Blinding efficacy and adverse events following repeated transcranial alternating current, direct current, and random noise stimulation.

As transcranial electrical stimulation (tES) protocols advance, assumptions underlying the technique need to be retested to ensure they still hold. Whilst the safety of stimulation has been demonstrated mainly for a small number of sessions, and small sample size, adverse events (AEs) following multiple sessions remain largely untested. Similarly, whilst blinding procedures are typically assumed to be effective, the effect of multiple stimulation sessions on the efficacy of blinding procedures also remains under question. This is especially relevant in multisite projects where small unintentional variations in protocol could lead to inter-site difference. We report AE and blinding data from 1,019 participants who received up to 11 semi-consecutive sessions of active or sham transcranial alternating current stimulation (tACS), direct current stimulation (tDCS), and random noise stimulation (tRNS), at 4 sites in the UK and US. We found that AEs were often best predicted by factors other than tES, such as testing site or session number. Results from the blinding analysis suggested that blinding was less effective for tDCS and tACS than tRNS. The occurrence of AEs did not appear to be linked to tES despite the use of smaller electrodes or repeated delivery. However, blinding efficacy was impacted in tES conditions with higher cutaneous sensation, highlighting a need for alternative stimulation blinding protocols. This may be increasingly necessary in studies wishing to deliver stimulation with higher intensities.

FAST: A Novel, Executive Function-Based Approach to Cognitive Enhancement.

The present study introduces a novel cognitive intervention aimed at improving fluid intelligence (Gf), based on a framework we refer to as FAST: Flexible, Adaptive, Synergistic Training. FAST leverages a combination of novel game-based executive function (EF) training-designed specifically to enhance the likelihood of transfer-and transcranial electrical stimulation (tES), with aims to synergistically activate and strengthen mechanisms of cognitive control critical to Gf. To test our intervention, we collected three Gf measures from 113 participants [the advanced short Bochumer Matrizen-Test (BOMAT), Raven's Advanced Progressive Matrices (APM), and matrices similar to Raven's generated by Sandia labs], prior to and following one of three interventions: (1) the FAST + tRNS intervention, a combination of 30 min of daily training with our novel training game, Robot Factory, and 20 min of concurrent transcranial random noise stimulation applied to bilateral dorsolateral prefrontal cortex (DLPFC); (2) an adaptively difficult Active Control intervention comprised of visuospatial tasks that specifically do not target Gf; or (3) a no-contact control condition. Analyses of changes in a Gf factor from pre- to post-test found numerical increases for the FAST + tRNS group compared to the two control conditions, with a 0.3 SD increase relative to Active Control (p = 0.07), and a 0.19 SD increase relative to a No-contact control condition (p = 0.26). This increase was found to be largely driven by significant differences in pre- and post-test Gf as measured on the BOMAT test. Progression through the FAST training game (Robot Factory) was significantly correlated with changes in Gf. This is in contrast with progress in the Active Control condition, as well as with changes in individual EFs during FAST training, which did not significantly correlate with changes in Gf. Taken together, this research represents a useful step forward in providing new insights into, and new methods for studying, the nature of Gf and its malleability. Though our results await replication and extension, they provide preliminary evidence that the crucial characteristic of Gf may, in fact, be the ability to combine EFs rapidly and adaptively according to changing demand, and that Gf may be susceptible to targeted training.

Modulating fluid intelligence performance through combined cognitive training and brain stimulation.

It is debated whether cognitive training of specific executive functions leads to far transfer effects, such as improvements in fluid intelligence (Gf). Within this context, transcranial direct current stimulation and recently also novel protocols such as transcranial random noise and alternating current stimulation are being investigated with regards to their ability to enhance cognitive training outcomes. We compared the effects of four different transcranial electrical brain stimulation protocols in combination with nine daily computerized training sessions on Gf. 82 participants were randomly assigned to receive transcranial direct current stimulation (tDCS), random noise stimulation (tRNS), multifocal alternating current stimulation at 40 Hz (mftACS), or multifocal tDCS (mftDCS) in combination with an adaptive and synergistic executive function (EF) training, or to a no-contact control group. EF training consisted of gamified tasks drawing on isolated as well as integrated executive functions (working memory, inhibition, cognitive flexibility). Transfer was assessed with a combined measure of Gf including three established tests (Bochumer Matrizentest - BOMAT, Raven's Advanced Progressive Matrices - RAPM, and Sandia Matrices). We found significant improvements in Gf for the tDCS, mftDCS, and tRNS groups when compared with the no-contact group. In contrast, the mftACS group did not improve significantly and showed a similar pattern as the no-contact group. Mediation analyses indicated that the improvement in Gf was mediated through game progression in the mftDCS and tRNS group. Electrical brain stimulation in combination with sustained EF training can lead to transfer effects in Gf, which are mediated by training progression.

Iterative Design and Testing for the Development of a Game-Based Chlamydia Awareness Intervention: A Pilot Study.

OBJECTIVES: Herein we describe a methodology for developing a game-based intervention to raise awareness of Chlamydia and other sexually transmitted infections among youth in Boston's underserved communities. MATERIALS AND METHODS: We engaged in three design-based experiments. These utilized mixed methods, including playtesting and assessment methods, to examine the overall effectiveness of the game. In this case, effectiveness is defined as (1) engaging the target group, (2) increasing knowledge about Chlamydia, and (3) changing attitudes toward Chlamydia testing. These three experiments were performed using participants from different communities and with slightly different versions of the game, as we iterated through the design/feedback process. RESULTS: Overall, participants who played the game showed a significant increase in participants' knowledge of Chlamydia compared with those in the control group (P = 0.0002). The version of the game, including elements specifically targeting systemic thinking, showed significant improvement in participants' intent to get tested compared with the version of the game without such elements (Stage 2: P > 0.05; Stage 3: P = 0.0045). Furthermore, during both Stage 2 and Stage 3, participants showed high levels of enjoyment, mood, and participation and moderate levels of game engagement and social engagement. During Stage 3, however, participants' game engagement (P = 0.0003), social engagement (P = 0.0003), and participation (P = 0.0003) were significantly higher compared with those of Stage 2. Thus, we believe that motivation improvements from Stage 2 to 3 were also effective. Finally, participants' overall learning effectiveness was correlated with their prepositive affect (r = 0.52) and their postproblem hierarchy (r = -0.54). CONCLUSION: The game improved considerably from its initial conception through three stages of iterative design and feedback. Our assessment methods for each stage targeted and integrated learning, health, and engagement outcomes. Lessons learned through this iterative design process are a great contribution to the games for health community, especially in targeting the development of health and learning goals through game design.

Models of cognitive performance based on home monitoring data.

Modeling cognitive performance using home monitoring data is a new approach to managing neurologic conditions and for monitoring the effects of cognitive exercise interventions. The data consists of activity monitoring from motion sensors and specific cognitive metrics embedded within our adaptive computer games. The frequency and continuity of data collection allows us to analyze within subject trends of cognitive performance and to assess day to day variability. This approach provides a framework for clinicians and care managers to have the potential of detecting patients' cognitive problems early and to have timely feedback on treatment interventions.

Unobtrusive monitoring of divided attention in a cognitive health coaching intervention for the elderly.

Assessment of cognitive functionality is an important aspect of care for elders. Unfortunately, few tools exist to measure divided attention, the ability to allocate attention to different aspects of tasks. An accurate determination of divided attention would allow inference of generalized cognitive decline, as well as providing a quantifiable indicator of an important component of driving skill. We propose a new method for determining relative divided attention ability through unobtrusive monitoring of computer use. Specifically, we measure performance on a dual-task cognitive computer exercise as part of a health coaching intervention. This metric indicates whether the user has the ability to pay attention to both tasks at once, or is primarily attending to one task at a time (sacrificing optimal performance). The monitoring of divided attention in a home environment is a key component of both the early detection of cognitive problems and for assessing the efficacy of coaching interventions.

Divided attention in computer game play: analysis utilizing unobtrusive health monitoring.

Divided attention is a vital cognitive ability used in important daily activities (e.g., driving), which tends to deteriorate with age. As with Alzheimer's and other neural degenerative conditions, treatment for divided attention problems is likely to be more effective the earlier it is detected. Thus, it is important that a method be found to detect changes in divided attention early on in the process, for both safety and health care reasons. We present here a new method for detecting divided attention unobtrusively, using performance on a computer game designed to force players to attend to different dimensions simultaneously in order to succeed. Should this model prove to predict scores on a standard test for divided attention, it could help to detect cognitive decline earlier in our increasingly computer-involved aging population, providing treatment efficacy benefits to those who will experience cognitive decline.

A framework for cognitive monitoring using computer game interactions.

Many countries are faced with a rapidly increasing economic and social challenge of caring for their elderly population. Cognitive issues are at the forefront of the list of concerns. People over the age of 75 are at risk for medically related cognitive decline and confusion, and the early detection of cognitive problems would allow for more effective clinical intervention. However, standard cognitive assessments are not diagnostically sensitive and are performed infrequently. To address these issues, we have developed a set of adaptive computer games to monitor cognitive performance in a home environment. Assessment algorithms for various aspects of cognition are embedded in the games. The monitoring of these metrics allows us to detect within subject trends over time, providing a method for the early detection of cognitive decline. In addition, the real-time information on cognitive state is used to adapt the user interface to the needs of the individual user. In this paper we describe the software architecture and methodology for monitoring cognitive performance using data from natural computer interactions in a home setting.

Cross talk between the intrarenal dopaminergic and cyclooxygenase-2 systems.

In mammalian kidney, dopamine produced in the proximal tubule (PT) acts as an autocrine/paracrine natriuretic hormone that inhibits salt and fluid reabsorption in the PT. In high-salt-treated animals, PT dopamine activity increases and inhibits reabsorption, leading to increased salt and fluid delivery to the macula densa (MD) and subsequent natriuresis and diuresis. Regulated cyclooxygenase-2 (COX-2) in the MD represents another intrinsic system mediating renal salt and water homeostasis. Renal cortical COX-2 is inversely related to salt intake, and decreased extracellular NaCl stimulates COX-2 expression in cultured MD/cortical thick ascending limb cells. The current study investigated interactions between renal dopamine and cortical COX-2 systems. In rats fed a control diet, the dopamine precursor l-dihydroxyphenylalanine (l-DOPA) or the DA1 receptor agonist SKF-81297 suppressed cortical COX-2 expression. High salt suppressed cortical COX-2 expression, which was attenuated by inhibition of dopamine production with benserazide or the DA1 receptor antagonist, SCH-23390. In contrast, l-DOPA or the dopamine-metabolizing enzyme inhibitor entacapone suppressed low-salt-induced cortical COX-2 expression. Inhibition of PT reabsorption with the carbonic anhydrase inhibitor acetazolamide suppressed cortical COX-2 expression. In contrast, treatment with distally acting diuretics led to elevation of cortical COX-2. These results indicate that dopamine modulates renal cortical COX-2 expression by modifying PT reabsorption.

Unobtrusive monitoring of computer interactions to detect cognitive status in elders.

The U.S. has experienced a rapid growth in the use of computers by elders. E-mail, Web browsing, and computer games are among the most common routine activities for this group of users. In this paper, we describe techniques for unobtrusively monitoring naturally occurring computer interactions to detect sustained changes in cognitive performance. Researchers have demonstrated the importance of the early detection of cognitive decline. Users over the age of 75 are at risk for medically related cognitive problems and confusion, and early detection allows for more effective clinical intervention. In this paper, we present algorithms for inferring a user's cognitive performance using monitoring data from computer games and psychomotor measurements associated with keyboard entry and mouse movement. The inferences are then used to classify significant performance changes, and additionally, to adapt computer interfaces with tailored hints and assistance when needed. These methods were tested in a group of elders in a residential facility.

PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells.

Mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene have been shown to cause autosomal recessive polycystic kidney disease (ARPKD), but the cellular functions of the gene product (PKHD1) remain uncharacterized. To illuminate its properties, the spatial and temporal expression patterns of PKHD1 were determined in mouse, rat, and human tissues by using polyclonal Abs and mAbs recognizing various specific regions of the gene product. During embryogenesis, PKHD1 is widely expressed in epithelial derivatives, including neural tubules, gut, pulmonary bronchi, and hepatic cells. In the kidneys of the pck rats, the rat model of which is genetically homologous to human ARPKD, the level of PKHD1 was significantly reduced but not completely absent. In cultured renal cells, the PKHD1 gene product colocalized with polycystin-2, the gene product of autosomal dominant polycystic disease type 2, at the basal bodies of primary cilia. Immunoreactive PKHD1 localized predominantly at the apical domain of polarized epithelial cells, suggesting it may be involved in the tubulogenesis and/or maintenance of duct-lumen architecture. Reduced PKHD1 levels in pck rat kidneys and its colocalization with polycystins may underlie the pathogenic basis for cystogenesis in polycystic kidney diseases.

Regulation of cyclooxygenase expression by vasopressin in rat renal medulla.

The antagonism between prostaglandin and vasopressin represents a classic negative feedback loop. It is not clear whether cyclooxygenase (COX)-2 and/or COX-1 expression is involved in elevated prostaglandin production stimulated by vasopressin in vivo. In the present study, we explored vasopressin regulation of medullary COX-2 and COX-1 expression acutely and chronically in rats. Medullary COX-1 expression was moderately lower and COX-2 expression was significantly lower in adult male Brattleboro rats than age-matched Long-Evans controls. Chronic treatment of Brattleboro rats with vasopressin for 1 wk led to a decrease in urine volume and a moderate increase in medullary COX-1; in contrast, medullary COX-2 expression was almost undetectable in untreated rats but was dramatically up-regulated with vasopressin treatment and was accompanied by increased urinary prostaglandin E(2) excretion. Further investigation revealed that both V1 and V2 receptors were involved in chronic medullary COX-1 and COX-2 up-regulation. Acute treatment with specific V1 or V2 receptor agonists resulted in specific increases in medullary COX-2, which was prevented by furosemide. Vasopressin did not affect COX-2 expression in cultured renomedullary interstitial cells. These data demonstrate that vasopressin stimulates medullary COX-2 expression through activation of both V1 and V2 receptors, and this stimulation is indirect and probably involves increased medullary electrolyte tonicity.

Home monitoring of computer interactions for the early detection of dementia.

Standard cognitive assessments to detect dementia are administered infrequently and often long after symptoms are clear to even family members. With the advent of new drugs and therapies to delay the onset of dementia, it is important to both detect signs as early as possible and to provide monitoring of cognitive changes. This paper describes unobtrusive methods for monitoring user interactions with a computer that serve as a basis for algorithms to measure cognitive performance. We adapted a standard computer game currently enjoyed by elders at risk for dementia in order to monitor natural performance on a task that involved significant strategic planning throughout the game. This enabled us to collect cognitive performance data on individuals at frequent intervals. We monitored move-by-move appropriateness as distance to solution, and additionally modeled user thought processes using between-move data from the mouse device. We then used our resulting dynamic user model both to adapt the game difficulty and to detect meaningful individual cognitive trends.

Regulation of renal cortical cyclooxygenase-2 in young rats.

Cyclooxygenase-2 (COX-2) is involved in kidney morphogenesis and is transiently elevated in the immature kidney. In adult rats, renal cortical COX-2 expression is tonically suppressed by mineralocorticoids (MC) and glucocorticoids (GC) and induced by chronic salt restriction. Young rats have low levels of GC and are in a state of relative volume depletion. The present study was designed to investigate the mechanisms underlying elevated cortical COX-2 expression in the immature kidney. Supplementation of GC or MC suppressed cortical COX-2 expression in suckling rats. GC suppression was significantly, but not completely, prevented by either an MC receptor antagonist or a GC receptor antagonist. MC suppression was completely prevented by a mineralocorticoid receptor antagonist. Salt supplementation suppressed cortical COX-2 expression in a dose- and time-dependent pattern in the suckling rats. Cortical COX-2 expression in the weanling rats was upregulated by a low-salt diet and downregulated by a high-salt diet. These results suggest that relative volume depletion and reduced GC levels are involved in elevated cortical COX-2 expression in the immature rodent kidney.

Mineralocorticoid regulation of cyclooxygenase-2 expression in rat renal medulla.

The renal inner medulla and its distal one-third, the papilla, are major sites of prostanoid synthesis involved in water and electrolyte homeostasis. These sites contain variable levels of cyclooxygenase (COX)-2, a key prostaglandin synthase enzyme that is sensitive to adrenal steroids. Immunoreactive renal medullary COX-2, restricted to interstitial cells in control adult rats, shows a gradient of intense staining at the tip of the papilla that gradually diminishes to undetectable levels in the proximal inner medulla. We used adrenalectomy (ADX) and steroid replacement to investigate the effects of steroids on papillary COX-2. Immunoblots demonstrate that papillary COX-2 was reduced by one-half after 2 wk ADX; glucocorticoid replacement ameliorated the decline but not to control levels. Mineralocorticoid (deoxycorticosterone acetate; DOCA) replacement stimulated papillary COX-2 more than fivefold over control; both the intensity of immunostaining and the numbers of COX-2-positive cells in the inner medulla increased. Similar stimulation of papillary COX-2 resulted from DOCA treatment of normal control rats, but the response was blunted in rats fed a low-salt diet and absent in Brattleboro rats. DOCA treatment of mouse renal medullary interstitial cells in culture had no effect, but increased tonicity of the culture medium with NaCl caused strong upregulation of COX-2. Urea, a permeant molecule, had no effect. Together, these results suggest that mineralocorticoids lead to upregulation of COX-2 in rat renal medulla by indirect pathways, probably involving induced electrolyte hypertonicity in the interstitial fluid.

Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension.

BACKGROUND: We previously reported that renal cortical cyclooxygenase (COX-2) expression increased following subtotal nephrectomy, and chronic treatment with a selective COX-2 inhibitor, SC58236, reduced proteinuria and retarded the development of glomerulosclerosis. The present studies were designed to examine the effects of COX-2 inhibition in a model of diabetic nephropathy. METHODS: Rats were divided into three groups: control, diabetic (streptozotocin-induced diabetic animals with superimposed DOCA/salt hypertension; right nephrectomy and DOCA treatment), and treated (administration of the selective COX-2 inhibitor, SC58236, to a subset of diabetic/DOCA/salt rats). Insulin was administered to maintain blood glucose in the 200 to 300 mg/dL range. RESULTS: Systolic blood pressure in the two diabetic groups was elevated within one week and remained elevated until sacrifice at six weeks (control, 108 +/- 2 mm Hg; diabetic, 158 +/- 4 mm Hg; treated, 156 +/- 7 mm Hg). When measured at six weeks, immunoreactive COX-2 expression in the renal cortex of the diabetic rats was 2.5 +/- 0.3-fold of control animals (N = 7). Immunohistochemical localization indicated increased expression in macula densa and surrounding cortical thick ascending limb of Henle (cTALH). The COX-2 inhibitor decreased COX-2 expression in diabetic rats to 1.3 +/- 0.1-fold control. In addition, SC58236 decreased expression of PAI-1 (diabetic vs. treated, 3.2 +/- 0.5 vs. 1.7 +/- 0.2-fold control, N = 7, P < 0.05), vascular endothelial growth factor (VEGF; 2.0 +/- 0.2 vs. 1.2 +/- 0.2; N = 7, P < 0.05), fibronectin (2.4 +/- 0.3 to 1.3 +/- 0.1; N = 7, P < 0.05) and transforming growth factor-beta (TGF-beta; 2.1 +/- 0.2 vs. 1.3 +/- 0.2; N = 7, P < 0.05). Proteinuria at six weeks was decreased in the SC58236-treated rats (149 +/- 8 vs. 92 +/- 8 mg/24 h; N = 7, P < 0.01). The mesangial sclerosis index, defined as increases in extracellular matrix within the mesangial space, was determined at six weeks; the control group had an index of 0.06 +/- 0.01, the diabetic group was 2.7 +/- 0.04 and the treated group was 0.6 +/- 0.03 (P < 0.0001 compared to the diabetic group). CONCLUSIONS: These results suggest that in an experimental model of diabetes and hypertension, inhibition of COX-2 expression decreases potential mediators of glomerular and tubulointerstitial injury and also decreases biochemical, functional and structural markers of renal injury.

Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1.

It is well known that nonselective, nonsteroidal anti-inflammatory drugs inhibit renal renin production. Our previous studies indicated that angiotensin-converting enzyme inhibitor (ACEI)-mediated renin increases were absent in rats treated with a cyclooxygenase (COX)-2-selective inhibitor and in COX-2 -/- mice. The current study examined further whether COX-1 is also involved in mediating ACEI-induced renin production. Because renin increases are mediated by cAMP, we also examined whether increased renin is mediated by the prostaglandin E(2) receptor EP(2) subtype, which is coupled to G(s) and increases cAMP. Therefore, we investigated if genetic deletion of COX-1 or EP(2) prevents increased ACEI-induced renin expression. Age- and gender-matched wild-type (+/+) and homozygous null mice (-/-) were administered captopril for 7 days, and plasma and renal renin levels and renal renin mRNA expression were measured. There were no significant differences in the basal level of renal renin activity from plasma or renal tissue in COX-1 +/+ and -/- mice. Captopril administration increased renin equally [plasma renin activity (PRA): +/+ 9.3 +/- 2.2 vs. 50.1 +/- 10.9; -/- 13.7 +/- 1.5 vs. 43.9 +/- 6.6 ng ANG I x ml(-1) x h(-1); renal renin concentration: +/+ 11.8 +/- 1.7 vs. 35.3 +/- 3.9; -/- 13.0 +/- 3.0 vs. 27.8 +/- 2.7 ng ANG I x mg protein(-1) x h(-1); n = 6; P < 0.05 with or without captopril]. ACEI also increased renin mRNA expression (+/+ 2.4 +/- 0.2; -/- 2.1 +/- 0.2 fold control; n = 6-10; P < 0.05). Captopril led to similar increases in EP(2) -/- compared with +/+. The COX-2 inhibitor SC-58236 blocked ACEI-induced elevation in renal renin concentration in EP(2) null mice (+/+ 24.7 +/- 1.7 vs. 9.8 +/- 0.4; -/- 21.1 +/- 3.2 vs. 9.3 +/- 0.4 ng ANG I x mg protein(-1) x h(-1); n = 5) as well as in COX-1 -/- mice (SC-58236-treated PRA: +/+ 7.3 +/- 0.6; -/- 8.0 +/- 0.9 ng ANG I x ml(-1) x h(-1); renal renin: +/+ 9.1 +/- 0.9; -/- 9.6 +/- 0.5 ng ANG I x mg protein(-1) x h(-1); n = 6-7; P < 0.05 compared with no treatment). Immunohistochemical analysis of renin expression confirmed the above results. This study provides definitive evidence that metabolites of COX-2 rather than COX-1 mediate ACEI-induced renin increases. The persistent response in EP(2) nulls suggests involvement of prostaglandin E(2) receptor subtype 4 and/or prostacyclin receptor (IP).