Alexander C. Conley

Anodal direct current stimulation in the healthy aged: Effects determined by the hemisphere stimulated.

Abstract Purpose: Research popularity and scope for the application of transcranial direct current stimulation have been steadily increasing yet many fundamental questions remain unanswered. We sought to determine if anodal stimulation of either hemisphere leads to improved performance of the contralateral hand and/or altered function of the ipsilateral hand, or affects movement preparation, in older subjects. Method: In this cross-over, double blind, sham controlled study, 34 healthy aged participants (age range 40– 86) were randomised to receive 20 minutes of stimulation to either the dominant or non-dominant motor cortex. The primary outcome was functional performance of both upper limbs measured by the Jebsen Taylor Test and hand grip strength. Additionally, we measured motor preparation using electrophysiological (EEG) recordings. Results: Anodal stimulation resulted in statistically significantly improved performance of the non-dominant hand (p <  0.01) but did not produce significant changes in the dominant hand on any measure (p >  0.05). This effect occurred irrespective of the hemisphere stimulated. Stimulation did not produce significant effects on measures of gross function, grip strength, reaction times, or electrophysiological measures on the EEG data. Conclusion: This study demonstrated that the hemispheres respond differently to anodal stimulation and the response appears to be task specific but not mediated by age.

Anodal tDCS over the Motor Cortex on Prepared and Unprepared Responses in Young Adults

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.

Determining the benefits of transcranial direct current stimulation (tDCS) on functional upper limb movement in chronic stroke

Transcranial direct current stimulation (tDCS) has been proposed as a tool to enhance stroke rehabilitation; however, evidence to support its use is lacking. The aim of this study was to investigate the effects of anodal and cathodal tDCS on upper limb function in chronic stroke patients. Twenty five participants were allocated to receive 20 min of 1 mA of anodal, cathodal or sham cortical stimulation in a random, counterbalanced order. Patients and assessors were blinded to the intervention at each time point. The primary outcome was upper limb performance as measured by the Jebsen Taylor Test of Hand Function (total score, fine motor subtest score and gross motor subtest score) as well as grip strength. Each outcome was assessed at baseline and at the conclusion of each intervention in both upper limbs. Neither anodal nor cathodal stimulation resulted in statistically significantly improved upper limb performance on any of the measured tasks compared with sham stimulation (P>0.05). When the data were analysed according to disability, participants with moderate/severe disability showed significantly improved gross motor function following cathodal stimulation compared with sham (P=0.014). However, this was accompanied by decreased key grip strength in the unaffected hand (P=0.003). We are unable to endorse the use of anodal and cathodal tDCS in the management of upper limb dysfunction in chronic stroke patients. Although there appears to be more potential for the use of cathodal stimulation in patients with severe disability, the effects were small and must be considered with caution as they were accompanied by unanticipated effects in the unaffected upper limb.

No Effect of Anodal Transcranial Direct Current Stimulation Over the Motor Cortex on Response-Related ERPs during a Conflict Task

Anodal transcranial direct current stimulation (tDCS) over the motor cortex is considered a potential treatment for motor rehabilitation following stroke and other neurological pathologies. However, both the context under which this stimulation is effective and the underlying mechanisms remain to be determined. In this study, we examined the mechanisms by which anodal tDCS may affect motor performance by recording event-related potentials (ERPs) during a cued go/nogo task after anodal tDCS over dominant primary motor cortex (M1) in young adults (Experiment 1) and both dominant and non-dominant M1 in older adults (Experiment 2). In both experiments, anodal tDCS had no effect on either response time (RT) or response-related ERPs, including the cue-locked contingent negative variation (CNV) and both target-locked and response-locked lateralized readiness potentials (LRP). Bayesian model selection analyses showed that, for all measures, the null effects model was stronger than a model including anodal tDCS vs. sham. We conclude that anodal tDCS has no effect on RT or response-related ERPs during a cued go/nogo task in either young or older adults.

EXPLORING NOVEL COGNITIVE AND ELECTROPHYSIOLOGICAL MARKERS OF TARGET ENGAGEMENT IN PHASE 1 AND 2 STUDIES OF PUTATIVE CHOLINERGIC COGNITIVE ENHANCERS

Background:High cholesterol is associated with increased risk of Alzheimer’s disease (AD). Treatment with statin drugs is associated with decreased AD risk and neurofibrillary tangle burden. To examine potential disease-modifying effects of simvastatin treatment, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using CSF AD biomarkers as the primary outcome measures. Methods: Participants were 45 to 64 years of age and statin na€ıve with normal cognition and normal or mildly elevated cholesterol. A total of 49 participants were randomized and 46 completed the study protocol (simvastatin group: n1⁄425 and placebo group: n1⁄421). Simvastatin was titrated to a final dose of 40 mg/day. CSF and blood samples were collected in the morning both at baseline and after 12 months of treatment. CSF Ab42, total-tau, and p-tau181 were measured using the INNO-BIA AlzBio3 assay (Fujirebio). Neuropsychological tests were performed before and after the treatment. We used analysis of covariance to assess biomarker change from baseline with concentration at end-of-study as the response variable, and concentration at baseline, treatment assignment and covariates of age, gender and APOE ε4 status as predictor variables. Results: The demographics and baseline biomarker values were similar between the groups. The changes from baseline did not differ significantly between treatment groups for any of the CSF biomarkers nor for cognition after adjusting for the covariates, with p-values of 0.53, 0.36 and 0.25 for CSF Ab42, total tau and pTau181, respectively (Figure 1). There was no significant modifying effect of gender, APOE ε4, or baseline HDL or triglycerides by treatment group on any of the CSFAD biomarkers (p > 0.05). However, a significant interaction between treatment group and baseline LDL was observed for pTau181 (p 1⁄4 0.003) after adjusting for covariates. Greater decreases from baseline in CSF pTau181 concentrations were associated with higher baseline LDL level for the simvastatin group, whereas the opposite was true for the placebo group (Figure 2). Conclusions: Simvastatin-related reductions in CSF pTau181 concentrations may be modulated by LDL cholesterol levels. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.

Transdermal Nicotine for the Treatment of Mood and Cognitive Symptoms in Nonsmokers With Late-Life Depression

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​.

Resting State Electroencephalography and Sports-Related Concussion: A Systematic Review

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.

Event-Related Potential Responses to Task Switching Are Sensitive to Choice of Spatial Filter

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.

Advances in Drug Discovery and Development in Geriatric Psychiatry

Purpose of ReviewThis 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 FindingsRecent 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.SummaryNew 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.

ESTROGEN TREATMENT IN YOUNG POSTMENOPAUSAL WOMEN WITH SUBJECTIVE COGNITIVE DECLINE DOES NOT MITIGATE ANTICHOLINERGIC EFFECTS ON COGNITIVE PERFORMANCE

group (P<0.05). ADAS-cog was significantly lower than that before treatment and control group (P<0.05). After 4 months of treatment, theMMSE of control group was higher than before treatment (P<0.05). After 4 months follow-up, WMS-IV was significantly lower than that before treatment (P<0.05). Conclusions: The moderate-Intensity aerobic exercise can improve the cognitive function, especially memory function in AD patients.