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Background Sensory hypersensitivity, defined as heightened awareness of and reactivity to external stimuli, is a bothersome symptom that affects up to 80% of adults with Tourette syndrome (TS). Such widespread prevalence suggests sensory hypersensitivity is a core feature of the disorder, but its severity and association with other clinical features of TS remain largely unexplored. Complicating matters, sensory hypersensitivity has been observed in two neurodevelopmental disorders commonly comorbid with TS: obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). Objective We sought to measure sensory hypersensitivity in TS patients relative to healthy controls and to investigate the relationship of sensory hypersensitivity with OCD and ADHD symptoms in the context of TS. Methods We recruited 34 adults with TS or chronic tic disorder to undergo evaluation with the Yale Global Tic Severity Scale (YGTSS) and a battery of validated self-report instruments assessing sensory hypersensitivity (Sensory Gating Inventory, SGI; Sensory Perception Quotient, SPQ), premonitory urge (Premonitory Urge to Tic Scale, PUTS), OCD (Dimensional Obsessive-Compulsive Scale, DOCS), and ADHD (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-V). Age- and sex-matched healthy controls were recruited to complete SGI and psychiatric measures. Results SGI and SPQ scores strongly correlated (rs = -0.73, p < 0.0001) within patients. SGI total score was significantly higher in patients versus controls (119.0 vs 67.6, U =-5.3, p < 0.0001), indicating greater sensory hypersensitivity in the tic disorder group. SGI score correlated modestly with PUTS, DOCS, and ASRS-V scores but not with YGTSS total tic score. Hierarchical linear regression analysis revealed that, of the tested variables, only DOCS score contributed significantly to mean SGI score, with β ranging from 1.03 (p = 0.044) to 1.41 (p = 0.001). A simple linear regression model with DOCS as the independent variable accounted for 31.9% of SGI score variance. Conclusion Sensory hypersensitivity is prominent in adults with tic disorder and is independently associated with obsessive-compulsive symptom severity.

We evaluated the associations of subjective (self-reported everyday cognition [ECog]) and objective cognitive measures with regional amyloid-β (Aβ) and tau accumulation in 86 clinically normal elderly subjects from the Alzheimer's Disease Neuroimaging Initiative. Regression analyses were conducted to identify whether individual ECog domains (Memory, Language, Organization, Planning, Visuospatial, and Divided Attention) were equally or differentially associated with regional [18F]florbetapir and [18F]flortaucipir uptake and how these associations compared to those obtained with objective cognitive measures. A texture analysis, the weighted 2-point correlation, was used as an additional approach for estimating the whole-brain tau burden without positron emission tomography intensity normalization. Although the strongest models for ECog domains included either tau (planning and visuospatial) or Aβ (memory and organization), the strongest models for all objective measures included Aβ. In Aβ-negative participants, the strongest models for all ECog domains of executive functioning included tau. Our results indicate differential associations of individual subjective cognitive domains with Aβ and tau in clinically normal adults. Detailed characterization of ECog may render a valuable prescreening tool for pathological prediction.

Sports-related concussion is associated with a range of short-term functional deficits that are commonly thought to recover within a two-week post-injury period for most, but certainly not all, persons. Resting state electroencephalography (rs-EEG) may prove to be an affordable, accessible, and sensitive method of assessing severity of brain injury and rate of recovery after a concussion. This article presents a systematic review of rs-EEG in sports-related concussion. A systematic review of articles published in the English language, up to June 2017, was retrieved via PsychINFO, Medline, Medline In Process, Embase, SportDiscus, CINAHL, and Cochrane Library, Reviews, and Trials. The following key words were used for database searches: electroencephalography, quantitative electroencephalography, qEEG, cranio-cerebral trauma, mild traumatic brain injury, mTBI, traumatic brain injury, brain concussion, concussion, brain damage, sport, athletic, and athlete. Observational, cohort, correlational, cross-sectional, and longitudinal studies were all included in the current review. Sixteen articles met inclusion criteria, which included data on 504 athletes and 367 controls. All 16 articles reported some abnormality in rs-EEG activity after a concussion; however, the cortical rhythms that were affected varied. Despite substantial methodological and analytical differences across the 16 studies, the current review suggests that rs-EEG may provide a reliable technique to identify persistent functional changes in athletes after a concussion. Because of the varied approaches, however, considerable work is needed to establish a systematic methodology to assess its efficacy as a marker of return-to-play.

Menopause is associated with increasing cognitive complaints and older women are at increased risk of developing Alzheimer disease compared to men. However, there is difficulty in early markers of risk using objective performance measures. We investigated the impact of subjective cognitive complaints on the cortical structure in a sample of younger postmenopausal women.Data for this cross-sectional study were drawn from the baseline visit of a longer double-blind study examining estrogen-cholinergic interactions in normal postmenopausal women. Structural Magnetic Resonance Imaging was acquired on 44 women, aged 50-60 years and gray-matter volume was defined by voxel-based morphometry. Subjective measures of cognitive complaints and postmenopausal symptoms were obtained as well as tests of verbal episodic and working memory performance.Increased levels of cognitive complaints were associated with lower gray-matter volume in the right medial temporal lobe (r = -0.445, P 0.002, R = 0.2). Increased depressive symptoms and somatic complaints were also related to increased cognitive complaints and smaller medial temporal volumes but did not mediate the effect of cognitive complaints. In contrast, there was no association between performance on the memory tasks and subjective cognitive ratings, or medial temporal lobe volume.The findings of the present study indicate that the level of reported cognitive complaints in postmenopausal women may be associated with reduced gray-matter volume which may be associated with cortical changes that may increase risk of future cognitive decline. : Video Summary:http://links.lww.com/MENO/A626.Video Summary:http://links.lww.com/MENO/A626.

Aging is associated with an increased prevalence of vascular health conditions that are linked to a disruption in the cerebral vasculature and white matter microstructural organization. In people with cardiovascular risk factors, increased cerebral arterial pulsatility is associated with poorer white matter microstructural organization and cognitive functioning. This study examines the relationship among arterial pulsatility, white matter microstructural organization, and cognitive ability in a healthy adult lifespan sample. One hundred and eighty-nine adults were divided into a younger adult (50 years, n = 92). The latter were further subdivided into two subgroups with (CV+, n = 25) and without (CV−, n = 67) cardiovascular risk factors. Arterial pulsatility was measured using cardiac-gated phase-contrast flow quantification sequence and three indexes of whole-brain white matter microstructural organization [i.e., fractional anisotropy (FA), radial diffusivity (RaD), mean diffusivity (MD)] were derived from diffusion-weighted imaging (DWI). Cognitive ability was assessed using global cognitive functioning (MoCA) and a measure of working memory [sensitivity (d′) from a 2-back task]. Neither the whole group analysis nor the younger adult group showed an association between measures of arterial pulsatility, global white matter microstructural organization, and cognition. In older adults, higher MD and RaD were associated with increased arterial pulsatility and poorer working memory performance. The indirect pathway from arterial pulsatility to working memory performance via both MD and RaD measures was significant in this group. Interestingly, a comparison of CV+ and CV− subgroups showed that this mediating relationship was only evident in older adults with at least one CV risk factor. These findings are consistent with cardiovascular risk factors as underlying arterial, white matter, and cognitive decline in cognitively normal older adults.

Introduction The development of neurotransmitter based cognitive enhancers for Alzheimer's disease have focused recently on allosteric modulation, as a way of reducing potential drug-limiting toxicities that have been the hallmark of earlier orthosteric compounds. VU319 is an investigational positive allosteric modulator of the M1 muscarinic acetylcholine receptor that has recently finished initial testing in healthy volunteers. Cognitive tasks and event-related potentials (ERPs) have been used during the randomized, double-blind, placebo controlled Single Ascending Dose (SAD) study of VU319. This presentation includes both data from the initial SAD study, and the Food Effect substudy. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state. Methods VU319 was given orally to 52 healthy volunteers aged 18-55?years. The SAD study tested 40 participants in five dose escalating cohorts of eight participants, in which six received VU319 and two received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. The five doses for the SAD study were 60, 120, 240, 400 and 600mg. Participants in the Food Effect substudy received VU319 at a single dose of 120mg. For the 5 cohorts of the SAD study, all participants were dosed in a fasted stated. In contrast, all 12 participants in the Food Effect substudy completed were dosed twice; once fasted, and once following breakfast. Cognitive and electrophysiological tasks were examined pre-dosing and at 5?hours post-dose. The tasks were selected for their sensitivity to cholinergic tone. Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Recorded ERP examined auditory and visual discrimination using oddball tasks, and an incidental memory task in which participants passively observed novel and repeated complex images. Results The analysis showed a trend for improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants on the highest dose of VU319 responded significantly faster to targets on the continuous performance test compared to participants on placebo (p = 0.03, effect size d = 1.2). Additionally, on the incidental memory task, participants who received the higher two doses of VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d > 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that the response time on the continuous performance task decreased in relation to increasing concentration of VU319 in the bloodstream. Conclusions We conclude that these results demonstrate potential enhancement of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by VU319 and therefore provide a potential framework to examine the cognitive impact of multiple doses of VU319 in AD patients. This research was funded by: This work was supported by the following grants: VKC Hobbs Discovery Grant 4-04-218-9745, Alzheimer's Association PCTR-16-383171; NICHD U54 HD083211, NCATS UL1 TR000445, 2RO1MH082867, R01MH073676, R01MH86601, MH087965, MH093366.

OBJECTIVE Late-life depression (LLD) is characterized by poor antidepressant response and cognitive dysfunction. This study examined whether transdermal nicotine benefits mood symptoms and cognitive performance in LLD. METHODS In a 12-week open-label outpatient study conducted between November 2016 and August 2017, transdermal nicotine was given to 15 nonsmoking older adults (≥ 60 years of age). Eligible participants met DSM-IV-TR criteria for major depressive disorder with ≥ 15 on the Montgomery-Asberg Depression Rating scale (MADRS) and endorsed subjective cognitive impairment. Transdermal nicotine patches were applied daily and titrated in a rigid dose escalation strategy to a maximum dose of 21.0 mg/d, allowing dose reductions for tolerability. The primary mood outcome was MADRS change measured every 3 weeks, with response defined as ≥ 50% improvement from baseline and remission as MADRS score ≤ 8. The primary cognitive outcome was the Conners Continuous Performance Test (CPT), a test of attention. RESULTS Robust rates of response (86.7%; 13/15 subjects) and remission (53.3%; 8/15 subjects) were observed. There was a significant decrease in MADRS scores over the study (β = -1.51, P < .001), with improvement seen as early as 3 weeks (Bonferroni-adjusted P value = .004). We also observed improvement in apathy and rumination. We did not observe improvement on the CPT but did observe improvement in subjective cognitive performance and signals of potential drug effects on secondary cognitive measures of working memory, episodic memory, and self-referential emotional processing. Overall, transdermal nicotine was well tolerated, although 6 participants could not reach the maximum targeted dose. CONCLUSIONS Nicotine may be a promising therapy for depressed mood and cognitive performance in LLD. A definitive placebo-controlled trial and establishment of longer-term safety are necessary before clinical usage. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02816138​.

PURPOSE OF REVIEW: This article reviews recent advances in drug discovery and development for geriatric psychiatry. Drug discovery for disorders of the central nervous system is a long and challenging process, with a high attrition rate from the preclinical stages through to marketing a compound. Developing drugs for geriatric neuropsychiatric conditions presents additional challenges, due to the complexity of the symptoms, comorbid diagnoses, and the variability of the population. Despite there being limited success over the past two decades, a number of new approaches have identified potential targets for preclinical development and ultimately clinical testing. RECENT FINDINGS: Recent approaches have tried to address specific mechanisms that relate to the disease progression. These approaches include combining a number of ligands into to multi-target compounds, or targeting specific types of cells such as protein kinases or myeloid cells. In addition, the increased use of induced pluripotent stem cell cultures has enabled new compounds to be tested on disease-specific tissues, increasing the success rate of the lead compounds going through the preclinical stages. SUMMARY: New pharmacological agents designed with advanced screening techniques and the shift towards systems pharmacology is changing the landscape of drug discovery in geriatric psychiatry. There is potential for these new agents to produce targeted effects in the framework of disorders that have long been untreatable.

Introduction Subjective cognitive decline (SCD) is increasingly recognized as the initial outward sign of preclinical Alzheimer's disease. The ability to explore associations between individual domains (memory, language, executive function, and visuospatial processing) within SCD and pathological biomarkers of early Alzheimer's disease (AD) would provide an important tool to understand the pathological basis of SCD and the risk of developing AD. This study utilizes multiple data analysis strategies to characterize the severity of tau and amyloid burden in clinically normal elderly adults (CN) and early mild cognitive impairment (EMCI) subjects in association with their subjective cognitive decline. Methods All subject data were downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. These included [18F]flortaucipir tau and [18F]florbetapir amyloid positron emission tomography (PET) images as well as the subjects’ SCD scores. For SCD, we used the self- and informant-reported individual items of Everyday Cognition questionnaire, including Everyday Memory, Everyday Language, Everyday Visuospatial abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The severity of the amyloid burden was calculated as the global PET standardized uptake value ratio (SUVR). The severity of the tau burden was assessed with both standard uptake-based approaches (tau SUVR in entorhinal, limbic, and isocortical Braak regions) and with a novel texture analysis tool, the weighted two-point correlation (wS2) analysis, which characterizes the spatial clustering of the tau-PET image as a sensitive early biomarker of abnormal tau accumulation and spread. Using a series of backward-elimination regression models, we identified the combination of predictors (from tau PET, global amyloid-PET, sex, APOE, and age) that constructed the best model to predict each Everyday Cognition item. Results Across the different cognitive tests, the wS2-based tau measures explained more variability, as indicated by p-values and elevated R-squared values, than standardized uptake value ratios from different anatomical regions, including the entorhinal cortex which is believed to be among the first regions to show signs of tau pathology. Our backward-elimination regression analyses (figure 1) suggested that the strongest models for predicting some of the subjective cognitive items (Everyday Memory, Everyday Language, Everyday Organization) were more likely amyloid-related whereas other items (Everyday Visuospatial, Everyday Planning) were more tau-related (together with age and sex). Conclusions Different pathological pathways may influence the manifestation of different subjective cognitive items. In vivo texture analysis techniques may be used as sensitive tools to explore these pathological pathways in association with the earliest signs of cognitive changes.

Event-related potential (ERP) studies using the task-switching paradigm show that multiple ERP components are modulated by activation of proactive control processes involved in preparing to repeat or switch task and reactive control processes involved in implementation of the current or new task. Our understanding of the functional significance of these ERP components has been hampered by variability in their robustness, as well as their temporal and scalp distribution across studies. The aim of this study is to examine the effect of choice of reference electrode or spatial filter on the number, timing and scalp distribution of ERP elicited during task-switching. We compared four configurations, including the two most common (i.e., average mastoid reference and common average reference) and two novel ones that aim to reduce volume conduction (i.e., reference electrode standardization technique (REST) and surface Laplacian) on mixing cost and switch cost effects in cue-locked and target-locked ERP waveforms in 201 healthy participants. All four spatial filters showed the same well-characterized ERP components that are typically seen in task-switching paradigms: the cue-locked switch positivity and target-locked N2/P3 effect. However, both the number of ERP effects associated with mixing and switch cost, and their temporal and spatial resolution were greater with the surface Laplacian transformation which revealed rapid temporal adjustments that were not identifiable with other spatial filters. We conclude that the surface Laplacian transformation may be more suited to characterize EEG signatures of complex spatiotemporal networks involved in cognitive control.

Introduction The decline of cholinergic functioning is associated with increased cognitive decline and the development of Alzheimer's disease (AD) pathology. At present, there is no pharmacological agent that slows the progression the disease. Muscarinic post positive allosteric modulators (PAMs) are a new class of compounds aiming to restore cholinergic functioning in patients suffering from AD pathology. PAMs of the M1 receptor can potentiate the response of the M1 receptor to acetylcholine, without inducing the harmful side-effects. This is due to the fact that PAMs do not bind at the target site, rather they boost the signal of acetylcholine when is engaged at the orthosteric receptor. The downside of using PAMs is that they have low affinity to radioactive ligands, so this reduces the utility of PET imaging. This creates a challenge in how to establish functional efficacy of the compound in both preclinical and clinical trials. Methods To address this challenge, we plan on using cognitive tasks and electroencephalography (qEEG) to identify dose-depended changes in cholinergic functioning. These functional biomarkers allow us to develop more detailed models of how M1PAMs may influence downstream cognitive processing. The cognitive and EEG measures presented have been shown to modulate cholinergic tone, therefore we should be able to identify effective target engagement. Results Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Tasks recorded by EEG tested auditory and visual discrimination using oddball tasks, and incidental memory. Conclusions These cognitive and electrophysiological results will assist in establishing functional targets for future studies using M1PAMs. This research was funded by Funding for this research comes from an Alzheimer's Association and the Alzheimer's Drug Discovery Foundation.

s / Brain Stimulation 8 (2015) 360e377 362 55% for attention in patients; 37% for executive function to 66% for memory in caregivers). Patient/caregiver agreement was moderate in 3 domains (kappa > 0.40). Objective deficit identification was poor among patients (8% to 45%) and caregivers (12% to 40%). Memory, visuospatial and executive problem report by caregivers was adequately verified (75% to 86%), but patient report only for memory (83%). Discussion: Findings suggests that patient report lacks sensitivity to objectively verified cognitive deficits, though specificity is good for memory. Patient report may be adequate to confirm a general cognitive problem, but should not be relied upon in DBS candidates to identify specific cognitive impairments. Neuropsychological evaluation is preferable to patient report to identify cognitive adverse events (e.g., frontal syndrome) in regulatory filings.

Anodal transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has been proposed as a possible therapeutic rehabilitation technique for motor impairment. However, despite extensive investigation into the effects of anodal tDCS on motor output, there is little information on how anodal tDCS affects response processes. In this study, we used a cued go/nogo task with both directional and non-directional cues to assess the effects of anodal tDCS over the dominant (left) primary motor cortex on prepared and unprepared motor responses. Three experiments explored whether the effectiveness of tDCS varied with timing between stimulation and test. Healthy, right-handed young adults participated in a double-blind randomised controlled design with crossover of anodal tDCS and sham stimulation. In Experiment 1, twenty-four healthy young adults received anodal tDCS over dominant M1 at least 40 mins before task performance. In Experiment 2, eight participants received anodal tDCS directly before task performance. In Experiment 3, twenty participants received anodal tDCS during task performance. In all three experiments, participants responded faster to directional compared to non-directional cues and with their right hand. However, anodal tDCS had no effect on go/nogo task performance at any stimulation – test interval. Bayesian analysis confirmed that anodal stimulation had no effect on response speed. We conclude that anodal tDCS over M1 does not improve response speed of prepared or unprepared responses of young adults in a go/nogo task.