Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates.

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2-0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

The effect of a one-year vigorous physical activity intervention on fitness, cognitive performance and mental health in young adolescents: the Fit to Study cluster randomised controlled trial.

BACKGROUND: Physical activity (PA) may positively stimulate the brain, cognition and mental health during adolescence, a period of dynamic neurobiological development. High-intensity interval training (HIIT) or vigorous PA interventions are time-efficient, scalable and can be easily implemented in existing school curricula, yet their effects on cognitive, academic and mental health outcomes are unclear. The primary aim of the Fit to Study trial was to investigate whether a pragmatic and scalable HIIT-style VPA intervention delivered during school physical education (PE) could improve attainment in maths. The primary outcome has previously been reported and was null. Here, we report the effect of the intervention on prespecified secondary outcomes, including cardiorespiratory fitness, cognitive performance, and mental health in young adolescents. METHODS: The Fit to Study cluster randomised controlled trial included Year 8 pupils (n = 18,261, aged 12-13) from 104 secondary state schools in South/Mid-England. Schools were randomised into an intervention condition (n = 52), in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year (2017-2018), or into a "PE as usual" control condition. Secondary outcomes included assessments of cardiorespiratory fitness (20-m shuttle run), cognitive performance (executive functions, relational memory and processing speed) and mental health (Strength and Difficulties Questionnaire and self-esteem measures). The primary intention-to-treat (ITT) analysis used linear models and structural equation models with cluster-robust standard errors to test for intervention effects. A complier-average causal effect (CACE) was estimated using a two-stage least squares procedure. RESULTS: The HIIT-style VPA intervention did not significantly improve cardiorespiratory fitness, cognitive performance (executive functions, relational memory or processed speed), or mental health (all p > 0.05). Subgroup analyses showed no significant moderation of intervention effects by sex, socioeconomic status or baseline fitness levels. Changes in cardiorespiratory fitness were not significantly related to changes in cognitive or mental health outcomes. The trial was marked by high drop-out and low intervention compliance. Findings from the CACE analysis were in line with those from the ITT analysis. CONCLUSION: The one-academic year HIIT-style VPA intervention delivered during regular school PE did not significantly improve fitness, cognitive performance or mental health, but these findings should be interpreted with caution given low implementation fidelity and high drop-out. Well-controlled, large-scale, school-based trials that examine the effectiveness of HIIT-style interventions to enhance cognitive and mental health outcomes are warranted. TRIAL REGISTRATION: ISRCTN registry, 15,730,512 . Trial protocol and analysis plan for primary outcome prospectively registered on 30th March 2017. ClinicalTrials.gov , NCT03286725 . Secondary measures (focus of current manuscript) retrospectively registered on 18 September 2017.

Effects of a programme of vigorous physical activity during secondary school physical education on academic performance, fitness, cognition, mental health and the brain of adolescents (Fit to Study): study protocol for a cluster-randomised trial.

BACKGROUND: Early adolescence is a period of dynamic neurobiological change. Converging lines of research suggest that regular physical activity (PA) and improved aerobic fitness have the potential to stimulate positive brain changes, improve cognitive function and boost academic attainment in this age group, but high-quality studies are needed to substantiate these findings. The primary aim of the Fit to Study trial is to investigate whether short infusions of vigorous PA (VPA) delivered during secondary school physical education (PE) can improve attainment in maths, as described in a protocol published by NatCen Social Research. The present protocol concerns the trial's secondary outcome measures, which are variables thought to moderate or mediate the relationship between PA and attainment, including the effect of the intervention on cardiorespiratory fitness, cognitive performance, mental health and brain structure and function. METHOD: The Fit to Study project is a cluster-randomised controlled trial that includes Year 8 pupils (aged 12-13) from secondary state schools in South/Mid-England. Schools were randomised into an intervention condition in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year, or a 'PE as usual' control condition. Intervention and control groups were stratified according to whether schools were single-sex or co-educational. Assessments take place at baseline (end of Year 7, aged 11-12) and after 12 months (Year 8). Secondary outcomes are cardiorespiratory fitness, objective PA during PE, cognitive performance and mental health. The study also includes exploratory measures of daytime sleepiness, attitudes towards daily PA and PE enjoyment. A sub-set of pupils from a sub-set of schools will also take part in a brain imaging sub-study, which is embedded in the trial. DISCUSSION: The Fit to Study trial could advance our understanding of the complex relationships between PA and aerobic fitness, the brain, cognitive performance, mental health and academic attainment during adolescence. Further, it will add to our understanding of whether school PE is an effective setting to increase VPA and fitness, which could inform future PA interventions and education policy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03286725 . Retrospectively registered on 18 September 2017. ClinicalTrials.gov, NCT03593863 . Retrospectively registered on 19 July 2018.

A randomized controlled trial of a walking training with simultaneous cognitive demand (dual-task) in chronic stroke.

BACKGROUND AND PURPOSE: The aim was to evaluate the tolerability of, adherence to and efficacy of a community walking training programme with simultaneous cognitive demand (dual-task) compared to a control walking training programme without cognitive distraction. METHODS: Adult stroke survivors at least 6 months after stroke with a visibly obvious gait abnormality or reduced 2-min walk distance were included in a two-arm parallel randomized controlled trial of complex intervention with blinded assessments. Participants received a 10 week, bi-weekly, 30 min treadmill programme at an aerobic training intensity (55%-85% heart rate maximum), either with or without simultaneous cognitive demands. Outcome was measured at 0, 11 and 22 weeks. The primary assessment involved 2-min walk tests with and without cognitive distraction to investigate the dual-task effect on walking and cognition; secondary results were the Short Form Health Survey 36, EuroQol-5D-5L, the Physical Activity Scale for the Elderly (PASE) and step activity. RESULTS: Fifty stroke patients were included; 43 received allocated training and 45 completed all assessments. The experimental group (n = 26) increased their mean (SD) 2-min walking distance from 90.7 (8.2) to 103.5 (8.2) m, compared with 86.7 (8.5) to 92.8 (8.6) m in the control group, and their PASE score from 74.3 (9.1) to 89.9 (9.4), compared with 94.7 (9.4) to 77.3 (9.9) in the control group. Statistically, only the change in the PASE differed between the groups (P = 0.029), with the dual-task group improving more. There were no differences in other measures. CONCLUSIONS: Walking with specific additional cognitive distraction (dual-task training) might increase activity more over 12 weeks, but the data are not conclusive.

Physical Activity, Fatigue, and Sleep in People with Parkinson's Disease: A Secondary per Protocol Analysis from an Intervention Trial.

Symptoms of Parkinson's can result in low physical activity and poor sleep patterns which can have a detrimental effect on a person's quality of life. To date, studies looking into exercise interventions for people with Parkinson's (PwP) for symptom management are promising but inconclusive. The aim of this study is to estimate the effect of a clearly defined exercise prescription on general physical activity levels, fatigue, sleep, and quality of life in PwP. Method. PwP randomised into either an exercise group (29; 16 males, 13 females; mean age 67 years (7.12)) or a control handwriting group (36; 19 males; 17 females; mean age 67 years (5.88)) as part of a larger trial were included in this substudy if they had completed a 6-month weekly exercise programme (intervention group) and had complete objective physical activity data (intervention and control group). Sleep and fatigue were recorded from self-reported measures, and physical activity levels measured through the use of accelerometers worn 24 hours/day over a seven-day testing period at baseline and following the 24-week intervention. A Wilcoxon's test followed by a Mann-Whitney post hoc analysis was used, and effect sizes were calculated. Results. Participants showed a significant increase in time spent in sedentary and light activities during the overnight period postintervention in both exercise and handwriting groups (p < 0.05) with a moderate effect found for the change in sedentary and light activities in the overnight hours for both groups, over time (0.32 and 0.37-0.38, resp.). There was no impact on self-reported fatigue or sleep. Conclusion. The observed moderate effect on sedentary and light activities overnight could suggest an objective improvement in sleep patterns for individuals participating in both exercise and handwriting interventions. This supports the need for further studies to investigate the role of behavioural interventions for nonmotor symptoms.

Visual hallucinations in the elderly: a case series and discussion of aetiology and treatment.

BACKGROUND: Visual hallucinations are a common phenomenon, among the older adult population. They can be functional or organic in aetiology. However, new onset visual hallucinations in this population are strongly suggestive of organic brain disease. Visual impairment, cerebrovascular disease and Parkinson's disease are three causes of visual hallucinations, considered in this case series. The evidence in the literature, for the treatment of these conditions is scant at best. There is a paucity of randomised controlled trials available concerning possible therapeutic options. Aims/Methods We describe three case reports of visual hallucinations due to diverse underlying aetiologies. We then discuss the aetiologies of visual hallucinations in general and then in these particular cases and finally include results of a literature search examining the available evidence for any therapeutic options proposed. RESULTS: Our three cases have different, underlying aetiologies. One case is of Charles Bonnet syndrome. The next is of visual hallucinations associated with vascular dementia. The final case is of visual hallucinations associated with Parkinson's disease. The first two cases are of particular interest due to the efficacy of Amisulpride in both clinical scenarios. CONCLUSIONS: Visual hallucinations are a common phenomenon in the elderly population They can be due to a myriad of underlying causes. There are a number of neurochemical factors and neuroanatomical structures implicated. The evidence for psychopharmacological interventions is scanty. Randomised controlled trials are lacking in the area. An interesting finding in this case series, was of the clinical utility of Amisulpiride. Given this agent's unique psychopharmacological profile it is possible that it may be efficacious in other cases of visual hallucinations associated with particular neurochemical factors.

Consistency of evoked responses to dual-stimulator, single-pulse transcranial magnetic stimulation in the lower limb of people with multiple sclerosis.

The purpose of this study was to explore the within session and test-retest consistency of motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) from the resting tibialis anterior (TA) muscle of 10 patients (two men, eight women) with clinically definite multiple sclerosis (MS). Dual stimulators were configured to produce a single pulse (DS/SP) through a hand-held coil. MEP were recorded in five blocks of five trials with a repeat test occurring 7-14 days later. Analysis of a trial sequence revealed the area of the first MEP trial of each block to be significantly different to subsequent trials (trials 2-5; p<0.05). We therefore discarded T1 from further analysis. Thereafter, repeated measures of analysis of variance of MEP characteristics and blocks of MEP (average of four trials) revealed no significant differences (p>0.05). The results of the repeat session revealed no significant differences in motor thresholds, MEP latency, MEP amplitude or MEP area between sessions (p>0.05). Test-retest intra-class coefficients of correlation and their 95% confidence intervals indicated high reliability (>0.80). Our results show that consistent, repeatable TMS measures can be obtained from the resting TA of MS patients using the DS/SP method.

Magneto-optical properties of wurtzite-phase InP nanowires.

The possibility to grow in zincblende (ZB) and/or wurtzite (WZ) crystal phase widens the potential applications of semiconductor nanowires (NWs). This is particularly true in technologically relevant III-V compounds, such as GaAs, InAs, and InP, for which WZ is not available in bulk form. The WZ band structure of many III-V NWs has been widely studied. Yet, transport (that is, carrier effective mass) and spin (that is, carrier g-factor) properties are almost experimentally unknown. We address these issues in a well-characterized material: WZ indium phosphide. The value and anisotropy of the reduced mass (µ exc) and g-factor (g exc) of the band gap exciton are determined by photoluminescence measurements under intense magnetic fields (B, up to 28 T) applied along different crystallographic directions. µ exc is 14% greater in WZ NWs than in a ZB bulk reference and it is 6% greater in a plane containing the WZ c axis than in a plane orthogonal to c. The Zeeman splitting is markedly anisotropic with g exc = |ge| = 1.4 for B⊥c (where ge is the electron g-factor) and g exc = |ge - gh,//| = 3.5 for B//c (where gh,// is the hole g-factor). A noticeable B-induced circular dichroism of the emitted photons is found only for B//c, as expected in WZ-phase materials.

Tuneable paramagnetic susceptibility and exciton g-factor in Mn-doped PbS colloidal nanocrystals.

We report on PbS colloidal nanocrystals that combine within one structure solubility in physiological solvents with near-infrared photoluminescence, and magnetic and optical properties tuneable by the controlled incorporation of magnetic impurities (Mn). We use high magnetic fields (B up to 30 T) to measure the magnetization of the nanocrystals in liquid and the strength of the sp-d exchange interaction between the exciton and the Mn-ions. With increasing Mn-content from 0.1% to 7%, the mass magnetic susceptibility increases at a rate of ∼ 10(-7) m(3) kg(-1) per Mn percentage; correspondingly, the exciton g-factor decreases from 0.47 to 0.10. The controlled modification of the paramagnetism, fluorescence and exciton g-factor of the nanocrystals is relevant to the implementation of these paramagnetic semiconductor nanocrystals in quantum technologies ranging from quantum information to magnetic resonance imaging.

Cardiovascular adaptation in people with multiple sclerosis following a twelve week exercise programme suggest deconditioning rather than autonomic dysfunction caused by the disease. Results from a randomized controlled trial.

BACKGROUND: Guidelines for optimal exercise doses in people with multiple sclerosis (MS) have to be established. We need to ascertain the basic physiological and perceptual response and adaptation to different exercise doses in this clinical population. AIM: The aim of this paper was to explore the response during maximal and sub-maximal exercise in people with MS prior to and following two different twelve week exercise programmes. DESIGN: Sub-analysis of per protocol exercise data of a two group, single blinded, randomised control trial. SETTING: Multicentre (community leisure and rehabilitation centres). POPULATION: Participants with MS assigned to a continuous (N.=12; mean±SE age=52.3±2.08; Barthel index median & range=19&13-20) or interval (N.=9; mean±SE age=49.3±3.5; Barthel index median & range=19&18-20) exercise programme. METHODS: Cardiovascular, respiratory and perceptual exercise response and adaption was measured at maximal and sub-maximal levels of physical exercise prior to and following a twelve week exercise programme, delivered at different intensities. RESULTS: Irrespective of the type of exercise programme followed, there was a significant increase in peak power (z=-1.98; P=0.05) and normalised oxygen uptake during unloaded cycling (z =-2.00; P=0.05). At discharge from the exercise programmes, the cardiovascular response to sub-maximal exercise had significantly changed (t(360) =-4.62; p<0.01). CONCLUSION: The response in people with MS at maximal and sub-maximal levels of physical exercise following a twelve week programme is analogous to non-diseased adults. CLINICAL REHABILITATION IMPACT: Cardiovascular adaptation in people with MS following a twelve week exercise programme suggests deconditioning rather than autonomic dysfunction caused by the disease.

Bone mineral density changes over a year in young females with schizophrenia: relationship to medication and endocrine variables.

INTRODUCTION: Hyperprolactinaemia is associated with the use of potent dopamine-2 receptor blocking anti-psychotic agents in schizophrenia and with bone loss in the general population. Significantly higher rates of reduced bone mineral density (BMD) have been identified in young pre-menopausal females with schizophrenia receiving prolactin-raising anti-psychotics compared to those receiving prolactin-sparing anti-psychotics. This prospective study compared BMD alterations over a period of 1 year in patients maintained on either prolactin-raising (e.g. risperidone, amisulpride or depot anti-psychotics) or prolactin-sparing (olanzapine) anti-psychotics. The effects of specific interventions to improve BMD were also examined in the context of whether patients were receiving either prolactin-raising or anti-psychotics or Olanzapine. METHODS: Pre-menopausal females (n=38) with a diagnosis of schizophrenia, who had received exclusively either prolactin-raising (n=25) or prolactin-sparing (n=13) anti-psychotics during their treatment history, had clinical, endocrine and bone marker assessments performed at baseline and every 3 months for a period of 1 year. BMD was measured by DEXA scan at baseline and at 1-year follow-up. Patients from both groups either received specific interventions (n=16) or no interventions (n=16) to improve bone density. RESULTS: There was an overall gain in lumbar BMD values in the prolactin-sparing subgroup, compared to an overall loss in the prolactin-raising subgroup (p=0.02), for the groups that received no specific interventions to improve BMD. Within the group that received specific interventions, the subgroup receiving prolactin-sparing anti-psychotics had a significant increase in lumbar (p=0.01) and hip (p=0.01) BMD over time, whereas alterations in the prolactin-raising subgroup were not significant. DISCUSSION: Women taking prolactin-raising anti-psychotics and not receiving specific interventions to improve bone density had evidence of ongoing bone demineralisation over a year; whereas women taking prolactin-sparing anti-psychotics had a modest overall increase in BMD. Most clinical interventions appeared to be helpful, but were significantly more effective in those taking prolactin-sparing anti-psychotics.

Cardiovascular risk factors in the urban Mexican population: the FRIMEX study.

BACKGROUND: Atherosclerotic ischaemic heart disease is the second leading cause of general mortality in Mexico due to the growing prevalence of atherosclerotic risk factors in our society. The data of the FRIMEX study (Factores de Riesgo en México, Risk Factors in Mexico), considered together with those of other contemporary epidemiological surveys, will aid in our comprehension of the current state of cardiovascular epidemics in Mexico. METHODS: Frequencies of obesity, hypertension and smoking, and total cholesterol and glucose in capillary blood were estimated in a non-probabilistic sample comprised of 140017 individuals (aged 44+/-13 years; 42% men and 58% women), from six Mexican cities (Mexico City, Guadalajara, Monterrey, Puebla, Leon and Tijuana). RESULTS: Obesity or overweight status was found in 71.9% of participants. Hypertension was found in 26.5%, and the proportions of awareness, treatment and control for this disease were 49.3, 73 and 36%, respectively. Prevalence of hypertension increased with age; while it was higher in men under 60 years of age, in the more aged individuals it was higher in women. Hypercholesterolaemia was found in 40% of the individuals and cholesterolaemia > or =240 mg/dl was significantly higher in women. Thirty-five and a half percent of men and 18.1% of women were smokers. Type 2 diabetes mellitus was found in 10.4% of participants. There was significant Pearson's correlation between body mass index and blood pressure, between hypertension and glucose levels, and between hypertension and total cholesterol concentrations. CONCLUSIONS: We conclude that this population has a high cardiovascular risk profile and a high probability of the occurrence of metabolic syndrome.

Needs assessment in dementia.

BACKGROUND: Resource allocation and service development traditionally focuses on diagnostic categories and consequent perceived need. Identification of the actual level of need in the elderly with dementia, and the degree to which it is unmet is necessary to plan services both individually and as a group. The aim of this study was to characterise the needs of a sample of community dwelling elderly patients with dementia who were referred to an old age psychiatry service in Ireland between July 2002 and July 2003. METHODOLOGY: Eighty-two consecutively referred community dwelling patients with ICD-10 diagnosis of dementia were assessed on The Care Needs Assessment Pack for Dementia (CareNap-D). Data on needs across seven domains (health and mobility, self-care and toileting, social interaction, thinking and memory, behaviour and mental state, housecare, community living) is presented (Reynolds T et al., 1998). RESULTS: Subjects had a mean of 33 (range: 13-56) identified needs. Approximately 1/3 of these were unmet with a mean of 13 (range: 0-37) and a mean of 20 (range: 4-39) were met. High levels of unmet need was identified in the domains of behaviour and mental state (84% of those with agitation) and of social interaction (79% of those with 'partaking in activities' need). The specific item of repetitive questioning occurred in 68 individuals and was unmet in 88% of these cases. Increasing age, lower MMSE score, and living alone were associated with greater total levels of unmet need. CONCLUSION: This data underlines the degree of unmet need in the community dwelling elderly with dementia and the importance of developing a spectrum of services on the basis of the actual needs identified.

Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia.

BACKGROUND: High rates of osteoporosis in schizophrenia may result from the prolactin-raising effects of some antipsychotic medication. Aims To examine bone mineral density in relation to relevant endocrine variables in patients with schizophrenia taking prolactin-raising antipsychotics. METHOD: Fifty-five patients who had been receiving prolactin-raising antipsychotic medication for >10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip bones. Among the endocrine variables assessed were plasma prolactin and sex hormones. RESULTS: Age-related reduced bone mineral density measures were found in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of the female patients. Higher doses of medication were associated with increased rates of both hyperprolactinaemia and bone mineral density loss. Bone loss for the whole group was correlated with medication dose, and for men was inversely correlated with testosterone values. CONCLUSIONS: These results suggest that patients with schizophrenia on long-term prolactin-raising antipsychotic medication are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinaemia-induced hypogonadism.

The practice of medicine in England about the year 1000.

The paper begins with the medical practitioners of late Anglo-Saxon England, were apparently both physicians and surgeons, describing the kinds of ailments they are evidenced as treating. The majority were monastic; whether there were also lay medics is uncertain. Most Anglo-Saxon ecclesiastical foundations appear to have had an infirmary, where sick monks or nuns, or those who were about to die, were looked after. Some infirmaries may have tended lay people, but there do not appear to have been any hospitals in the later medieval sense. The rest of the paper looks at the contents of one manuscript written about the year 1000: London, British Library MS. Harley 585, which contains texts of three compilations in old English: the Herbarium and the Medicina de Quadrupedibus, both translated from Latin, and the Lacnunga, which is a collection of remedies from diverse sources, some translated from Latin, some of native origin, some wholly rational, some containing Christian or folkloric incantations and rituals, and including four metrical charms. Because of its lack of selectivity and orgarization, it gives an invaluable insight into the condition of, and the attitude to, Anglo-Saxon medicine about the end of the first millennium.

Characterization of the F1F0-ATPase and the tightly-bound ATPase activities in submitochondrial particles from human term placenta.

In a previous study we demonstrated the existence of a tightly-bound ATPase in the human placental mitochondria (Martínez et al., 1993). The current study characterizes the ATP hydrolysis produced by the F1F0-ATPase and the tightly-bound ATPase in submitochondrial particles from the human term placenta. Both enzymes were not differentiated by pH. Inhibitors were necessary to distinguish the activity of each enzyme. The kinetic of the total ATP hydrolysis fitted into a model of two enzymes. During the characterization, it was observed that the tightly-bound ATPase activity was partially inhibited by vanadate and Mg2+, whereas the F1F0-ATPase was totally inhibited by Mg2+. Different nucleotides were hydrolyzed by the tightly-bound ATPase; the F1F0-ATPase hydrolyzed exclusively ATP. Glucose-6-phosphate, p-nitrophenylphosphate, or pyrophosphate were not hydrolyzed by the F1F0-ATPase, although some hydrolysis was observed with the tightly-bound ATPase. It is concluded that the tightly-bound ATPase activity corresponded to a 5'-nucelotidase, and that the human placental mitochondria could participate in the metabolism of nucleotides.