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Background: Women account for two thirds of the prevalence and incidence of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aβ1–42) and tau, for which early detection is crucial in prevention of the disease. Objective: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aβ1–42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. Methods: 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50–85). CSF samples of Aβ1–42 and tau and scores of general cognition were also obtained. Results: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. Conclusion: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aβ1–42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

1 Hz repetitive transcranial magnetic stimulation (rTMS) was used to decrease excitability of right pars triangularis (R PTr) to determine whether increased R PTr activity during picture naming in older adults hampers word finding. We hypothesized that decreasing R PTr excitability would reduce interference with word finding, facilitating faster picture naming. 15 older and 16 younger adults received two rTMS sessions. In one, speech onset latencies for picture naming were measured after both sham and active R PTr stimulation. In the other session, sham and active stimulation of a control region, right pars opercularis (R POp), were administered before picture naming. Order of active vs. sham stimulation within session was counterbalanced. Younger adults showed no significant effects of stimulation. In older adults, a trend indicated that participants named pictures more quickly after active than sham R PTr stimulation. However, older adults also showed longer responses during R PTr than R POp sham stimulation. When order of active vs. sham stimulation was modeled, older adults receiving active stimulation first had significantly faster responding after active than sham R PTr stimulation and significantly faster responding after R PTr than R POp stimulation, consistent with experimental hypotheses. However, older adults receiving sham stimulation first showed no significant differences between conditions. Findings are best understood, based on previous studies, when the interaction between the excitatory effects of picture naming and the inhibitory effects of 1 Hz rTMS on R PTr is considered. Implications regarding right frontal activity in older adults and for design of future experiments are discussed.

Recent stroke studies have shown that the ipsi-lesional thalamus longitudinally and significantly decreases after stroke in the acute and subacute stages. However, additional considerations in the chronic stages of stroke require exploration including time since stroke, gender, intracortical volume, aging, and lesion volume to better characterize thalamic differences after cortical infarct. This cross-sectional retrospective study quantified the ipsilesional and contralesional thalamus volume from 69 chronic stroke subjects’ anatomical MRI data (age 35–92) and related the thalamus volume to time since stroke, gender, intracortical volume, age, and lesion volume. The ipsi-lesional thalamus volume was significantly smaller than the contra-lesional thalamus volume (t(68) = 13.89, p

A small number of studies have described verbal selection deficits in Parkinson’s disease (PD) when selection must occur among competing alternatives. However, these studies have largely focused on single-word processing, or have utilised sentence stems that carry high contextual constraint, thus reducing selection demands. The present study aimed to determine the influence of variable contextual constraint on the selection of a verbal response in PD. This was achieved using an adaption of the Hayling Sentence Completion Task whereby PD participants and matched controls were required to provide a single word to complete a cloze probability sentence stem that carried a low, medium, or high degree of contextual constraint. Results revealed no main effect of group in terms of response time or accuracy, though a group-by-condition interaction in accuracy was noted. This was characterised by a significant difference in accuracy between low and medium levels of constraint for control participants, but no significant difference for the PD group. Functional MRI data revealed marked between-group differences in underlying neural activity. The control group showed increased recruitment of the dorsal striatum and the vlPFC under conditions that placed greater demands upon selection (i.e. low and medium constraint), and greater activity overall in the left dlPFC and right vlPFC. However, in the PD group, behavioural performance appeared to be maintained despite underlying decreases in frontostriatal activity, suggesting other compensatory mechanisms that may include changes in functional connectivity or an over-medication effect in frontal networks in response to loss of signalling in cortico-subcortical pathways.

Restoring function to damaged neural pathways, or promoting compensatory strategies to overcome dysfunctional neural pathways have been topics of inquiry within motor rehabilitation. This study considers these topics in Parkinson’s disease (PD), where disruption within the striatal-thalamic-cortical (STC) circuits can cause impairment in internally guided (IG) movements. A related, but separate externally guided (EG) movement network, recruits the intact cerebellar-thalamic-cortical (CTC) loop to facilitate movement in response to sensory cues, and is effective in remediating motor function. Partnered dance with leading and following roles may be used as proxies for training IG and EG strategies respectively, in PD and can test which strategy is more effective in remediating effects of PD. Leaders determine variables associated with IG and communicate step amplitude, timing, and direction to the follower. Followers use an EG strategy to sense and interpret directional pressure cues from the leader and then enact an appropriate movement response. This study examines how IG and EG training strategy affects STC and CTC circuits and their behavioral outcomes to examine whether compensatory or direct entrainment of neural pathways is more effective in PD. Fifty-eight participants were recruited with mild-moderate PD (stages 1-3) and randomly assigned to EG, IG or non-dance education control group and assessed before and after 12 weeks of biweekly interventions. Participants were assessed with standard cognitive and motor behavioral measures and lay in a Magnetic Resonance Imaging (MRI) scanner while they tapped their foot under two conditions: internal (tapping a learned rhythm: IT) and external (participant taps in response to an assistant’s felt tap on the participant’s hand: ET) guidance. The foot-tapping data collected with an accelerometer were evaluated by analyzing the frequency spectrum to calculate amplitude and timing of the foot taps. The functional (fMRI) data were pre-processed (AFNI), registered (MNI), and analyzed for changes in activation using a general linear model in SAS and AFNI. Postintervention, both the EG and the IG groups showed clinically significant changes on disease severity, but the EG group showed improvements on cognitive, motor, and mood variables. The EG group also outperformed the IG group in the in-scanner task performance measured by the foot accelerometer. Imaging data revealed a significant increase in the EG group in the primary motor cortex lower limb region and the parts of the cerebellar circuits, particularly right Cerebellar Lobule VIIIa. The control group showed an increase in activity in the putamen compared to the IG and EG groups that could be due to a different compensatory pathway. All findings were corroborated using a region of interest approach examining the same pathways according to an atlas. Our results indicate that the most effective strategy for the PD participants involved external cues that increased activity in the compensatory CTC pathway, the primary motor region, and significant improvements on almost all behavioral measurements.

Around 200,000 veterans (up to 32% of those deployed) of the 1991 Gulf War (GW) suffer from GW illness (GWI), which is characterized by multiple deficits in cognitive, affective, sensory and nociception domains. In this study we employed resting state fMRI (rsfMRI) to map impairments in brain function in GWI with advanced network analysis. RsfMRI data was obtained from 60 GWI veterans and 30 age-matched military controls. Group independent component analysis (GICA) was conducted to probe the functional connectivity networks in all 90 subjects. GICA revealed impaired functional connectivity (FC) in GWI veterans between a number of brain function networks consistent with their self-reported symptoms. GWI veterans exhibited impaired FC between language networks, and sensory input networks of all modalities as well as motor output networks. GWI veterans also exhibited impaired FC between different sensory perception and motor networks, and between different networks in the sensorimotor domain. These FC impairments provide putative mechanism of central nervous system dysfunction in GWI.

Background Previous studies investigating nigral iron accumulation used T2 or T2 *-weighted contrasts to define the regions of interest (ROIs) in the substantia nigra with mixed results. Because these contrasts are not sensitive to neuromelanin, ROIs may have inadvertently missed the SNpc. An approach sensitive to neuromelanin should yield consistent results. We examine iron deposition in ROIs derived from neuromelanin-sensitive and T2 *-weighted contrasts, respectively. Methods T1 -weighted and multiecho gradient echo imaging data were obtained in 2 cohorts. Multiecho gradient echo imaging data were analyzed using neuromelanin-sensitive SNpc ROIs as well as T2 *-weighted SNr ROIs. Results When compared with controls, significantly larger R2 * values were seen in the SNpc of PD patients in both cohorts. Mean R2 * values in the SNr of PD patients showed no consistency, with 1 cohort showing a small, statistically significant increase, whereas the other cohort exhibited no statistical difference. Conclusion Mean R2 * in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. © 2018 International Parkinson and Movement Disorder Society.

Background: Assessments of functional connectivity of default mode network (DMN) and positive task-related networks (TRNs) using independent component analysis (ICA) may help describe long-term eff...

Study Objectives Daytime sleepiness is a manifestation of multiple sleep and neurologic disorders. Few studies have assessed patterns of regional brain metabolism across different disorders of excessive daytime sleepiness. One such disorder, idiopathic hypersomnia (IH), is particularly understudied. Methods People with IH, narcolepsy (NT1), and non-sleepy controls underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) with electroencephalography (EEG). Participants were instructed to resist sleep and were awoken if sleep occurred. Voxel-wise parametric analysis identified clusters that significantly differed between each pair of groups, with a minimum cluster size of 100 voxels at a cluster detection threshold of p < 0.005. Correlations between glucose metabolism and sleep characteristics were evaluated. Results Participants (77% women) had IH (n = 16), NT1 (n = 14), or were non-sleepy controls (n = 9), whose average age was 33.8 (±10.7) years. Compared to controls, NT1 participants demonstrated hypermetabolism in fusiform gyrus, middle occipital gyrus, superior and middle temporal gyri, insula, cuneus, precuneus, pre- and post-central gyri, and culmen. Compared to controls, IH participants also demonstrated hypermetabolism in precuneus, inferior parietal lobule, superior and middle temporal gyri, and culmen. Additionally, IH participants demonstrated altered metabolism of the posterior cingulate. Most participants fell asleep. Minutes of N1 during uptake was significantly negatively correlated with metabolism of the middle temporal gyrus. Conclusion NT1 and IH demonstrate somewhat overlapping, but distinct, patterns of regional metabolism.

Elevated expression of β-amyloid (Aβ1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of Aβ1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/tCr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.

Objective To evaluate the feasibility of recruitment, preliminary efficacy, and acceptability of auricular percutaneous electrical nerve field stimulation (PENFS) for the treatment of fibromyalgia in veterans, using neuroimaging as an outcome measure and a biomarker of treatment response. Design Randomized, controlled, single-blind. Setting Government hospital. Subjects Twenty-one veterans with fibromyalgia were randomized to standard therapy (ST) control or ST with auricular PENFS treatment. Methods Participants received weekly visits with a pain practitioner over 4 weeks. The PENFS group received reapplication of PENFS at each weekly visit. Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) data were collected within 2 weeks prior to initiating treatment and 2 weeks following the final treatment. Analysis of rs-fcMRI used a right posterior insula seed. Pain and function were assessed at baseline and at 2, 6, and 12 weeks post-treatment. Results At 12 weeks post-treatment, there was a nonsignificant trend toward improved pain scores and significant improvements in pain interference with sleep among the PENFS treatment group as compared with the ST controls. Neuroimaging data displayed increased connectivity to areas of the cerebellum and executive control networks in the PENFS group as compared with the ST control group following treatment. Conclusions There was a trend toward improved pain and function among veterans with fibromyalgia in the ST + PENFS group as compared with the ST control group. Pain and functional outcomes correlated with altered rs-fcMRI network connectivity. Neuroimaging results differed between groups, suggesting an alternative underlying mechanism for PENFS analgesia.

Quantifying accurate functional magnetic resonance imaging (fMRI) activation maps can be dampened by spatio‐temporally varying task‐correlated motion (TCM) artifacts in certain task paradigms (e.g., overt speech). Such real‐world tasks are relevant to characterize longitudinal brain reorganization poststroke, and removal of TCM artifacts is vital for improved clinical interpretation and translation. In this study, we developed a novel independent component analysis (ICA)‐based approach to denoise spatio‐temporally varying TCM artifacts in 14 persons with aphasia who participated in an overt language fMRI paradigm. We compared the new methodology with other existing approaches such as “standard” volume registration, nonselective motion correction ICA packages (i.e., AROMA), and combining the novel approach with AROMA. Results show that the proposed methodology outperforms other approaches in removing TCM‐related false positive activity (i.e., improved detectability power) with high spatial specificity. The proposed method was also effective in maintaining a balance between removal of TCM‐related trial‐by‐trial variability and signal retention. Finally, we show that the TCM artifact is related to clinical metrics, such as speech fluency and aphasia severity, and the implication of TCM denoising on such relationship is also discussed. Overall, our work suggests that routine bulkhead motion based denoising packages cannot effectively account for spatio‐temporally varying TCM. Further, the proposed TCM denoising approach requires a one‐time front‐end effort to hand label and train the classifiers that can be cost‐effectively utilized to denoise large clinical data sets., Quantifying accurate functional magnetic resonance imaging (fMRI) activation maps can be dampened by spatio‐temporally varying task‐correlated motion (TCM) artifacts in certain task paradigms (e.g., overt speech). In this study, we developed a novel independent component analysis (ICA)‐based approach to denoise spatio‐temporally varying TCM artifacts in fourteen persons with aphasia who participated in an overt language fMRI paradigm. Results show that the proposed methodology outperforms other approaches in removing TCM‐related false positive activity (i.e., improved detectability power) with high spatial specificity. The proposed method was also effective in maintaining a balance between removal of TCM‐related trial‐by‐trial variability and signal retention. Finally, we show that the TCM artifact is related to clinical metrics, such as speech fluency and aphasia severity, and the implication of TCM denoising on such relationship is also discussed.

Objective:Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation.Methods:Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment.Results:A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = −.50, p = .01) and was not associated with visual attention (FA: r = −.11, p = .59; RD: r = −.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = −.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = −.10, p = .62).Conclusions:The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

We have previously shown that aerobic exercise improves measures of verbal fluency in older adults, and such an improvement is correlated with improved cardiovascular reserve (i.e., estimates of VO2). Due to increasing popularity in computer-based cognitive training, we explored whether the addition of cognitive training to aerobic exercise would further enhance the beneficial cognitive impact of exercise. Therefore, this study sought to test the hypothesis that a cognitive training regimen alone would directly improve executive function and that this effect would be potentiated with the addition of aerobic exercise. The interventions lasted 12 weeks, and cognitive assessments were taken immediately prior to and after the interventions. We found that only the groups employing aerobic exercise showed improvements in verbal fluency (semantic and letter) and cardiovascular fitness with no other executive functions being significantly impacted. Cognitive training alone was associated with decreased verbal fluency. These data replicate previous findings which indicate that aerobic exercise may have a remedial or mitigating effect of cognitive decline. In addition, they provide evidence that the addition of concurrent cognitive training to an aerobic exercise program does not provide synergistic improvement in executive functions.

Adult survivors of pediatric brain tumors exhibit deficits in executive functioning. Given that brain tumors and medical treatments for brain tumors result in disruptions to white matter, a network analysis was used to explore the topological properties of white matter networks. This study used diffusion tensor imaging and deterministic tractography in 38 adult survivors of pediatric brain tumors (mean age in years = 23.11 (SD = 4.96), 54% female, mean years post diagnosis = 14.09 (SD = 6.19)) and 38 healthy peers matched by age, gender, handedness, and socioeconomic status. Nodes were defined using the Automated Anatomical Labeling (AAL) parcellation scheme, and edges were defined as the mean fractional anisotropy of streamlines that connected each node pair. Global efficiency and average clustering coefficient were reduced in survivors compared to healthy peers with preferential impact to hub regions. Global efficiency mediated differences in cognitive flexibility between survivors and healthy peers, as well as the relationship between cumulative neurological risk and cognitive flexibility. These results suggest that adult survivors of pediatric brain tumors, on average one and a half decades post brain tumor diagnosis and treatment, exhibit altered white matter topology in the form of suboptimal integration and segregation of large scale networks, and that disrupted topology may underlie executive functioning impairments. Network based studies provided important topographic insights on network organization in long-term survivors of pediatric brain tumor., Highlights • Long term brain tumor survivorship is associated with altered white matter networks. • Hub regions were preferentially impacted in survivors. • Network properties explain cognitive flexibility differences between survivors and peers.

Functional connectivity using task-residual data capitalizes on remaining variance after mean task-related signal is removed from a time series. The degree of network specificity in language and attention domains featured by task-residual and resting-state data types were compared. Functional connectivity based on task-residual data evidenced stronger laterality of the language and attention connections and thus greater network specificity compared to resting-state functional connectivity of the same connections. Covariance between network nodes of task-residuals may thus reflect the degree to which two regions are coordinated in their specific activity, rather than a general shared co-activation. Task-residual functional connectivity provides complementary data to that of resting-state, emphasizing network relationships during task engagement.

Previous studies have demonstrated that fibromyalgia results in gray matter alterations as well as changes in GABA concentrations in various cortical regions when compared to healthy controls [1,2,3]. In veterans with fibromyalgia, we investigate the effect of PENFS on gray matter alterations and GABA concentrations and correlate them with clinical outcomes such as pain scores and function. PENFS applied to the ear stimulates auricular branches of cranial nerves including the vagus. Subjects: 21 veterans aged 20-60 years old with fibromyalgia were randomized to standard therapy control (ST) or standard therapy with auricular PENFS (ST+PENFS). (ST+PENFS: n = 12; ST: n = 9) Total n = 21. Intervention: ST involved standard therapy. ST+PENFS group included ST+PENFS weekly (5 days on) for 4 weeks. Imaging: Neuroimaging data was collected within 2 weeks of initiating treatment and 2 weeks following the final treatment. Self-reported pain and function were assessed and correlated to MRI timepoints. Analysis was performed of GABA concentrations using a right posterior insula voxel placement. Volumetric assessments were performed of the structural MRI data. Clinical assessments were also conducted. Findings: auricular PENFS results in novel changes observed as neural plasticity on fMRI. This study provides valuable insight on the role of potential biomarkers such as GABA and further investigates cortical gray matter alterations and its association with pain. This research was supported in part by Career Development Awards 1IK1RX002113-01A2, 1IK2RX003227-01 (Anna Woodbury), and 1IK2RX002934 (Venkatagiri Krishnamurthy); by Senior Research Career Scientist Award Grant B6364L (Bruce Crosson) and Center Grant 5I50RX002358 from the US Department of Veterans Affairs Rehabilitation Research and Development Service; and by the National Institute of Mental Health of the National Institutes of Health under Award No. R01MH105561 and R01MH118771 (Ying Guo).

Reading is a learned activity that engages multiple cognitive systems. In a cohort of typical and struggling adult readers we show evidence that successful oral reading of real words is related to gamma-amino-butyric acid (GABA) concentration in the higher-order language system, whereas reading of unfamiliar pseudo-words is not related to GABA in this system. We also demonstrate the capability of resting state functional connectivity (rsFC) combined with GABA measures to predict single real word compared to pseudo-word reading performance. Results show that the strength of rsFC between left fusiform gyrus (L-FG) and higher-order language systems predicts oral reading behavior of real words, irrespective of the local concentration of GABA. On the other hand, pseudo-words, which require grapheme-to-phoneme conversion, are not predicted by the connection between L-FG and higher-order language system. This suggests that L-FG may have a multi-functional role: lexical processing of real words and grapheme-to-phoneme processing of pseudo-words. Additionally, rsFC between L-FG, pre-motor, and putamen areas are positively related to the oral reading of both real and pseudo-words, suggesting that text may be converted into a phoneme sequence for speech initiation and production regardless of whether the stimulus is a real word or pseudo-word. In summary, from a systems neuroscience perspective, we show that: (i) strong rsFC between higher order visual, language, and pre-motor areas can predict and differentiate efficient oral reading of real and pseudo-words. (ii) GABA measures, along with rsFC, help to further differentiate the neural pathways for previously learned real words versus unfamiliar pseudo-words.

Given the profound impact of language impairment after stroke (aphasia), neuroplasticity research is garnering considerable attention as means for eventually improving aphasia treatments and how they are delivered. Functional and structural neuroimaging studies indicate that aphasia treatments can recruit both residual and new neural mechanisms to improve language function and that neuroimaging modalities may hold promise in predicting treatment outcome. In relatively small clinical trials, both non-invasive brain stimulation and behavioural manipulations targeting activation or suppression of specific cortices can improve aphasia treatment outcomes. Recent language interventions that employ principles consistent with inducing neuroplasticity also are showing improved performance for both trained and novel items and contexts. While knowledge is rapidly accumulating, larger trials emphasising how to select optimal paradigms for individualised aphasia treatment are needed. Finally, a model of how to incorporate the growing knowledge into clinical practice could help to focus future research.

Introduction: In posterior fossa tumor survivors, lower white matter integrity (WMI) in the right cerebellar-left frontal pathway has been well documented and appears to be related to proximity to the cerebellum, radiation treatment, as well as time since treatment in both cranial radiation and surgery-only treatment groups. The current study investigated theories of transneural degeneration following cerebellar tumor resection that may underlie or relate to reductions in WMI and regional brain volumes using correlations. We hypothesized a positive relationship between the volume of the right cerebellum and known white matter output pathways, as well as with the volume of structures that receive cerebellar projections along the pathway. Methods: Adult survivors of childhood brain tumors were recruited (n = 29; age, M = 22 years, SD = 5; 45% female). Age- and gender-matched controls were also included (n = 29). Participants completed 3 T diffusion-weighted and T1 MPRAGE MRI scans. Brain structure volume relative to intracranial vault served as regional volumetric measures. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. In the survivor group, partial correlations between WMI and regional volume included controlling for disease severity. Results: In posterior fossa tumor survivors, the volumes of the cerebellum, thalamus, and frontal lobe were correlated with WMI of the thalamic-frontal segment of the cerebellar-frontal pathway (r = 0.41–0.49, p .05; RD, r = 0.53, p