Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer's Disease.

Background: Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.

Diffusion Tensor Imaging Along Perivascular Spaces (DTI-ALPS) to Assess Effects of Age, Sex, and Head Size on Interstitial Fluid Dynamics in Healthy Subjects.

Diffusion tensor imaging along perivascular spaces (DTI-ALPS) is a novel MRI method for assessing brain interstitial fluid dynamics, potentially indexing glymphatic function. Failed glymphatic clearance is implicated in Alzheimer's disease (AD) pathophysiology. We assessed the contribution of age and female sex (strong AD risk factors) to DTI-ALPS index in healthy subjects. We also for the first time assessed the effect of head size. In accord with prior studies, we show reduced DTI-ALPS index with aging, and in men compared to women. However, head size may be a major contributing factor to this counterintuitive sex difference.

Functional Magnetic Resonance Imaging Activation During Unscripted Discourse in People With Poststroke Aphasia.

PURPOSE: The purpose of this project was to determine the feasibility of employing a functional magnetic resonance imaging (fMRI) task that captured activation associated with overt, unscripted (or free) discourse of people with aphasia (PWA), using a continuous scan paradigm. METHOD: Seven participants (six females, ages 48-70 years) with chronic poststroke aphasia underwent two fMRI scanning sessions that included a discourse fMRI paradigm that consisted of five 1-min picture description tasks, using personally relevant photographs, interspersed with two 30-s control periods where participants looked at a fixation cross. Audio during the continuous fMRI scan was collected and marked with speaking times and coded for correct information units. Activation maps from the fMRI data were generated for the contrast between speaking and control conditions. In order to show the effects of the multi-echo data analysis, we compared it to a single-echo analysis by using only the middle echo (echo time of 30 ms). RESULTS: Through the implementation of the free discourse fMRI task, we were able to elicit activation that included bilateral regions in the planum polare, central opercular cortex, precentral gyrus, superior temporal gyrus, middle temporal gyrus, superior temporal gyrus, Crus I of the cerebellum, as well as bilateral occipital regions. CONCLUSIONS: We describe a new tool for assessing discourse recovery in PWA. By demonstrating the feasibility of a natural language paradigm in patients with chronic, poststroke aphasia, we open a new area for future research.

Neural Changes in Children With Residual Speech Sound Disorder After Ultrasound Biofeedback Speech Therapy.

PURPOSE: Children with residual speech sound disorders (RSSD) have shown differences in neural function for speech production, as compared to their typical peers; however, information about how these differences may change over time and relative to speech therapy is needed. To address this gap, we used functional magnetic resonance imaging (fMRI) to examine functional activation and connectivity on adaptations of the syllable repetition task (SRT-Early Sounds and SRT-Late Sounds) in children with RSSD before and after a speech therapy program. METHOD: Sixteen children with RSSD completed an fMRI experiment before (Time 1) and after (Time 2) a speech therapy program with ultrasound visual feedback for /ɹ/ misarticulation. Progress in therapy was measured via perceptual ratings of productions of untreated /ɹ/ word probes. To control for practice effects and developmental change in patterns of activation and connectivity, 17 children with typical speech development (TD) completed the fMRI at Time 1 and Time 2. Functional activation was analyzed using a region-of-interest approach and functional connectivity was analyzed using a seed-to-voxel approach. RESULTS: Children with RSSD showed a range of responses to therapy. After correcting for multiple comparisons, we did not observe any statistically significant cross-sectional differences or longitudinal changes in functional activation. A negative relationship between therapy effect size and functional activation in the left visual association cortex was on the SRT-Late Sounds after therapy, but it did not survive correction for multiple comparisons. Significant longitudinal changes in functional connectivity were observed for the RSSD group on SRT-Early Sounds and SRT-Late Sounds, as well as for the TD group on the SRT-Early Sounds. RSSD and TD groups showed connectivity differences near the left insula on the SRT-Late Sounds at Time 2. CONCLUSION: RSSD and treatment with ultrasound visual feedback may thus be associated with neural differences in speech motor and visual association processes recruited for speech production.

Augmented pain-evoked primary sensorimotor cortex activation in adolescent girls with juvenile fibromyalgia.

ABSTRACT: Juvenile fibromyalgia (JFM) is a chronic widespread pain condition that primarily affects adolescent girls. Previous studies have found increased sensitivity to noxious pressure in adolescents with JFM. However, the underlying changes in brain systems remain unclear. The aim of this study was to characterize pain-evoked brain responses and identify brain mediators of pain hypersensitivity in adolescent girls with JFM. Thirty-three adolescent girls with JFM and 33 healthy adolescent girls underwent functional magnetic resonance imaging scans involving noxious pressure applied to the left thumbnail at an intensity of 2.5 or 4 kg/cm 2 and rated pain intensity and unpleasantness on a computerized Visual Analogue Scale. We conducted standard general linear model analyses and exploratory whole-brain mediation analyses. The JFM group reported significantly greater pain intensity and unpleasantness than the control group in response to noxious pressure stimuli at both intensities ( P < 0.05). The JFM group showed augmented right primary somatosensory cortex (S1) activation to 4 kg/cm 2 (Z > 3.1, cluster-corrected P < 0.05), and the peak S1 activation magnitudes significantly correlated with the scores on the Widespread Pain Index ( r = 0.35, P = 0.048) with higher activation associated with more widespread pain. We also found that greater primary sensorimotor cortex activation in response to 4 kg/cm 2 mediated the between-group differences in pain intensity ratings ( P < 0.001). In conclusion, we found heightened sensitivity to noxious pressure stimuli and augmented pain-evoked sensorimotor cortex responses in adolescent girls with JFM, which could reflect central sensitization or amplified nociceptive input.

The evolution of economic and political inequality: minding the gap.

The extent of economic and political inequality, their change over time, and the forces shaping them have profound implications for the sustainability of a society and the well-being of its members. Here we review the evolution of economic and political inequality broadly, though with particular attention to Europe and the USA. We describe legal/institutional, technological and social forces that have shaped this evolution. We highlight the cumulative effects of inequality across generations as channelled through wealth and inheritance but also through other intergenerational connections. We also review the state of research on the effects of inequality on economic growth, health and societal cohesion. This article is part of the theme issue 'Evolutionary ecology of inequality'.

ABCD_Harmonizer: An Open-source Tool for Mapping and Controlling for Scanner Induced Variance in the Adolescent Brain Cognitive Development Study.

Data from multisite magnetic resonance imaging (MRI) studies contain variance attributable to the scanner that can reduce statistical power and potentially bias results if not appropriately managed. The Adolescent Cognitive Brain Development (ABCD) study is an ongoing, longitudinal neuroimaging study acquiring data from over 11,000 children starting at 9-10 years of age. These scans are acquired on 29 different scanners of 5 different model types manufactured by 3 different vendors. Publicly available data from the ABCD study include structural MRI (sMRI) measures such as cortical thickness and diffusion MRI (dMRI) measures such as fractional anisotropy. In this work, we 1) quantify the variance attributable to scanner effects in the sMRI and dMRI datasets, 2) demonstrate the effectiveness of the data harmonization approach called ComBat to address scanner effects, and 3) present a simple, open-source tool for investigators to harmonize image features from the ABCD study. Scanner-induced variance was present in every image feature and varied in magnitude by feature type and brain location. For almost all features, scanner variance exceeded variability attributable to age and sex. ComBat harmonization was shown to effectively remove scanner induced variance from all image features while preserving the biological variability in the data. Moreover, we show that for studies examining relatively small subsamples of the ABCD dataset, the use of ComBat harmonized data provides more accurate estimates of effect sizes compared to controlling for scanner effects using ordinary least squares regression.

Drug-Coated Balloon Angioplasty for Thoracic Great Vessel Stenosis Due to Takayasu Arteritis With 1-Year Follow-up.

PURPOSE: Takayasu arteritis is a large-vessel vasculitis in women of childbearing age that affects large vessels including the aorta and its main branches. Inflammation of arteries can produce lesions that lead to occlusion, stenosis, or aneurysms which can lead to complications. If signs of organ dysfunction are present, vascular intervention may be necessary. CASE REPORT: In this article, we present a case of Takayasu arteritis with high-grade stenosis of all the great vessels of the thoracic aorta treated with drug-coated balloon (DCB) angioplasty and stenting requiring multiple follow-up interventions over a 1-year follow-up. CONCLUSION: The DCB angioplasty is a potential endovascular treatment for thoracic great artery stenosis in Takayasu arteritis that could be further explored.

Association of Hoover's Sign with Maximal Expiratory-to-Inspiratory Pressure Ratio in Patients with COPD.

Purpose: In chronic obstructive pulmonary disease (COPD) some patients develop paradoxical inspiratory rib motion, which is termed Hoover's sign. Our objective was to determine whether Hoover's sign is associated with a difference in the maximal expiratory pressure (MEP), the maximal inspiratory pressure (MIP), the MEP/MIP ratio, and other features on pulmonary function tests (PFTs). Methods: This observational prospective single-center cohort study enrolled patients with an established diagnosis of COPD with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3 (severe) and 4 (very severe) based on PFTs. Respiratory pressure measurements were also collected. Patients were examined for the presence or absence of Hoover's sign on physical examination by 2 internal medicine resident physicians trained in examining for Hoover's sign by a pulmonologist. Results: A total of 71 patients were examined for the presence of Hoover's sign. Hoover's sign was present in 49.3% of patients. Observer agreement (k statistic) was 0.8 for Hoover's sign. Median MEP/MIP was significantly greater in patients with Hoover's sign than those without Hoover's sign (1.88 versus 1.16, p<0.001). Patients with Hoover's sign also had a significantly lower MIP (39.0 versus 58.0, p<0.001) and higher residual volume (RV) to total lung capacity (TLC) ratio indicating a higher degree of air trapping (65 versus 59.5, p<0.014). Conclusion: The presence of Hoover's sign in patients with COPD is associated with a higher MEP/MIP ratio. This suggests respiratory pressure measurements can predict diaphragm dysfunction in patients with GOLD stage 3 and 4 COPD. Patients with Hoover's sign were also found to have a lower MIP and more air trapping.

Examining reaction time variability on the stop-signal task in the ABCD study.

OBJECTIVE: Reaction time variability (RTV) has been estimated using Gaussian, ex-Gaussian, and diffusion model (DM) indices. Rarely have studies examined interrelationships among these performance indices in childhood, and the use of reaction time (RT) computational models has been slow to take hold in the developmental psychopathology literature. Here, we extend prior work in adults by examining the interrelationships among different model parameters in the ABCD sample and demonstrate how computational models of RT can clarify mechanisms of time-on-task effects and sex differences in RTs. METHOD: This study utilized trial-level data from the stop signal task from 8916 children (9-10 years old) to examine Gaussian, ex-Gaussian, and DM indicators of RTV. In addition to describing RTV patterns, we examined interrelations among these indicators, temporal patterns, and sex differences. RESULTS: There was no one-to-one correspondence between DM and ex-Gaussian parameters. Nonetheless, drift rate was most strongly associated with standard deviation of RT and tau, while nondecisional processes were most strongly associated with RT, mu, and sigma. Performance worsened across time with changes driven primarily by decreasing drift rate. Boys were faster and less variable than girls, likely attributable to girls' wide boundary separation. CONCLUSIONS: Intercorrelations among model parameters are similar in children as has been observed in adults. Computational approaches play a crucial role in understanding performance changes over time and can also clarify mechanisms of group differences. For example, standard RT models may incorrectly suggest slowed processing speed in girls that is actually attributable to other factors.

Higher body mass index is associated with worse hippocampal vasoreactivity to carbon dioxide.

Background and objectives: Obesity is a risk factor for cognitive decline. Probable mechanisms involve inflammation and cerebrovascular dysfunction, leading to diminished cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). The hippocampus, crucially involved in memory processing and thus relevant to many types of dementia, poses a challenge in studies of perfusion and CVR, due to its location, small size, and complex shape. We examined the relationships between body mass index (BMI) and hippocampal resting CBF and CVR to carbon dioxide (CVRCO2) in a group of cognitively normal middle-aged and older adults. Methods: Our study was a retrospective analysis of prospectively collected data. Subjects were enrolled for studies assessing the role of hippocampal hemodynamics as a biomarker for AD among cognitively healthy elderly individuals (age > 50). Participants without cognitive impairment, stroke, and active substance abuse were recruited between January 2008 and November 2017 at the NYU Grossman School of Medicine, former Center for Brain Health. All subjects underwent medical, psychiatric, and neurological assessments, blood tests, and MRI examinations. To estimate CVR, we increased their carbon dioxide levels using a rebreathing protocol. Relationships between BMI and brain measures were tested using linear regression. Results: Our group (n = 331) consisted of 60.4% women (age 68.8 ± 7.5 years; education 16.8 ± 2.2 years) and 39.6% men (age 70.4 ± 6.4 years; education 16.9 ± 2.4 years). Approximately 22% of them (n = 73) were obese. BMI was inversely associated with CVRCO2 (ß = -0.12, unstandardized B = -0.06, 95% CI -0.11, -0.004). A similar relationship was observed after excluding subjects with diabetes and insulin resistance (ß = -0.15, unstandardized B = -0.08, 95% CI -0.16, -0.000). In the entire group, BMI was more strongly related to hippocampal CVRCO2 in women (ß = -0.20, unstandardized B = -0.08, 95% CI -0.13, -0.02). Discussion: These findings lend support to the notion that obesity is a risk factor for hippocampal hemodynamic impairment and suggest targeting obesity as an important prevention strategy. Prospective studies assessing the effects of weight loss on brain hemodynamic measures and inflammation are warranted.

Speech cortical activation and connectivity in typically developing children and those with listening difficulties.

Listening difficulties (LiD) in people who have normal audiometry are a widespread but poorly understood form of hearing impairment. Recent research suggests that childhood LiD are cognitive rather than auditory in origin. We examined decoding of sentences using a novel combination of behavioral testing and fMRI with 43 typically developing children and 42 age matched (6-13 years old) children with LiD, categorized by caregiver report (ECLiPS). Both groups had clinically normal hearing. For sentence listening tasks, we found no group differences in fMRI brain cortical activation by increasingly complex speech stimuli that progressed in emphasis from phonology to intelligibility to semantics. Using resting state fMRI, we examined the temporal connectivity of cortical auditory and related speech perception networks. We found significant group differences only in cortical connections engaged when processing more complex speech stimuli. The strength of the affected connections was related to the children's performance on tests of dichotic listening, speech-in-noise, attention, memory and verbal vocabulary. Together, these results support the novel hypothesis that childhood LiD reflects difficulties in language rather than in auditory or phonological processing.

Positron Emission Tomography reveals age-associated hypothalamic microglial activation in women.

In rodents, hypothalamic inflammation plays a critical role in aging and age-related diseases. Hypothalamic inflammation has not previously been assessed in vivo in humans. We used Positron Emission Tomography (PET) with a radiotracer sensitive to the translocator protein (TSPO) expressed by activated microglia, to assess correlations between age and regional brain TSPO in a group of healthy subjects (n = 43, 19 female, aged 23-78), focusing on hypothalamus. We found robust age-correlated TSPO expression in thalamus but not hypothalamus in the combined group of women and men. This pattern differs from what has been described in rodents. Prominent age-correlated TSPO expression in thalamus in humans, but in hypothalamus in rodents, could reflect evolutionary changes in size and function of thalamus versus hypothalamus, and may be relevant to the appropriateness of using rodents to model human aging. When examining TSPO PET results in women and men separately, we found that only women showed age-correlated hypothalamic TSPO expression. We suggest this novel result is relevant to understanding a stark sex difference in human aging: that only women undergo loss of fertility-menopause-at mid-life. Our finding of age-correlated hypothalamic inflammation in women could have implications for understanding and perhaps altering reproductive aging in women.

Processing of pain by the developing brain: evidence of differences between adolescent and adult females.

ABSTRACT: Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17 years) and 30 adult (ages 35-55 years) females underwent a functional magnetic resonance imaging scan involving acute pain. Participants received 12 ten-second noxious pressure stimuli that were applied to the left thumbnail at 2.5 and 4 kg/cm 2 , and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared with adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm 2 but not 4 kg/cm 2 . Adolescents showed greater medial-lateral prefrontal cortex and supramarginal gyrus activation in response to 2.5 kg/cm 2 and greater medial prefrontal cortex and rostral anterior cingulate responses to 4 kg/cm 2 . Adolescents showed greater pain-evoked responses in the neurologic pain signature and greater activation in the default mode and ventral attention networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in default mode and ventral attention regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides first evidence of greater low-pain sensitivity and pain-evoked brain responses in female adolescents (vs adult women) in regions important for nociceptive, affective, and cognitive processing, which may be associated with differences in peripheral nociception.

Automated grading of enlarged perivascular spaces in clinical imaging data of an acute stroke cohort using an interpretable, 3D deep learning framework.

Enlarged perivascular spaces (EPVS), specifically in stroke patients, has been shown to strongly correlate with other measures of small vessel disease and cognitive impairment at 1 year follow-up. Typical grading of EPVS is often challenging and time consuming and is usually based on a subjective visual rating scale. The purpose of the current study was to develop an interpretable, 3D neural network for grading enlarged perivascular spaces (EPVS) severity at the level of the basal ganglia using clinical-grade imaging in a heterogenous acute stroke cohort, in the context of total cerebral small vessel disease (CSVD) burden. T2-weighted images from a retrospective cohort of 262 acute stroke patients, collected in 2015 from 5 regional medical centers, were used for analyses. Patients were given a label of 0 for none-to-mild EPVS (< 10) and 1 for moderate-to-severe EPVS (≥ 10). A three-dimensional residual network of 152 layers (3D-ResNet-152) was created to predict EPVS severity and 3D gradient class activation mapping (3DGradCAM) was used for visual interpretation of results. Our model achieved an accuracy 0.897 and area-under-the-curve of 0.879 on a hold-out test set of 15% of the total cohort (n = 39). 3DGradCAM showed areas of focus that were in physiologically valid locations, including other prevalent areas for EPVS. These maps also suggested that distribution of class activation values is indicative of the confidence in the model's decision. Potential clinical implications of our results include: (1) support for feasibility of automated of EPVS scoring using clinical-grade neuroimaging data, potentially alleviating rater subjectivity and improving confidence of visual rating scales, and (2) demonstration that explainable models are critical for clinical translation.

Brain Structural Changes During Juvenile Fibromyalgia: Relationships With Pain, Fatigue, and Functional Disability.

OBJECTIVE: Juvenile fibromyalgia (FM) is a prevalent chronic pain condition affecting children and adolescents worldwide during a critical period of brain development. To date, no published studies have addressed the pathophysiology of juvenile FM. This study was undertaken to characterize gray matter volume (GMV) alterations in juvenile FM patients for the first time, and to investigate their functional and clinical relevance. METHODS: Thirty-four female adolescents with juvenile FM and 38 healthy adolescents underwent a structural magnetic resonance imaging examination and completed questionnaires assessing core juvenile FM symptoms. Using voxel-based morphometry, we assessed between-group GMV differences and associations between GMV and functional disability, fatigue, and pain interference in juvenile FM. We also studied whether validated brain patterns predicting pain, cognitive control, or negative emotion were amplified/attenuated in juvenile FM patients and whether structural alterations reported in adult FM were replicated in adolescents with juvenile FM. RESULTS: Compared to controls, juvenile FM patients showed GMV reductions in the anterior midcingulate cortex (aMCC) region (family-wise error corrected P [PFWE-corr ] = 0.04; estimated with threshold-free cluster enhancement [TFCE]; n = 72) associated with pain. Within the juvenile FM group, patients reporting higher functional disability had larger GMV in inferior frontal regions (PFWE-corr = 0.006; TFCE estimated; n = 34) linked to affective, self-referential, and language-related processes. Last, GMV reductions in juvenile FM showed partial overlap with findings in adult FM, specifically for the anterior/posterior cingulate cortices (P = 0.02 and P = 0.03, respectively; n = 72). CONCLUSION: Pain-related aMCC reductions may be a structural hallmark of juvenile FM, whereas alterations in regions involved in emotional, self-referential, and language-related processes may predict disease impact on patients' well-being. The partial overlap between juvenile and adult FM findings strengthens the importance of early symptom identification and intervention to prevent the transition to adult forms of the disease.

Tau PET following acute TBI: Off-target binding to blood products, tauopathy, or both?

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.

Rationale, study design and implementation of the LUCINDA Trial: Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's.

The LUCINDA Trial (Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's) is a 52 week, randomized, placebo-controlled trial of leuprolide acetate (Eligard) in women with Alzheimer's disease (AD). Leuprolide acetate is a gonadotropin analogue commonly used for hormone-sensitive conditions such as prostate cancer and endometriosis. This repurposed drug demonstrated efficacy in a previous Phase II clinical trial in those women with AD who also received a stable dose of the acetylcholinesterase inhibitor donepezil (Bowen et al., 2015). Basic biological, epidemiological and clinical trial data suggest leuprolide acetate mediates improvement and stabilization of neuropathology and cognitive performance via the modulation of gonadotropin and/or gonadotropin-releasing hormone signaling. LUCINDA will enroll 150 women with mild-moderate AD who are receiving a stable dose of donepezil from three study sites in the United States. Cognition and function are the primary outcome measures as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Blood and MRI biomarkers are also measured to assess hormonal, inflammatory and AD biomarker changes. We present the protocol for LUCINDA and discuss trial innovations and challenges including changes necessitated by the covid-19 pandemic and study drug procurement issues.

Neuroimaging of the Syllable Repetition Task in Children With Residual Speech Sound Disorder.

Purpose This study investigated phonological and speech motor neural networks in children with residual speech sound disorder (RSSD) during an overt Syllable Repetition Task (SRT). Method Sixteen children with RSSD with /ɹ/ errors (6F [female]; ages 8;0-12;6 [years;months]) and 16 children with typically developing speech (TD; 8F; ages 8;5-13;7) completed a functional magnetic resonance imaging experiment. Children performed the SRT ("SRT-Early Sounds") with the phonemes /b, d, m, n, ɑ/ and an adapted version ("SRT-Late Sounds") with the phonemes /ɹ, s, l, tʃ, ɑ/. We compared the functional activation and transcribed production accuracy of the RSSD and TD groups during both conditions. Expected errors were not scored as inaccurate. Results No between-group or within-group differences in repetition accuracy were found on the SRT-Early Sounds or SRT-Late Sounds tasks at any syllable sequence length. On a first-level analysis of the tasks, the TD group showed expected patterns of activation for both the SRT-Early Sounds and SRT-Late Sounds, including activation in the left primary motor cortex, left premotor cortex, bilateral anterior cingulate, bilateral primary auditory cortex, bilateral superior temporal gyrus, and bilateral insula. The RSSD group showed similar activation when correcting for multiple comparisons. In further exploratory analyses, we observed the following subthreshold patterns: (a) On the SRT-Early Sounds, greater activation was found in the left premotor cortex for the RSSD group, while greater activation was found in the left cerebellum for the TD group; (b) on the SRT-Late Sounds, a small area of greater activation was found in the right cerebellum for the RSSD group. No within-group functional differences were observed (SRT-Early Sounds vs. SRT-Late Sounds) for either group. Conclusions Performance was similar between groups, and likewise, we found that functional activation did not differ. Observed functional differences in previous studies may reflect differences in task performance, rather than fundamental differences in neural mechanisms for syllable repetition.

Altered functional network connectivity and working memory dysfunction in adolescents with epilepsy.

Adolescents with epilepsy are at risk for deficits in working memory, which could lead to learning difficulties and poor academic outcomes. We used task-based functional magnetic resonance imaging (fMRI) to examine potential disruption in working memory function in adolescents with epilepsy as compared to healthy controls. We recruited 29 adolescents (13-17 years) with non-lesional epilepsy and 20 healthy controls. All participants performed an N-back fMRI task and neuropsychological testing. A general linear model approach was used to create group activation maps of N-back fMRI for epilepsy and control groups and both groups combined (p < 0.05 corrected for multiple comparisons). Functionally defined regions of interest (ROIs) were identified based on clusters of combined group activation (z > 5). Subsets of these functional ROIs corresponding to cingulo-opercular and fronto-parietal networks were selected and differences in functional connectivity between the epilepsy and control groups were assessed. Adolescents with epilepsy had significantly poorer working memory scores compared to controls. For the N-back fMRI task, there were no significant differences in group activation. Functional connectivity was significantly reduced between the left frontal operculum and anterior cingulate gyrus (cingulo-opercular network) in adolescents with epilepsy compared to controls. This study demonstrates working memory deficits and an altered pattern of connectivity in brain networks supporting working memory in adolescents with epilepsy. Working memory performance was worse in adolescents with epilepsy; though scores were not directly correlated with reduced connectivity. These results suggest the neural substrates of working memory in adolescents with epilepsy may differ from those in typically-developing adolescents, and require further investigation to understand the reasons for poorer working memory performance.