropriately selected patients. We sought to understand the effects of the carotid intervention on cognitive function in a well-defined cohort of prospectively recruited patients. METHODS: A total of 170 consecutive patients undergoing carotid intervention for severe carotid stenosis were recruited. Patients received neuropsychometric testing preintervention, and at 1, 6, and 12 months postoperative. Patients were screened with the Mini-Mental State Examination. Rey Auditory Verbal Learning test (RAVLT) test was the primary outcome measure and multiple cognitive tests were used to evaluate executive function. Paired t test and McNemar test were performed to compare age-adjusted and education-adjusted postoperative scores at the individual time point with the preoperative scores. RESULTS: Our patients had a high prevalence of cardiovascular risks and 51.2% of whom were symptomatic. The usages of statin and antiplatelet were high (88.8% and 69.4%, respectively). A total of 140 patients had 1 or more postoperative neuropsychometric tests in addition to their preoperative tests were included. The average RAVLT preoperative score was lower ( z =-0.79, SD=1.3, confidence interval: -1 to -0.53) than the age-adjusted norm. We observed a significant improvement in RAVLT memory scores at 1 and 6 months postoperative compared with preoperative. We also observed significant improvement in multiple executive functions measures up to 12 months postoperative. The improvement on patients with preoperative stroke symptoms was less consistent. CONCLUSIONS: This prospective study showed that carotid intervention improved memory and executive function in patients with the severe carotid occlusive disease. It highlights the cognitive benefit of the carotid intervention in appropriately selected patients.

Frontoparietal activation during visual conjunction search: Effects of bottom-up guidance and adult age.

We conducted functional magnetic resonance imaging (fMRI) with a visual search paradigm to test the hypothesis that aging is associated with increased frontoparietal involvement in both target detection and bottom-up attentional guidance (featural salience). Participants were 68 healthy adults, distributed continuously across 19 to 78 years of age. Frontoparietal regions of interest (ROIs) were defined from resting-state scans obtained prior to task-related fMRI. The search target was defined by a conjunction of color and orientation. Each display contained one item that was larger than the others (i.e., a size singleton) but was not informative regarding target identity. Analyses of search reaction time (RT) indicated that bottom-up attentional guidance from the size singleton (when coincident with the target) was relatively constant as a function of age. Frontoparietal fMRI activation related to target detection was constant as a function of age, as was the reduction in activation associated with salient targets. However, for individuals 35 years of age and older, engagement of the left frontal eye field (FEF) in bottom-up guidance was more prominent than for younger individuals. Further, the age-related differences in left FEF activation were a consequence of decreasing resting-state functional connectivity in visual sensory regions. These findings indicate that age-related compensatory effects may be expressed in the relation between activation and behavior, rather than in the magnitude of activation, and that relevant changes in the activation-RT relation may begin at a relatively early point in adulthood. Hum Brain Mapp 38:2128-2149, 2017. © 2017 Wiley Periodicals, Inc.

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.

As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

Association between increased magnetic susceptibility of deep gray matter nuclei and decreased motor function in healthy adults.

In the human brain, iron is more prevalent in gray matter than in white matter, and deep gray matter structures, particularly the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus, exhibit especially high iron content. Abnormally elevated iron levels have been found in various neurodegenerative diseases. Additionally, iron overload and related neurodegeneration may also occur during aging, but the functional consequences are not clear. In this study, we explored the correlation between magnetic susceptibility--a surrogate marker of brain iron--of these gray matter structures with behavioral measures of motor and cognitive abilities, in 132 healthy adults aged 40-83 years. Latent variables corresponding to manual dexterity and executive functions were obtained using factor analysis. The factor scores for manual dexterity declined significantly with increasing age. Independent of gender, age, and global cognitive function, increasing magnetic susceptibility in the globus pallidus and red nuclei was associated with decreasing manual dexterity. This finding suggests the potential value of magnetic susceptibility, a non-invasive quantitative imaging marker of iron, for the study of iron-related brain function changes.

Age mediation of frontoparietal activation during visual feature search.

Activation of frontal and parietal brain regions is associated with attentional control during visual search. We used fMRI to characterize age-related differences in frontoparietal activation in a highly efficient feature search task, detection of a shape singleton. On half of the trials, a salient distractor (a color singleton) was present in the display. The hypothesis was that frontoparietal activation mediated the relation between age and attentional capture by the salient distractor. Participants were healthy, community-dwelling individuals, 21 younger adults (19-29 years of age) and 21 older adults (60-87 years of age). Top-down attention, in the form of target predictability, was associated with an improvement in search performance that was comparable for younger and older adults. The increase in search reaction time (RT) associated with the salient distractor (attentional capture), standardized to correct for generalized age-related slowing, was greater for older adults than for younger adults. On trials with a color singleton distractor, search RT increased as a function of increasing activation in frontal regions, for both age groups combined, suggesting increased task difficulty. Mediational analyses disconfirmed the hypothesized model, in which frontal activation mediated the age-related increase in attentional capture, but supported an alternative model in which age was a mediator of the relation between frontal activation and capture.

TMS-derived short afferent inhibition discriminates cognitive status in older adults without dementia.

Aging is a complex and diverse biological process characterized by progressive molecular, cellular, and tissue damage, resulting in a loss of physiological integrity and heightened vulnerability to pathology. This biological diversity corresponds with highly variable cognitive trajectories, which are further confounded by genetic and environmental factors that influence the resilience of the aging brain. Given this complexity, there is a need for neurophysiological indicators that not only discern physiologic and pathologic aging but also closely align with cognitive trajectories. Transcranial Magnetic Stimulation (TMS) may have utility in this regard as a non-invasive brain stimulation tool that can characterize features of cortical excitability. Particularly, as a proxy for central cholinergic function, short-afferent inhibition (SAI) dysfunction is robustly associated with cognitive deficits in the latter stages of Alzheimer's Disease and Related Dementia (ADRD). In this study, we evaluated SAI in healthy young adults and older adults who, though absent clinical diagnoses, were algorithmically classified as cognitively normal (CN) or cognitively impaired (CI) according to the Jak/Bondi actuarial criteria. We report that SAI is preserved in the Old-CN cohort relative to the young adults, and SAI is significantly diminished in the Old-CI cohort relative to both young and CN older adults. Additionally, diminished SAI was significantly associated with impaired sustained attention and working memory. As a proxy measure for central cholinergic deficits, we discuss the potential value of SAI for discerning physiological and pathological aging.

Exploring the potential of combining transcranial magnetic stimulation and electroencephalography to investigate mild cognitive impairment and Alzheimer's disease: a systematic review.

Transcranial magnetic stimulation (TMS) and electroencephalography (EEG) are non-invasive techniques used for neuromodulation and recording brain electrical activity, respectively. The integration of TMS-EEG has emerged as a valuable tool for investigating the complex mechanisms involved in age-related disorders, such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). By systematically synthesizing TMS-EEG studies, this review aims to shed light on the neurophysiological mechanisms underlying MCI and AD, while also exploring the practical applications of TMS-EEG in clinical settings. PubMed, ScienceDirect, and PsychInfo were selected as the databases for this review. The 22 eligible studies included a total of 592 individuals with MCI or AD as well as 301 cognitively normal adults. TMS-EEG assessments unveiled specific patterns of corticospinal excitability, plasticity, and brain connectivity that distinguished individuals on the AD spectrum from cognitively normal older adults. Moreover, the TMS-induced EEG features were observed to be correlated with cognitive performance and the presence of AD pathological biomarkers. The comprehensive examination of the existing studies demonstrates that the combination of TMS and EEG has yielded valuable insights into the neurophysiology of MCI and AD. This integration shows great potential for early detection, monitoring disease progression, and anticipating response to treatment. Future research is of paramount importance to delve into the potential utilization of TMS-EEG for treatment optimization in individuals with MCI and AD.

Differential impacts of healthy cognitive aging on directed and random exploration.

Deciding whether to explore unknown opportunities or exploit well-known options is a ubiquitous part of our everyday lives. Extensive work in college students suggests that young people make explore-exploit decisions using a mixture of information seeking and random behavioral variability. Whether, and to what extent, older adults use the same strategies is unknown. To address this question, 51 older adults (ages 65-74) and 32 younger adults (ages 18-25) completed the Horizon Task, a gambling task that quantifies information seeking and behavioral variability as well as how these strategies are controlled for the purposes of exploration. Qualitatively, we found that older adults performed similar to younger adults on this task, increasing both their information seeking and behavioral variability when it was adaptive to explore. Quantitively, however, there were substantial differences between the age groups, with older adults showing less information seeking overall and less reliance on variability as a means to explore. In addition, we found a subset of approximately 26% of older adults whose information seeking was close to zero, avoiding informative options even when they were clearly the better choice. Unsurprisingly, these "information avoiders" performed worse on the task. In contrast, task performance in the remaining "information seeking" older adults was comparable to that of younger adults suggesting that age-related differences in explore-exploit decision making may be adaptive except when they are taken to extremes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Transcranial Magnetic Stimulation of the Default Mode Network to Improve Sleep in Individuals With Insomnia Symptoms: Protocol for a Double-Blind Randomized Controlled Trial.

BACKGROUND: Cortical hyperarousal and ruminative thinking are common aspects of insomnia that have been linked with greater connectivity in the default mode network (DMN). Therefore, disrupting network activity within the DMN may reduce cortical and cognitive hyperarousal and facilitate better sleep. OBJECTIVE: This trial aims to establish a novel, noninvasive method for treating insomnia through disruption of the DMN with repetitive transcranial magnetic stimulation, specifically with continuous theta burst stimulation (cTBS). This double-blind, pilot randomized controlled trial will assess the efficacy of repetitive transcranial magnetic stimulation as a novel, nonpharmacological approach to improve sleep through disruption of the DMN prior to sleep onset for individuals with insomnia. Primary outcome measures will include assessing changes in DMN functional connectivity before and after stimulation. METHODS: A total of 20 participants between the ages of 18 to 50 years with reported sleep disturbances will be recruited as a part of the study. Participants will then conduct an in-person screening and follow-on enrollment visit. Eligible participants then conduct at-home actigraphic collection until their first in-residence overnight study visit. In a double-blind, counterbalanced, crossover study design, participants will receive a 40-second stimulation to the left inferior parietal lobule of the DMN during 2 separate overnight in-residence visits. Participants are randomized to the order in which they receive the active stimulation and sham stimulation. Study participants will undergo a prestimulation functional magnetic resonance imaging scan and a poststimulation functional magnetic resonance imaging scan prior to sleep for each overnight study visit. Sleep outcomes will be measured using clinical polysomnography. After their first in-residence study visit, participants conduct another at-home actigraphic collection before returning for their second in-residence overnight study visit. RESULTS: Our study was funded in September 2020 by the Department of Defense (W81XWH2010173). We completed the enrollment of our target study population in the October 2022 and are currently working on neuroimaging processing and analysis. We aim to publish the results of our study by 2024. Primary neuroimaging outcome measures will be tested using independent components analysis, seed-to-voxel analyses, and region of interest to region of interest analyses. A repeated measures analysis of covariance (ANCOVA) will be used to assess the effects of active and sham stimulation on sleep variables. Additionally, we will correlate changes in functional connectivity to polysomnography-graded sleep. CONCLUSIONS: The presently proposed cTBS protocol is aimed at establishing the initial research outcomes of the effects of a single burst of cTBS on disrupting the network connectivity of the DMN to improve sleep. If effective, future work could determine the most effective stimulation sites and administration schedules to optimize this potential intervention for sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov NCT04953559; https://clinicaltrials.gov/ct2/show/NCT04953559. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51212.

Cognitive effects of carotid revascularization in octogenarians.

BACKGROUND: Cognitive impairment is the epitome of cerebrovascular diseases, causing a significant economic burden on our health care system. Growing evidence has indicated the benefits of carotid interventions in patients with severe carotid atherosclerosis. However, the neurocognitive outcome of carotid revascularization in octogenarians is not clearly understood. We aim to evaluate postintervention cognitive changes in seniors older than 80 years. METHODS: We prospectively recruited 170 patients undergoing carotid interventions. Neurocognitive testing was performed preoperatively and at 1, 6, and 12 months postoperatively. Episodic memory was assessed with Rey's Auditory Verbal Learning Test. Other executive functions and language measures were also evaluated at individual time points. Raw test scores were converted to z-scores or scaled scores adjusted for age and education. The sample was divided into 2 groups based on age: octogenarian (≥80 years) and nonoctogenarian (<80 years old). Postoperative cognitive scores were compared to baseline within each subcohort. RESULTS: A total of 23 subjects (13%) were octogenarians, and 147 (87%) were younger than 80 years. Younger patients demonstrated significant cognitive improvements up to 12 months postop compared to the baseline. However, octogenarians exhibited a lack of improvement in verbal memory, measures of executive function, and language at all 3 postintervention time points. CONCLUSION: Carotid interventions improve cognitive functions in younger patients with carotid occlusive atherosclerosis. However, no cognitive benefits were seen in male seniors older than 80 years. Further investigations are warranted to better understand the postinterventional cognitive changes in octogenarians.

Association Between Responsiveness to Transcranial Magnetic Stimulation and Interhemispheric Functional Connectivity of Sensorimotor Cortex in Older Adults.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic technique, and is believed to accomplish its effect by influencing the stimulated and remotely connected areas. However, responsiveness to rTMS shows high interindividual variability, and this intersubject variability is particularly high in older adults. It remains unclear whether baseline resting-state functional connectivity (rsFC) contributes to this variability in older adults. The aims of this study are to (1) examine rTMS effects over the primary motor cortex (M1) in older adults, and (2) identify baseline network properties that may contribute to the interindividual variability. Methods: We tested response to intermittent theta burst stimulation (iTBS), an effective rTMS protocol, over M1 by using both electromyography and resting-state functional magnetic resonance imaging in older adults. Outcome measures included motor-evoked potential (MEP) elicited by single-pulse transcranial magnetic stimulation and rsFC before and after an iTBS session. Results: iTBS significantly increased MEP amplitudes and rsFC between the stimulation site, sensorimotor cortex, and supplementary motor area (SMA) in older adults. iTBS-induced changes in MEP amplitude were positively correlated with increases in interhemispheric rsFC after iTBS. Furthermore, older adults with lower baseline interhemispheric rsFC between sensorimotor cortex and SMA exhibited stronger MEP response after iTBS. Discussion: Findings of the study suggest that different levels of interhemispheric communication during resting state might contribute to the response heterogeneity to iTBS in older adults. Interhemispheric rsFC may have great potential serving as a useful marker for predicting iTBS responsiveness in older adults. ClinicalTrials.gov ID: 1707654427 Impact statement Factors contributing to interindividual variability of the responsive to repetitive transcranial magnetic stimulation (rTMS) in older adults remain poorly understood. In this study, we examined the effects of rTMS over the primary motor cortex in older adults, and found that response to rTMS is associated with prestimulation interhemispheric connectivity in the sensorimotor and premotor areas. Findings of the study have great potential to be translated into a connectivity-based strategy for identification of responders for rTMS in older adults.

Opioid-induced microglia reactivity modulates opioid reward, analgesia, and behavior.

Opioid-induced microglia reactivity affects opioid reward and analgesic processes in ways that may contribute to the neurocognitive impairment observed in opioid addicted individuals. Opioids elicit microglia reactivity through the actions of opioid metabolites at TLR4 receptors, that are located primarily on microglia but are also present on astrocytes. Specifically, the M3G metabolite, which has no affinity for opioid receptors, exerts off-target effects on TLR4 receptors that can trigger downstream immunologic consequences. This off-target microglial reactivity, and the subsequent increase in microglial release of TNFα, IL-1ß, and BDNF, have been suggested to modulate both opioid-induced reward and opioid-induced analgesia. Despite occurring independently of each other, these neuro-immune effects could converge and result in overactivation of the insula. This would produce an imbalance between the "impulsive system" and the "executive system", such that the impulsive system's influence over behavior becomes dominant. This state, derived from changes in microglial reactivity, could contribute to impairment in a range of neurocognitive domains that are intricately involved in addiction and lead to increases in addiction-related behaviors.

Efficacy of repetitive transcranial magnetic stimulation in treating stroke aphasia: Systematic review and meta-analysis.

OBJECTIVE: This meta-analysis examined the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) in treating post-stroke aphasia with a goal to identify parameters that are associated with successful treatment outcomes. METHODS: Following PRISMA guidelines, ten electronic databases were searched from inception till June 4th 2020. A total of 24 studies (out of 1971 records) with 567 participants met selection criteria and were included in the meta-analysis. RESULTS: The overall pooled meta-analysis revealed a significant medium effect size in favor of rTMS treatment: Standard mean difference (SMD) of 0.655 (95% CI = [0.481, 0.830], z = 7.369, p < 0.001). Moderator subgroup analyses indicated that participants' clinical characteristics and rTMS parameters moderated treatment effects. The strongest effects were observed for naming, followed by speech production, repetition and comprehension. The results indicate that with 10 to 15 sessions of 1-Hz rTMS administered 20-40 min per day over right BA45 (Brodmann's area 45), significant language improvements can be observed for up to 12 months. CONCLUSIONS: Our findings suggest that the rTMS technique can enhance rehabilitation of language skills in post-stroke aphasia when administered according to the established safety parameters. SIGNIFICANCE: Our results have implications for treatment of post-stroke aphasia. In subacute aphasia, low frequency rTMS over right BA45 improved naming, repetition, speech fluency and writing but not comprehension, whereas in chronic aphasia naming and speech production improved, but repetition and comprehension showed smaller gains.

Brain function complexity during dual-tasking is associated with cognitive impairment and age.

BACKGROUND AND PURPOSE: Early diagnosis of cognitive impairment is important because symptoms can be delayed through therapies. Synaptic disconnections are the key characteristics of dementia, and through nonlinear complexity analysis of brain function, it is possible to identify long-range synaptic disconnections in the brain. METHODS: We investigated the capability of a novel upper-extremity function (UEF) dual-task paradigm in the functional MRI (fMRI) setting, where the participant flexes and extends their arm while counting, to differentiate between cognitively normal (CN) and those with mild cognitive impairment (MCI). We used multiscale entropy (MSE) complexity analysis of the blood oxygen-level dependent time-series across neural networks and brain regions. Outside of the fMRI, we used the UEF dual-task test, while the elbow kinematics were measured using motion sensors, to record the motor function score. RESULTS: Results showed 34% lower MSE values in MCI compared to CN (p<.04 for all regions and networks except cerebellum when counting down by one; effect size = 1.35±0.15) and a negative correlation between MSE values and age (average r2 of 0.30 for counting down by one and 0.36 for counting backward by three). Results also showed an improvement in the logistic regression model sensitivity by 14-24% in predicting the presence of MCI when brain function measure was added to the motor function score (kinematics data). CONCLUSIONS: Current findings suggest that combining measures of neural network and motor function, in addition to neuropsychological testing, may provide an accurate tool for assessing early-stage cognitive impairment and age-related decline in cognition.

Cortical excitability and plasticity in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis of transcranial magnetic stimulation studies.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique. When stimulation is applied over the primary motor cortex and coupled with electromyography measures, TMS can probe functions of cortical excitability and plasticity in vivo. The purpose of this meta-analysis is to evaluate the utility of TMS-derived measures for differentiating patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively normal older adults (CN). METHODS: Databases searched included PubMed, Embase, APA PsycInfo, Medline, and CINAHL Plus from inception to July 2021. RESULTS: Sixty-one studies with a total of 2728 participants (1454 patients with AD, 163 patients with MCI, and 1111 CN) were included. Patients with AD showed significantly higher cortical excitability, lower cortical inhibition, and impaired cortical plasticity compared to the CN cohorts. Patients with MCI exhibited increased cortical excitability and reduced plasticity compared to the CN cohort. Additionally, lower cognitive performance was significantly associated with higher cortical excitability and lower inhibition. No seizure events due to TMS were reported, and the mild adverse response rate is approximately 3/1000 (i.e., 9/2728). CONCLUSIONS: Findings of our meta-analysis demonstrate the potential of using TMS-derived cortical excitability and plasticity measures as diagnostic biomarkers and therapeutic targets for AD and MCI.

Dual-task performance is associated with brain MRI Morphometry in individuals with mild cognitive impairment.

BACKGROUND AND PURPOSE: Cognitive impairment is a critical health problem in the elderly population. Research has shown that patients with mild cognitive impairment (MCI) may develop dementia in later years. Therefore, early identification of MCI could allow for interventions to help delay the progression of this devastating disease. Our objective in this study was to detect the early presence of MCI in elderly patients via neuroimaging and dual-task performance. METHODS: Brain MRI scans from 21 older adult volunteers, including cognitively healthy adults (HA, n = 9, age = 68-79 years) and mild cognitively impaired (MCI, n = 12, age = 66-92 years) were analyzed using automatic segmentation techniques. Regional volume, surface area, and thickness measures were correlated with simultaneous performance of motor and cognitive tasks (dual-task) within a novel upper-extremity function (UEF) test, using multivariate analysis of variance models. RESULTS: We found significant associations of dual-task performance with volume of five cortical brain regions (P ≤ .048) and thickness of 13 regions (P ≤ .043) within the frontal, temporal, and parietal lobes. There was a significant interaction effect of cognitive group on dual-task score for the inferior temporal gyrus volume (P ≤ .034), and the inferior parietal lobule, inferior temporal gyrus, and middle temporal gyrus average thickness (P ≤ .037). CONCLUSIONS: This study highlighted the potential of dual-tasking and MRI morphometric changes as a simple and accurate tool for early detection of cognitive impairment among community-dwelling older adults. The strong interaction effects of cognitive group on UEF dual-task score suggest higher association between atrophy of these brain structures and compromised dual-task performance among the MCI group.

Practical Application of DaTQUANT with Optimal Threshold for Diagnostic Accuracy of Dopamine Transporter SPECT.

Evaluation of Parkinsonian Syndromes (PS) with Ioflupane iodine-123 dopamine transporter single photon emission computed tomography (DaT-SPECT), in conjunction with history and clinical examination, aids in diagnosis. FDA-approved, semi-quantitative software, DaTQUANTTM (GE Healthcare, Chicago, IL, USA) is available to assist in interpretation. This study aims to evaluate the optimal variables and thresholds of DaTQUANT to yield the optimal diagnostic accuracy. It is a retrospective review with three different patient populations. DaT-SPECT images from all three study groups were evaluated using DaTQUANTTM software, and both single and multi-variable logistic regression were used to model PS status. The optimal models were chosen via accuracy, sensitivity, and specificity, then evaluated on the other study groups. Among single variable models, the posterior putamen yielded the highest accuracy (84% to 95%), while balancing sensitivity and specificity. Multi-variable models did not substantially improve the accuracy. When the optimal single variable models for each group were used to evaluate the remaining two groups, comparable results were achieved. In typical utilization of DaT-SPECT for differentiation between nigrostriatal degenerative disease (NSDD) and non-NSDD, the posterior putamen was the single variable that yielded the highest accuracy across three different patient populations. The posterior putamen's recommended thresholds for DaTQUANT are SBR ≤ 1.0, z-score of ≤-1.8 and percent deviation ≤ -0.34.