Using DTI to assess white matter microstructure in cerebral small vessel disease (SVD) in multicentre studies.

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized ß =0.268), mental flexibility (ß =0.306), verbal fluency (ß =0.376), and Montreal Cognitive Assessment (MoCA) (ß =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies.

Distinct modulatory effects of satiety and sibutramine on brain responses to food images in humans: a double dissociation across hypothalamus, amygdala, and ventral striatum.

We used functional magnetic resonance imaging to explore brain responses to food images in overweight humans, examining independently the impact of a prescan meal ("satiety") and the anti-obesity drug sibutramine, a serotonin and noradrenaline reuptake inhibitor. We identified significantly different responses to these manipulations in amygdala, hypothalamus, and ventral striatum. Each region was specifically responsive to high-calorie compared to low-calorie food images. However, the ventral striatal response was attenuated by satiety (but unaffected by sibutramine), while the hypothalamic and amygdala responses were attenuated by drug but unaffected by satiety. Direct assessment of regional interactions confirmed the significance of this double dissociation. We explored the regional responses in greater detail by determining whether they were predictive of eating behavior and weight change. We observed that across the different regions, the individual-specific magnitude of drug- and satiety-induced modulation was associated with both variables: the sibutramine-induced modulation of the hypothalamic response was correlated with the drug's impact on both weight and subsequently measured ad libitum eating. The satiety-induced modulation of striatal response also correlated with subsequent ad libitum eating. These results suggest that hypothalamus and amygdala have roles in the control of food intake that are distinct from those of ventral striatum. Furthermore, they support a regionally specific effect on brain function through which sibutramine exerts its clinical effect.

Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease: The PRESERVE Randomized Clinical Trial.

Importance: Blood pressure (BP) lowering is considered neuroprotective in patients with cerebral small vessel disease; however, more intensive regimens may increase cerebral hypoperfusion. This study examined the effect of standard vs intensive BP treatment on cerebral perfusion in patients with severe small vessel disease. Objective: To investigate whether standard vs intensive BP lowering over 3 months causes decreased cerebral perfusion in small vessel disease. Design, Setting, and Participants: This randomized clinical trial took place at 2 English university medical centers. Patients were randomized via a central online system (in a 1:1 ratio). Seventy patients with hypertension and with magnetic resonance imaging-confirmed symptomatic lacunar infarct and confluent white matter hyperintensities were recruited between February 29, 2012, and October 21, 2015, and randomized (36 in the standard group and 34 in the intensive group). Analyzable data were available in 62 patients, 33 in the standard group and 29 in the intensive group, for intent-to-treat analysis. This experiment examines the 3-month follow-up period. Interventions: Patients were randomized to standard (systolic, 130-140 mm Hg) or intensive (systolic, <125 mm Hg) BP targets, to be achieved through medication changes. Main Outcomes and Measures: Cerebral perfusion was measured using arterial spin labeling; the primary end point was change in global perfusion between baseline and 3 months, compared between treatment groups by analysis of variance. Linear regression compared change in perfusion against change in BP. Magnetic resonance imaging scan analysis was masked to treatment group. Results: Among 62 analyzable patients, the mean age was 69.3 years, and 60% (n = 37) were male. The mean (SD) systolic BP decreased by 8 (12) mm Hg in the standard group and by 27 (17) mm Hg in the intensive group (P < .001), with mean (SD) achieved pressures of 141 (13) and 126 (10) mm Hg, respectively. Change in global perfusion did not differ between treatment groups: the mean (SD) change was -0.5 (9.4) mL/min/100 g in the standard group vs 0.7 (8.6) mL/min/100 g in the intensive group (partial η2, 0.004; 95% CI, -3.551 to 5.818; P = .63). No differences were observed when the analysis examined gray or white matter only or was confined to those achieving target BP. The number of adverse events did not differ between treatment groups, with a mean (SD) of 0.21 (0.65) for the standard group and 0.32 (0.75) for the intensive group (P = .44). Conclusions and Relevance: Intensive BP lowering did not reduce cerebral perfusion in severe small vessel disease. Trial Registration: isrctn.org Identifier: ISRCTN37694103.

Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis.

OBJECTIVE: The authors examined research on effects, costs, and patient and caregiver views of pharmacological management strategies for Lewy body dementia. METHOD: Studies were identified through bibliographic databases, trials registers, gray literature, reference lists, and experts. The authors used the search terms "Lewy or parkinson" and "dementia" through March 2015 and used the following inclusion criteria: participants with diagnoses of Lewy body dementia, dementia with Lewy bodies, or Parkinson's disease dementia (or participants' caregivers); investigation of pharmacological management strategies; outcome measures and test scores reported. Data extraction and quality assessment were conducted by at least two authors. Meta-analyses were conducted, and when studies could not be combined, summaries were provided. RESULTS: Forty-four studies examining 22 strategies were included in the review. Meta-analysis indicated beneficial effects of donepezil and rivastigmine for cognitive and psychiatric symptoms. Rivastigmine, but not donepezil, was associated with greater risk of adverse events. Meta-analysis of memantine suggested that it is well tolerated but with few benefits. Descriptive summaries provide some evidence of benefits for galantamine, modafinil, levodopa, rotigotine, clozapine, duloxetine, clonazepam, ramelteon, gabapentin, zonisamide, and yokukansan. Piracetam, amantadine, selegiline, olanzapine, quetiapine, risperidone, and citalopram do not appear to be effective. CONCLUSIONS: High-level evidence related to pharmacological strategies for managing Lewy body dementia is rare. Strategies for important areas of need in Lewy body dementia, such as autonomic symptoms and caregiver burden, have not been investigated, nor have the views of patients and caregivers about pharmacological strategies.

Studying food reward and motivation in humans.

A key challenge in studying reward processing in humans is to go beyond subjective self-report measures and quantify different aspects of reward such as hedonics, motivation, and goal value in more objective ways. This is particularly relevant for the understanding of overeating and obesity as well as their potential treatments. In this paper are described a set of measures of food-related motivation using handgrip force as a motivational measure. These methods can be used to examine changes in food related motivation with metabolic (satiety) and pharmacological manipulations and can be used to evaluate interventions targeted at overeating and obesity. However to understand food-related decision making in the complex food environment it is essential to be able to ascertain the reward goal values that guide the decisions and behavioral choices that people make. These values are hidden but it is possible to ascertain them more objectively using metrics such as the willingness to pay and a method for this is described. Both these sets of methods provide quantitative measures of motivation and goal value that can be compared within and between individuals.

Neural and behavioral effects of a novel mu opioid receptor antagonist in binge-eating obese people.

BACKGROUND: Binge eating is associated with obesity and has been conceptualized as "food addiction." However, this view has received only inconsistent support in humans, and limited evidence relates key neurocircuitry to the disorder. Moreover, relatively few studies have used pharmacologic functional magnetic resonance imaging to probe the underlying basis of altered eating behaviors. METHODS: In a double-blind, placebo-controlled, parallel group study, we explored the effects of a potent mu-opioid receptor antagonist, GSK1521498, in obese individuals with moderate binge eating. Subjects were tested during a baseline placebo run-in period and retested after 28-days of drug (n = 21) or placebo (n = 21) treatment. Using functional magnetic resonance imaging and behavioral measures, we determined the drug's effects on brain responses to food images and, separately, on motivation to expend energy to view comparable images. RESULTS: Compared with placebo, GSK1521498 was associated with a significant reduction in pallidum/putamen responses to pictures of high-calorie food and a reduction in motivation to view images of high-calorie food. Intriguingly, although motivational responding was reduced, subjective liking for the same images actually increased following drug treatment. CONCLUSIONS: Stimulus-specific putamen/pallidal responses in obese people with binge eating are sensitive to altered mu-opioid function. This neuromodulation was accompanied by reductions in motivational responding, as measured by grip force, although subjective liking responses to the same stimuli actually increased. As well as providing evidence for a link between the opioid system and food-related behavior in binge-eating obese individuals, these results support a dissociation across measures of motivation and liking associated with food-related stimuli in these individuals.

Ketamine effects on memory reconsolidation favor a learning model of delusions.

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.

Ketamine perturbs perception of the flow of time in healthy volunteers.

RATIONALE: Disturbances in the subjective experience of time have been observed both in schizophrenia and following acute administration of ketamine. However, effects of ketamine on more objective timing tasks have not yet been measured in humans, nor has it been established that timing effects are not merely secondary to a more general dysfunction in working memory (WM). OBJECTIVE AND METHODS: In a double-blind placebo-controlled crossover study, we characterised the effects of ketamine (100 ng/ml blood plasma level) on performance of perceptual timing and colour discrimination tasks, which were matched for WM and attentional demands. To test the ubiquity of ketamine's effects on timing, we also examined two distinct measures of temporal predictability. RESULTS: Ketamine significantly distorted the subjective experience of time as measured by the Clinician-Administered Dissociative States Scales. Critically, ketamine also impaired accuracy on the perceptual timing task while having no effect on performance of the colour perception task. Although ketamine did not impair the ability to use prelearned temporal (or spatial) cues to predict target onset (or location), it did slow reaction times at long delays following non-informative neutral cues, suggesting an impaired ability to use the unidirectional flow of time itself to make temporal predictions. CONCLUSIONS: Ketamine induced selective impairments in timing, which could not be explained by more fundamental effects on the ability to hold information in WM. Rather our collected findings suggest that ketamine may disturb timing by selectively impairing the way in which information is temporally manipulated within WM.