Effectiveness of an Intensive, Functional, and Gamified Rehabilitation Program on Upper Limb Function in People With Stroke (EnteRtain): A Multicenter Randomized Clinical Trial.

BACKGROUND1: Despite a growing interest in gaming rehabilitation for upper limb (UL) recovery post-stroke, studies investigating the effects of game-based rehabilitation incorporating functional games are lacking. OBJECTIVE: To investigate the efficacy of an intensive, functional, gamified rehabilitation program compared to task-based training on UL motor function in acute/sub-acute stroke survivors. METHODS: This randomized, multicenter, single-blind, clinical trial comprises 120 participants with unilateral stroke who were randomized to receive either gamified training (n = 64) using the ArmAble™ [experimental group (EG)] or task-based training (n = 56) in conjunction with conventional therapy for 2 hours per day, 6 days per week for 2 weeks, followed by UL rehabilitation for another 4 weeks at home. Primary outcomes evaluated by a blinded assessor included the Fugl-Meyer Assessment-Upper Extremity (FM-UE), and Action Research Arm Test (ARAT). Data were analyzed using a linear mixed-effect regression model. RESULTS: The mean (standard deviation) age of the participants was 54.4 ± 11.7 years (78.1% men) in the EG and 57.7 ± 10.9 years (73.2% men) in the comparator group (CG). The median (interquartile range) time since stroke was 30.0 (54.0) days in the EG and 22.5 (45.0) days in the CG. Following the 2-week intervention, a statistically significant improvement was observed in the EG for the FM-UE [between-group mean differences (95% confidence interval): -3.9 (-6.5, -1.3); P = .003]; but not for the ARAT [-2.9 (-5.8, 0.0); P = .051]. Gains at 6 weeks were significantly greater in the EG for both FM-UE [-3.9 (-6.5, -1.3); P = .003]; and ARAT [-3.0 (-5.9, -0.0); P = .046]. CONCLUSION: Gamified rehabilitation using the ArmAble™ device has shown immediate and short-term improvement in UL function after acute/sub-acute stroke. CLINICAL TRIALS REGISTRY NUMBER: CTRI/2020/09/027651.

Do kinematic measures, added to clinical measures, better predict upper extremity motor impairments at three months post-stroke?

OBJECTIVE: Predicting post-stroke recovery through prediction models is crucial for choosing appropriate treatment options. However, the existing models predominantly incorporate clinical measures although measurement of movement quality using kinematic measures is essential for distinguishing various types of recovery. Thus, this study aimed at determining if, by considering varied aspects of recovery, adding kinematic measurements over clinical measures would better predict upper extremity (UE) motor impairments at three months post-stroke. MATERIALS AND METHODS: Eighty-nine stroke survivors (58.9 ± 11.8 years) were assessed for clinical predictors between 4 and 7 days, kinematic predictors within 1 month, and the impairment outcome of the Fugl Meyer Assessment of the UE (FM-UE) at three months post-stroke. Significant predictors (p<0.05) with a variation inflation factor (VIF) <10 were selected for model development. After performing further step-wise selection, three models incorporating clinical outcomes, kinematic measurements, and a combination of these two, respectively, were formulated. RESULTS: The clinical model (R2 = 0.70) included shoulder abduction finger extension (SAFE) scores, the National Institutes of Health Stroke Scale (NIHSS), and the Montreal Cognitive Assessment (MoCA). The kinematic model (R2 = 0.34) included total displacement, total time, and reaction time. The combined model (R2 = 0.72) comprised of SAFE score and shoulder flexion. All the models had a minimal mean squared error on cross validation, which indicated a good validity. CONCLUSION: The performance of clinical and combined prediction models for predicting three-month post-stroke UE motor recovery was nearly similar. However, in order to detect minimal changes over time and to understand all aspects of motor recovery, there is a need to add instrument-based kinematic measures.

Predicting post-stroke motor recovery of upper extremity using clinical variables and performance assays: A prospective cohort study protocol.

BACKGROUND AND PURPOSE: Measurement of movement quality is essential to distinguish motor recovery patterns and optimize rehabilitation strategies post-stroke. Recently, the Stroke Recovery and Rehabilitation Roundtable Taskforce (SRRR) recommended four kinetic and kinematic performance assays to measure upper extremity (UE) movements and distinguish behavioral restitution and compensation mechanisms early post-stroke. The purpose of this study is to develop and validate a prediction model to analyze the added prognostic value of performance assays over clinical variables assessed up to 1-month post stroke for predicting recovery of UE motor impairment, capacity and quality of movement (QoM) measured at 3 months post-stroke onset. METHODS: In this prospective cohort study, 120 stroke survivors will be recruited within seven days post-stroke. Candidate predictors such as baseline characteristics, demographics and performance assays as per SRRR recommendations along with tonic stretch reflex threshold will be measured up to 1-month post-stroke. Upper extremity motor recovery will be evaluated in terms of motor impairment (Fugl-Meyer assessment for UE), UE capacity measured with Action Research Arm Test (ARAT) and QoM (movement smoothness in the form of peak metrics [PM]) assessed with a reach-to-grasp-to-mouth task (mimicking a drinking task) at 3 months post-stroke. Three multivariable linear regression models will be developed to predict factors responsible for the outcomes of Fugl-Meyer assessment for upper extremity (FM-UE), ARAT and movement quality. The developed models will be internally validated using a split-sample method. DISCUSSION: This study will provide a validated prediction model inclusive of clinical and performance assays that may assist in prediction of UE motor recovery. Predicting the amount of recovery and differentiating between behavioral restitution and compensation (as reflected by the FM-UE, QoM and ARAT) would enable us in realistic goal formation and planning rehabilitation. It would also help in encouraging patients to partake in early post-stroke rehabilitation thus improving the recovery potential.

Successful treatment of severe form of bovine tropical theileriosis in dairy cattle and genotyping of Theileria annulata isolates of Tamil Nadu, India.

Bovine tropical theileriosis (BTT) is a tick-borne protozoan disease of cattle and responsible for major economic losses to the dairy farmers in India. This report describes diagnosis, genotyping and successful treatment of heavy infection of Theileria annulata in an organized dairy farm at Kattupakkam, Chennai. Four cross bred cows of 2 to 5 years of age showed clinical signs i.e., anorexia, salivation and panting. Clinical examination revealed pyrexia (40.0 °C to 40.1 °C), pale mucus membranes, enlarged prescapular lymph nodes and haemoglobinuria. The peripheral blood smear examination of infected cows revealed presence of piroplasm within the RBCs indicating high parasitemia. Haematology results suggested that decreased levels of Hb, RBC, WBC and PCV in the infected cows when compared with normal reference values. There were increased serum ALT and AST values and reduced serum total protein, albumin, calcium and phosphorous values in the infected cows. Semi-nested PCR using T. annulata specific oligonucleotide primers amplified 199 bp of the partial T. annulata 18S rRNA gene. Presence of four satellite markers TS6, TS8, TS9, and TS12 in the Theileria annulata isolates 1 and 2 indicating that the isolates were the same haplotype and suggested the infection in the farm was due to a single haplotype of T. annulata parasite. Based on the clinical signs, microscopic examination of blood smear and molecular diagnosis, the condition was diagnosed as tropical theileriosis. Infected cows were successfully treated with a single deep intramuscular injection of buparvaquone (Zubion®, INTAS pharmaceuticals LTD, Ahmedabad, India) along with supportive medication.

Adaptive sports for promoting physical activity in community-dwelling adults with stroke: A feasibility study.

BACKGROUND: Despite proven health benefits of regular participation in physical activities (PA), adults with stroke fail to achieve recommended levels of PA. Sports being an enjoyable activity is more likely to encourage participation. Therefore, the objectives of the present study are i) to develop and test the feasibility of adaptive sports for promoting PA and Quality of Life (QoL) in community-dwelling adults with stroke, and ii) to explore the participants perception and experiences of playing adaptive sports. METHODS: Two focus groups were conducted among the eight experts and a person with stroke to develop adaptive sports. To test the feasibility of these adaptive sports, in a multi methods study eighteen community dwelling adults with stroke were recruited. Participants played adaptive sports twice a week for two months in a community center. Participants pre and post intervention PA levels and QoL were measured. Participants were also interviewed at the end of the program to explore their experiences of participation in adaptive sports. RESULTS: At the end of the program retention rate of the participants was 83.33% and there was a significant improvement in PA levels, while the improvement in QoL was not statistically significant. Participants expressed positive experience with the program. There were no adverse events during or after the participation. Health benefits, fitness, and fun were reported as facilitators, while lack of access to the sporting facility and lack of caregiver support were reported as barriers to participation. CONCLUSION: Adaptive sports appear to be safe, feasible, and well accepted by the adults with stroke.

Effectiveness of an intensive, functional, gamified Rehabilitation program in improving upper limb motor function in people with stroke: A protocol of the EnteRtain randomized clinical trial.

INTRODUCTION: Game-based rehabilitation is an emerging therapeutic intervention that allows intensive, repetitive, task-based training to improve upper limb (UL) function following stroke, based on the principles of neuro-plasticity and motor (re)learning. Rehabilitation using commercial gaming system will be motivating, enjoyable, challenging and affordable. Therefore, the present study aims at assessing the effectiveness of an intensive, functional, gamified rehabilitation program using the ArmAble™ device in improving UL motor function in people with stroke. METHOD: In this single-blinded, multi-centric, randomized clinical trial, 120 adults with acute/sub-acute unilateral stroke will be randomized to receive an intensive, functional, gamified training program using the ArmAble™ or task-based training along with a conventional therapy for 2 h/day, 6 days/week for 2 weeks, followed by a home-based, functional rehabilitation program for another 4 weeks (~30 min/day, 6 days/week). Primary outcomes evaluated by a blinded assessor at the baseline, 2 weeks and 6 weeks' post-intervention will include the Fugl-Meyer assessment - upper extremity and the action research arm test. A linear mixed effect regression model or relevant non-parametric tests will be used to analyze the data for all outcomes. An intention-to-treat analysis will be used with missing data handled by multiple imputation. DISCUSSION: Rehabilitation provided with the ArmAble™ device, if found effective, can be used from the early stages post-stroke to provide intensive, repetitive, gamified training to improve UL motor function. TRIAL REGISTRATION NUMBER: CTRI/2020/09/027651.

Effects of game-based rehabilitation on upper limb function in adults within the first six months following stroke: protocol for a systematic review and meta-analysis.

OBJECTIVE: To evaluate and summarize the level of evidence for the immediate, short-term, and long-term effects of game-based rehabilitation on upper limb function in adults within the first six months following stroke. INTRODUCTION: A game-based intervention is a valuable therapeutic tool for incorporating principles of motor learning and neuroplasticity in the rehabilitation of upper limb function post-stroke. Most of the existing reviews on game-based rehabilitation are focused on the chronic phase of stroke. However, as maximum upper limb motor recovery occurs in the first six months after stroke, further exploration of the effects of game-based rehabilitation in this phase is necessary. INCLUSION CRITERIA: We will include randomized clinical trials assessing the immediate, short-term, and long-term effects of game-based rehabilitation on upper limb function in adults within the first six months following stroke. METHODS: The systematic review will follow the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) checklist and JBI methodology for systematic reviews of effectiveness. A database-specific search strategy will be used in CINAHL, PubMed, Scopus, Web of Science, ProQuest, PEDro, OT Seeker, and Ovid MEDLINE to identify studies in the English language with no date limit. Two reviewers will independently screen, extract data from, and assess risk of bias in the eligible studies. Meta-analysis and publication bias evaluation will be done when adequate data are available. If a meta-analysis is precluded, then a narrative synthesis will be done. The Grading of Recommendations Assessment Development and Evaluation (GRADE) criteria will be used to assess the certainty of evidence for the outcome measures of interest. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020190100.

Does the Environment Cause Changes in Hemiparetic Lower Limb Muscle Activity and Gait Velocity During Walking in Stroke Survivors?

Stroke survivors often face difficulty in community ambulation though they attain steady-state walking in clinical setups. Compliance and unpredictability of the environment may alter the muscle activity and challenge the individual's gait. Successful reintegration into the community requires gait assessment and training in a real-life challenging environment. Little is known about the assessment and training of gait in the community environment under challenging mobility dimensions. Hence, we aimed to study the changes that real-life environmental dimensions have on the activity of selected muscles in hemiparetic lower limb and gait velocity in stroke survivors. METHODS: An observational cross-sectional study was conducted on 16 ambulatory stroke survivors to assess the hemiparetic lower limb muscle activity during walking in real-life environmental dimensions. Participants were made to walk in the community on a walkway consisting of even surface, ramp, stairs, uneven terrain and obstacles. They were also made to manoeuvre through traffic and pick a load while walking for a distance in the walkway. Muscle activity of Rectus Femoris, Biceps Femoris, Gastrocnemius Medialis and Tibialis Anterior of the paretic lower limb were continuously recorded while walking using wireless surface electromyography. Gait velocity for the entire walkway and level of perceived difficulty while walking in different dimensions were also measured. Paired t-test was used to compare the percentage Maximum Voluntary Contraction (%MVC) of lower limb muscles between even surface and real-life environment dimensions while walking. One sample t-test was used to compare the gait velocity in real-life dimensions versus gait velocity in even surface measured in an earlier study. RESULTS: There was a significant reduction (p < 0.01) in the activity of all four hemiparetic lower limb muscles while walking under the influence of real-life environmental dimensions compared to even surface. Gait velocity (0.33 ± 0.17 m/s) was significantly lower than that is essential to be a community ambulator. The level of perceived difficulty across all dimensions was reported qualitatively with the highest difficulty reported during stair and obstacle clearance. CONCLUSION: Real-life environmental dimensions lead to the reduction of paretic lower limb muscle activities and gait velocity during walking in community-dwelling stroke survivors. Stroke survivors perceived more difficulty while walking in real-life environment dimensions particularly while negotiating stairs and obstacles. SIGNIFICANCE: Knowledge about the influence of real-life environmental dimensions will help the clinicians to target rehabilitation methods to improve walking adaptability.

Short-term balance training with computer-based feedback in children with cerebral palsy: A feasibility and pilot randomized trial.

OBJECTIVE: To assess the feasibility of using short-term balance training with computer-based visual feedback (BTVF) and its effect on standing balance in children with bilateral spastic cerebral palsy (BSCP). METHODS: Out of the fourteen children with BSCP (mean age = 10.31 years), seven children received four sessions of BTVF (two such sessions/day, each session = 15 min) in comparison to the control group that received standard care. Feasibility was measured as percentages of recruitment, retention and safety and balance was measured using a posturography machine as sway velocity (m/s) and velocity moment (m/s2) during quiet standing. RESULTS: No serious adverse events occurred in either group. There were no differences in the retention percentages and in any clinical outcome measure between both groups. CONCLUSION: Use of BTVF is feasible in children with BSCP but further investigation is required to estimate a dose-effect relationship.

Postural sway in diabetic peripheral neuropathy among Indian elderly.

BACKGROUND & OBJECTIVES: Diabetic peripheral neuropathy (DPN) is a major complication of type 2 diabetes and have long term complications on the postural control of the affected population. The objectives of this study were to evaluate postural stability in patients with DPN and to examine correlation of Michigan Neuropathy Screening Instrument (MNSI) with duration of diabetes, age and postural stability measures. METHODS: Participants were included if they had clinical neuropathy which was defined by MNSI. Sixty one patients gave their consent to participate in the study and were evaluated on posturography for postural stability measures in four conditions. Repeated measures of analysis of variance (RANOVA) was used to analyze the changes in postural stability measures in different conditions. RESULTS: An increase in mean value of postural stability measures was observed for velocity moment 20.4±1.3, 24.3±2.2, 42.3±20.7, 59±43.03, mediolateral displacement 0.21±0.10, 0.22±0.18, 0.03±0.11, 0.34±0.18, and anteroposterior displacement 0.39 ± 0.09, 0.45±0.12, 0.47±0.13, 0.51±0.20 from EO to EC, EOF, and ECF, respectively. There was a significant difference (P<0.05) in participants with DPN, with greater sway amplitude on firm and foam surface in all the conditions. Moderate correlation of MNSI with age (r=0.43) and postural stability measures were also observed. INTERPRETATION & CONCLUSIONS: Evaluation of postural stability in Indian DPN population suggests balance impairments on either firm and foam surfaces, with greater likelihood of fall being on foam or deformable surfaces among elderly adults with neuropathy (CTRI/2011/07/001884).

Adhesion of anaerobic bacteria to platelet containers.

Anaerobic Propionibacterium acnes and Staphylococcus saccharolyticus are frequently isolated during platelet screening with anaerobic culture methods. Although neither P. acnes nor S. saccharolyticus proliferates during platelet storage, both species survive well in this environment. This study was aimed at determining whether strains of P. acnes and/or S. saccharolyticus form surface-attached bacterial cell aggregates, known as biofilms, under platelet storage conditions. We report that these organisms are able to adhere to the inner surface of platelet containers in tight interaction with activated platelets.

Bacterial growth in red blood cell units exposed to uncontrolled temperatures: challenging the 30-minute rule.

BACKGROUND AND OBJECTIVES: The '30-min rule' requires discarding red blood cells (RBCs) exposed to uncontrolled temperatures for >30 min to ensure safe RBC transfusion. This study was aimed at determining whether multiple room temperature (RT) exposures promote bacterial growth. MATERIALS AND METHODS: Pooled and split RBC units were inoculated with ~1 CFU/ml of Serratia marcescens, Yersinia enterocolitica, Escherichia coli or Staphylococcus epidermidis. Control units remained in storage, while test units were exposed to RT for six 30-min or three 60-min intervals. Bacterial concentrations and endotoxin levels were determined after each exposure and at 42 days of storage. RBC core temperature and RT were monitored in mock units with Escort iLog temperature loggers. A mixed model was used for statistical analyses. RESULTS: Red blood cell core temperature reached 10.7 ± 0.4°C and 14.2 ± 0.2°C during 30- and 60-min exposures, respectively. Staphylococcus epidermidis and E. coli did not grow in either control or exposed RBCs. Yersinia enterocolitica concentration and endotoxin levels were similar in both control and test units. Serratia marcescens concentration and endotoxin levels were higher in exposed units; however, differences between units exposed for 30 min or 60 min were not observed. CONCLUSION: There is no added risk to RBC safety by increasing RT exposures to 60 min with each removal from storage for up to a total of 3 h during RBC shelf life. Therefore, extending the 30-min limitation in RBCs exposed to uncontrolled temperatures to 60 min should be considered by regulatory agencies.

Free chelatable zinc modulates the cholinergic function during hypobaric hypoxia-induced neuronal damage: an in vivo study.

The deregulation of cholinergic system and associated neuronal damage is thought to be a major contributor to the pathophysiologic sequelae of hypobaric hypoxia-induced memory impairment. Uniquely, the muscarinic receptors also play a role in zinc uptake. Despite the potential role of muscarinic receptors in the development of post hypoxia cognitive deficits, no studies to date have evaluated the mechanistic relationship between memory dysfunction and zinc homeostasis in brain. In the present study, we evaluated the effect of Ca(2)EDTA, a specific zinc chelator in the spatial working and associative memory deficits following hypobaric hypoxia. Our results demonstrate that accumulation of intracellular free chelatable zinc in the hippocampal CA3 pyramidal neurons is accompanied with neuronal loss and memory impairment in hypobaric hypoxic condition. Chelation of this free zinc with Ca(2)EDTA (1.25 mM/kg) ameliorated the hippocampus-dependent spatial as well as associative memory dysfunction and neuronal damage observed on exposure to hypobaric hypoxia. The zinc chelator significantly alleviated the downregulation in expression of choline acetyltransferase, muscarinic receptor 1 and 4, and acetylcholinesterase activity due to hypobaric hypoxia. Our data suggest that the free chelatable zinc released during hypobaric hypoxia might play a critical role in the neuronal damage and the alteration in cholinergic function associated with hypobaric hypoxia-induced memory impairment. We speculate that zinc chelation might be a potential therapy for hypobaric hypoxia-induced cognitive impairment.

Involvement of angiotensin converting enzyme in cerebral hypoperfusion induced anterograde memory impairment and cholinergic dysfunction in rats.

Forebrain cholinergic dysfunction is the hallmark of vascular dementia (VaD) and Alzheimer's dementia (AD) induced by cerebral hypoperfusion during aging. The aim of the present study is to evaluate the role of angiotensin converting enzyme (ACE) in cerebral hypoperfusion-induced dementia and cholinergic dysfunction. Chronic cerebral hypoperfusion (CHP) was induced by permanent bilateral common carotid artery (2VO) occlusion in rats. Chronic cerebral hypoperfusion resulted in anterograde memory impairment revealed from Morris water maze (MWM) and passive avoidance step through tasks (PA), which was significantly attenuated by ACE inhibitor, captopril. Cerebral hypoperfusion down-regulated the relative expression of cholinergic muscarinic receptor (ChM-1r) and choline acetyltransferase (ChAT) as well as up-regulated the angiotensin II type-1 receptor (AT-1) expression in hippocampus of vehicle treated CHP group on the 54th day post-hypoperfusion. The diminished number of presynaptic cholinergic neurons and the pyramidal neurons were evident from ChAT-immunofluorescence and the hematoxylin and eosin (H&E) staining studies respectively in hippocampal Cornu ammonis1 (CA1); region of vehicle-treated hypoperfused animals. Further the lipid peroxidation level was also found to be elevated in the hippocampus of the vehicle-treated group. Our results demonstrated that continuous captopril treatment (50 mg/kg, i.p. twice daily) for 15 days mitigated the hypoperfusion-induced cholinergic hypofunction and neurodegeneration in hippocampus. The present study robustly reveals that the angiotensinergic system plays a pivotal role in progression of neuronal death and memory dysfunctions during cerebral hypoperfusion.

Nitric oxide associated with iNOS expression inhibits acetylcholinesterase activity and induces memory impairment during acute hypobaric hypoxia.

The mechanisms responsible for cholinergic dysfunction associated learning and memory impairment during hypoxia are not well-understood. However it is known that inflammatory mediators like inducible nitric oxide synthase (iNOS) hamper the functions of cholinergic neurons. In this present experiment we made an effort to study the iNOS expression mediated retrograde and anterograde memory impairment in Balb/c mice following acute hypobaric hypoxia (at an altitude of 23,000ft for 6h) using elevated plus maze and passive avoidance step-through tasks. Our results demonstrated that hypoxia transiently impairs the retrograde memory without affecting the anterograde memory functions, accompanied with a substantial rise in iNOS expression and nitric oxide levels in cerebral cortex on days 2 and 3 post hypoxia. Treatment with aminoguanidine (iNOS inhibitor ), resulted in down-regulation of the iNOS expression, attenuation of the surge of nitric oxide (NO) in cerebral cortex and reversal of retrograde memory impairment due to hypoxia. Moreover the reduced AChE activity and elevated lipid peroxidation in cerebral cortex were evident during post hypoxia re-oxygenation period, which was not observed in the hippocampus. Additionally, NO donor spermine NONOate could inhibit the AChE activity in brain homogenates in a concentration-dependent manner, which further substantiate that nitric oxide produced during post hypoxia re-oxygenation, primarily contributes to the observed inhibition of cortical AChE activity. Based on these experiments we hypothesize that the NO burst as a result of iNOS upregulation during hypoxia interrupts the memory consolidation by altering the cholinergic functions.

Benzamide protects delayed neuronal death and behavioural impairment in a mouse model of global cerebral ischemia.

The present study is aimed at evaluating the functional and neuroprotective effect of benzamide, a poly-(ADP-ribose) polymerase (PARP) inhibitor on delayed neuronal death (DND) in hippocampus CA1 region and memory impairment following global cerebral ischemia (GCI) in a mouse model. GCI was induced by bilateral common carotid artery occlusion (BCAo) for 20 min followed by reperfusion for 9 days. Postischemic continuous treatment with benzamide (160 mg/kg b w i.p. for 9 days) significantly reversed the GCI-induced anterograde memory impairment in passive avoidance step through and elevated plus maze tasks. The observed memory impairment in vehicle treated ischemia group was found to be well correlated with DND and downregulation of cholinergic muscarinic receptor-1 expression, which was possibly mediated by inflammation and apoptosis, as revealed from inducible nitric oxide synthase (iNOS) expression and number of TUNEL positive neurons in hippocampus CA1 region. It is clear from the present experiment that benzamide treatment significantly decreases the iNOS expression and number of apoptotic neurons and thereby improves the neuronal survival and memory during GCI. Our present findings provide compelling evidence that multiple doses of benzamide treatment is a promising therapeutic approach for cerebrovascular and neurodegenerative diseases, which deserves further clinical evaluation.

Effect of losartan and enalapril on cognitive deficit caused by Goldblatt induced hypertension.

The present study was designed to evaluate the learning and memory, in an altered physiological state associated with increased blood pressure and activated renin angiotensin system in Wistar rats. The role of angiotensin in cognitive function was assessed by treatment with angiotensin converting enzyme (ACE) inhibitor enalapril (2 mg/kg), angiotensin 1 receptor (AT(1)) antagonist losartan (5 mg/kg) and their combination. The experimental renal hypertension was induced by the method of Goldblatt. Learning and memory was assessed using the radial arm maze test. Acetylcholine esterase (AChE) levels in the pons medulla, hippocampus, striatum and frontal cortex were measured as a cholinergic marker of learning and memory. Results indicate that in comparison to normotensive rats, renal hypertensive rats committed significantly higher number of errors and took more trials and days to learn the radial arm maze learning and exhibited memory deficit in the radial arm maze retrieval after two weeks of retention interval, indicating impaired acquisition and memory. Treatment with enalapril, losartan and their combination attenuated the observed memory deficits indicating a possible role of renin angiotensin system in cognitive function. AChE level was reduced in hippocampus and frontal cortex of renal hypertensive rats which could be attributed to the observed memory deficit in hypertensive rats. It can be concluded that, renal hypertensive rats had a poor acquisition, retrieval of the learned behavior, perhaps a possible disturbance in memory consolidation process and that this state was reversed with ACE inhibitor enalapril and AT 1 receptor antagonist losartan.

Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.

Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an FMRI study.

We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.

Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory.

We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.