Activation in the Ipsilateral Posterior Parietal Cortex during Tool Use: A PET Study

The basis of perceptual assimilation of tool and hand has been considered to be in modification of body schemata, for which integration of multimodal sensory information about our body parts is required. Using positron emission tomography and H(2)(15)O, we aimed to identify brain regions that change their neural activity in association with changes in neural processing of visual and/or somatosensory information when humans use a simple tool. Normal subjects were instructed to manipulate a small graspable object with a pair of tongs or with the fingers of their right or left hand. The only site activated during manipulation with the tool, compared with the fingers, with the right hand was the lateral edge of the right intraparietal sulcus (IPS). During manipulation using the left hand with the tool, compared with using the fingers, an area in the middle part of the left IPS was activated. Areas in the contralateral hemisphere were activated during both the tool-use and the finger-use tasks compared to the control task, but there was no statistically significant difference between the tool-use and the finger-use tasks. Therefore, the results suggest that the ipsilateral posterior parietal cortex was recruited during the tool-use tasks to integrate visuosomatosensory information.     

Uncoupling Cognitive Workload and Prefrontal Cortical Physiology: A PET rCBF Study

Working memory is a fundamental cognitive building block involved in the short-term maintenance and transformation of information. In neuropsychological studies, working memory has been shown to be of limited capacity; however, the neurophysiological concomitants of this capacity limitation have not been explored. In this study we used the [¹⁵O]water PET rCBF technique and statistical parametric mapping to examine normal subjects while they performed two cognitive tasks, both individually and simultaneously. One task was the Wisconsin Card Sorting Test, a complex reasoning task involving working memory, and the other was a rapidly paced auditory verbal shadowing task. When both tasks were performed simultaneously, there were significant decrements in performance compared with the individual task performance scores, indicating that cognitive workload had been increased. Analysis of the rCBF maps showed that when the two tasks were performed together, in contrast to when they were performed separately, there was less prefrontal activation. These results suggest that increases in cognitive workload do not necessarily recruit and then sustain cortical neurophysiological resources to a maximum, but rather may actually be accompanied by a diminution in cortical activity.     

Late Onset of Anterior Prefrontal Activity during True and False Recognition: An Event-Related fMRI Study

Previous studies using PET and fMRI to examine memory retrieval have been limited by the requirement to test different types of items in separate blocks and to average data across items and response types within blocks. We used recently developed procedures for analyzing event-related mixed trial data from fMRI experiments to compare brain activity during true recognition of previously studied words and false recognition of semantic associates. A previous PET study using blocked testing procedures reported similarities and differences in rCBF patterns associated with true and false recognition (Schacteret al.,1996a). We examined brain activity during blocked testing of studied words and nonstudied semantic associates (similar to PET), and also during event-related mixed trials, where studied words and nonstudied semantic associates are intermixed. Six subjects initially heard lists of semantically related words and were later tested for old/new recognition with studied words and nonstudied semantic associates, either in separate blocks or intermixed randomly for the event-related analysis. Compared to a fixation control condition, a variety of regions previously reported in the PET study showed significant activation for both true and false recognition, including anterior prefrontal, frontal opercular, medial parietal, and visual cortex extending into hippocampal/parahippocampal regions. Differences across trial types were not clearly present. Event-related analyses of time course data show a relatively late onset and sustained duration for anterior prefrontal signal changes compared to signal changes in other activated regions. Further study is needed to resolve whether this late onset originates from variance in hemodynamic response properties or is attributable to delayed neural activity. The delayed onset is consistent with the idea that anterior prefrontal regions participate in postretrieval monitoring processes.     

Common carotid segmentation in 18F-sodium fluoride PET/CT scans: Head-to-head comparison of artificial intelligence-based and manual method

Background

Carotid atherosclerosis is a major cause of stroke, traditionally diagnosed late. Positron emission tomography/computed tomography (PET/CT) with ¹⁸F-sodium fluoride (NaF) detects arterial wall micro-calcification long before macro-calcification becomes detectable by ultrasound, CT or magnetic resonance imaging. However, manual PET/CT processing is time-consuming and requires experience. We compared a convolutional neural network (CNN) approach with manual segmentation of the common carotids.

Methods

Segmentation in NaF-PET/CT scans of 29 healthy volunteers and 20 angina pectoris patients were compared for segmented volume (Vol) and mean, maximal, and total standardized uptake values (SUVmean, SUVmax, and SUVtotal). SUVmean was the average of SUVmeans within the VOI, SUVmax the highest SUV in all voxels in the VOI, and SUVtotal the SUVmean multiplied by the Vol of the VOI. Intra and Interobserver variability with manual segmentation was examined in 25 randomly selected scans.

Results

Bias for Vol, SUVmean, SUVmax, and SUVtotal were 1.33 ± 2.06, −0.01 ± 0.05, 0.09 ± 0.48, and 1.18 ± 1.99 in the left and 1.89 ± 1.5, −0.07 ± 0.12, 0.05 ± 0.47, and 1.61 ± 1.47, respectively, in the right common carotid artery. Manual segmentation lasted typically 20 min versus 1 min with the CNN-based approach. Mean Vol deviation at repeat manual segmentation was 14% and 27% in left and right common carotids.

Conclusions

CNN-based segmentation was much faster and provided SUVmean values virtually identical to manually obtained ones, suggesting CNN-based analysis as a promising substitute of slow and cumbersome manual processing.     

聋人与正常人视觉频率反应特征的功能MRI研究

目的 应用功能磁共振成像(fMRI)技术，研究聋人与正常人的枕叶视皮层对不同闪烁频率刺激的功能活动特征。方法 给予18名聋人及22名正常人五种闪烁频率的视觉刺激，同时以fMRI技术对其枕叶成像。应用AFNI软件分析处理。结果 聋人组与正常人组的枕叶视皮层在各个频率下均表现出明显兴奋，两组受试者的激活区强度(MR信号增加幅度)均随频率的增加有显著的变化(F=2．702，P=0．034)，其中聋人组在频率为10Hz时表现出最多的激活和最大的信号强度增加幅度，而正常人在频率为6Hz时表现出最多的激活和最大的信号强度增加幅度，其频率和耳聋因素的交互影响显著(F=2．945，P=0．023)。结论 聋人与正常人对闪烁频率的基本反应规律相似。但引起视皮层最大兴奋的闪烁频率聋人高于正常人。     

轻、中度疼痛对第一、第二躯体感觉皮质激活的功能磁共振成像研究

目的研究轻、中度疼痛电刺激对第一躯体感觉皮质(SⅠ)和第二躯体感觉皮质(SⅡ)的激活规律。方法对7名右利手健康志愿者右足测定痛觉阈值后,给予痛觉阈值和2倍痛觉阈值刺激,进行视觉模拟评分(VAS)和疼痛分级,行功能磁共振成像。结果痛觉阈值和2倍痛觉阈值刺激分别引起志愿者轻度疼痛和中度疼痛;两种刺激均可激活SⅠ和SⅡ,并以左侧为主。其中,轻度疼痛主要激活左侧SⅠ,对两侧SⅡ激活区域小;中度疼痛明显激活左侧SⅠ和双侧SⅡ。结论 SⅠ对轻、中度疼痛电刺激反应一致,但SⅡ对中度疼痛电刺激的反应更为明显。     

A regression analysis study of the primary somatosensory cortex during pain

Several functional imaging studies of pain, using a number of different experimental paradigms and a variety of reference states, have failed to detect activations in the somatosensory cortices, while other imaging studies of pain have reported significant activations in these regions. The role of the somatosensory areas in pain processing has therefore been debated. In the present study the left hand was immersed in painfully cold water (standard cold pressor test) and in nonpainfully cold water during 2 min, and PET-scans were obtained either during the first or the second minute of stimulation. We observed no significant increase of activity in the somatosensory regions when the painful conditions were directly compared with the control conditions. In order to better understand the role of the primary somatosensory cortex (S1) in pain processing we used a regression analysis to study the relation between a ROI (region of interest) in the somatotopic S1-area for the stimulated hand and other regions known to be involved in pain processing. We hypothesized that although no increased activity was observed in the S1 during pain, this region would change its covariation pattern during noxious input as compared to the control stimulation if it is involved in or affected by the processing of pain. In the nonpainful cold conditions widespread regions of the ipsilateral and contralateral somatosensory cortex showed a positive covariation with the activity in the S1-ROI. However, during the first and second minute of pain this regression was significantly attenuated. During the second minute of painful stimulation there was a significant positive covariation between the activity in the S1-ROI and the other regions that are known to be involved in pain processing. Importantly, this relation was significantly stronger for the insula and the orbitofrontal cortex bilaterally when compared to the nonpainful state. The results indicate that the S1-cortex may be engaged in or affected by the processing of pain although no differential activity is observed when pain is compared with the reference condition.     

Local Brain Functional Activity Following Early Deprivation: A Study of Postinstitutionalized Romanian Orphans

Early global deprivation of institutionalized children may result in persistent specific cognitive and behavioral deficits. In order to examine brain dysfunction underlying these deficits, we have applied positron emission tomography using 2-deoxy-2-[(18)F]fluoro-D-glucose in 10 children (6 males, 4 females, mean age 8.8 years) adopted from Romanian orphanages. Using statistical parametric mapping (SPM), the pattern of brain glucose metabolism in the orphans was compared to the patterns obtained from two control groups: (i) a group of 17 normal adults (9 males, 8 females, mean age 27.6 years) and (ii) a group of 7 children (5 males and 2 females, mean age 10.7 years) with medically refractory focal epilepsy, but normal glucose metabolism pattern in the contralateral hemisphere. Consistent with previous studies of children adopted from Romanian orphanages, neuropsychological assessment of Romanian orphans in the present study showed mild neurocognitive impairment, impulsivity, and attention and social deficits. Comparing the normalized glucose metabolic rates to those of normal adults, the Romanian orphans showed significantly decreased metabolism bilaterally in the orbital frontal gyrus, the infralimbic prefrontal cortex, the medial temporal structures (amygdala and head of hippocampus), the lateral temporal cortex, and the brain stem. These findings were confirmed using a region-of-interest approach. SPM analysis showed significantly decreased glucose metabolism in the same brain regions comparing the orphans to the nonepileptic hemisphere of the childhood epilepsy controls. Dysfunction of these brain regions may result from the stress of early global deprivation and may be involved in the long-term cognitive and behavioral deficits displayed by some Romanian orphans.     

Simultaneous quantification of myocardial perfusion,oxidative metabolism,cardiac efficiency and pump function at rest and during supine bicycle exercise using 1‐11C‐acetate PET – a pilot study

Background: PET using 1‐¹¹C‐acetate (ACE‐PET) applied at rest is used for measuring absolute myocardial blood flow (MBF) and oxidative metabolic rate (k_mono). We evaluated the feasibility of quantitative ACE‐PET during exercise. Methods: Five endurance athletes underwent dynamic PET scanning at rest and during supine bicycle stress. Exercise was maintained at a workload of 120 Watt for 17 min. The rate‐pressure product (RPP) was recorded repeatedly. MBF, k_mono in left (LV) and right (RV) ventricular wall, cardiac output (CO), cardiac efficiency and a lung uptake value reflecting left heart diastolic pressures were calculated from the PET data using previously validated models. Results: MBF increased from 0·71 ± 0·17 to 2·48 ± 0·25 ml min^?1 per ml, LV‐k_mono from 0·050 ± 0·005 to 0·146 ± 0·021 min^?1, RV‐k_mono from 0·023 + 0·006 to 0·087 + 0·014 min^‐1, RPP from 4·7 ± 0·8 to 13·2 ± 1·4 mmHg × min^?1 × 10³ and Cardiac Output from 5·2 ± 1·1 to 12·3 ± 1·2 l min ^?1 (all P < 0·001). Cardiac efficiency was unchanged (P = 0·99). Lung uptake decreased from 1·1 ± 0·2 to 0·6 ± 0·1 ml g^?1 (P < 0·001). Discussion: A number of important parameters related to cardiac function can be quantified non‐invasively and simultaneously with a short scanning protocol during steady state supine bicycling. This might open up new opportunities for studies of the integrated cardiac physiology in health and early asymptomatic disease.     

In vivo detection of striatal dopamine release during reward: a PET study with [(11)C]raclopride and a single dynamic scan approach

A new simple method is proposed to detect, using PET and [(11)C]raclopride, changes in striatal extracellular dopamine concentration during a rewarded effortful task. This approach aimed to increase the sensitivity in detection of these effects. It requires a single-dynamic PET study and combines the classic kinetic compartmental model with the general linear model of SPM to provide statistical inference on changes in [(11)C]raclopride time-activity curve due to endogenous dopamine release during two short periods of activation. Kinetic simulations predicted that 100% dopamine increase during two 5-min periods starting at 30 and 60 min after the injection can be detected. Moreover the effects of dopamine release on the [(11)C]raclopride time-activity-curve are different from those induced by CBF increase. These simulated curves were used to construct the statistical linear model and to test voxel-by-voxel in healthy subjects the hypothesis that dopamine is released in the ventral striatum during periods of unexpected monetary gains, but not during periods of unexpected monetary loss. The experimental results are in line with the expected results although the amplitude of the effects due to dopamine release is moderate. The advantages and the limits of this method as well as the relevance of the results for dopamine involvement in reward processing are discussed.     

Human cortical EEG rhythms during long-term episodic memory task. A high-resolution EEG study of the HERA model

Many recent neuroimaging studies of episodic memory have indicated an asymmetry in prefrontal involvement, with the left prefrontal cortex more involved than the right in encoding, the right more than the left in retrieval (hemispheric encoding and retrieval asymmetry, or HERA model). In this electroencephalographic (EEG) high-resolution study, we studied brain rhythmicity during a visual episodic memory (recognition) task. The theta (4-6 Hz), alpha (6-12 Hz) and gamma (28-48 Hz) oscillations were investigated during a visuospatial long-term episodic memory task including an encoding (ENC) and retrieval (RET) phases. During the ENC phase, 25 figures representing interiors of buildings ("indoor") were randomly intermingled with 25 figures representing landscapes ("landscapes"). Subject's response was given at left ("indoor") or right ("landscapes") mouse button. During the RET phase (1 h later), 25 figures representing previously presented "indoor" pictures ("tests") were randomly intermingled with 25 figures representing novel "indoor" ("distractors"). Again, a mouse response was required. Theta and alpha EEG results showed no change of frontal rhythmicity. In contrast, the HERA prediction of asymmetry was fitted only by EEG gamma responses, but only in the posterior parietal areas. The ENC phase was associated with gamma EEG oscillations over left parietal cortex. Afterward, the RET phase was associated with gamma EEG oscillations predominantly over right parietal cortex. The predicted HERA asymmetry was thus observed in an unexpected location. This discrepancy may be due to the differential sensitivity of neuroimaging methods to selected components of cognitive processing. The strict relation between gamma response and perception suggests that retrieval processes of long-term memory deeply impinged upon sensory representation of the stored material.     

Lack of endogenous opioid release during sustained visceral pain: A [C]carfentanil PET study

Opioidergic neurotransmission in the central nervous system is involved in somatic pain, but its role in visceral pain remains unknown. We aimed to quantify endogenous opioid release in the brain during sustained painful gastric distension. Therefore, 2 dynamic [¹¹C]carfentanil positron emission tomography scans were performed in 20 healthy subjects during 2 conditions: sustained (20 minutes) painful proximal gastric balloon distension at predetermined individual discomfort threshold (PAIN) and no distension (NO PAIN), in counterbalanced order. Pain levels were assessed during scanning using visual analogue scales and after scanning using the McGill Pain Questionnaire. Emotional state was rated after scanning using the Positive and Negative Affect Schedule. Distribution volume ratios in 21 volumes of interest in the pain matrix were used to quantify endogenous opioid release. During the PAIN compared to the NO PAIN condition, volunteers reported a significantly higher increase in negative affect (5.50 ± 1.29 versus 0.10 ± 1.08, P = .0147) as well as higher pain ratings (sensory: 74.05 ± 9.23 versus 1.50 ± 0.95, P < .0001; affective: 91.42 ± 8.13 versus 4.33 ± 6.56, P < .0001). No difference in endogenous opioid release was demonstrated in any of the volumes of interest. Thus, contrary to its somatic counterpart, no opioid release is detected in the brain during sustained visceral pain, despite similar pain intensities. Endogenous opioids may play a less important role in visceral compared to somatic pain.     

Site-specific Effects of Transcranial Direct Current Stimulation on Sleep and Pain in Fibromyalgia: A Randomized, Sham-controlled Study

Objective: To investigate whether active anodal transcranial direct current stimulation (tDCS) (of dorsolateral prefrontal cortex [DLPFC] and primary motor cortex [M1]) as compared to sham treatment is associated with changes in sleep structure in fibromyalgia. Methods: Thirty‐two patients were randomized to receive sham stimulation or active tDCS with the anode centered over M1 or DLPFC (2 mA, 20 minutes for five consecutive days). A blinded evaluator rated the clinical symptoms of fibromyalgia. All‐night polysomnography was performed before and after five consecutive sessions of tDCS. Results: Anodal tDCS had an effect on sleep and pain that was specific to the site of stimulation: such as that M1 and DLPFC treatments induced opposite effects on sleep and pain, whereas sham stimulation induced no significant sleep or pain changes. Specifically, whereas M1 treatment increased sleep efficiency (by 11.8%, P = 0.004) and decreased arousals (by 35.0%, P = 0.001), DLPFC stimulation was associated with a decrease in sleep efficiency (by 7.5%, P = 0.02), an increase in rapid eye movement (REM) and sleep latency (by 47.7%, P = 0.0002, and 133.4%, P = 0.02, respectively). In addition, a decrease in REM latency and increase in sleep efficiency were associated with an improvement in fibromyalgia symptoms (as indexed by the Fibromyalgia Impact Questionnaire). Finally, patients with higher body mass index had the worse sleep outcome as indexed by sleep efficiency changes after M1 stimulation. Interpretation: Our findings suggest that one possible mechanism to explain the therapeutic effects of tDCS in fibromyalgia is via sleep modulation that is specific to modulation of primary M1 activity. ?     

Inter- and Intra-Operator Reliability and Repeatability of Shear Wave Elastography in the Liver: A Study in Healthy Volunteers

This study assessed the reproducibility of shear wave elastography (SWE) in the liver of healthy volunteers. Intra- and inter-operator reliability and repeatability were quantified in three different liver segments in a sample of 15 subjects, scanned during four independent sessions (two scans on day 1, two scans 1 wk later) by two operators. A total of 1440 measurements were made. Reproducibility was assessed using the intra-class correlation coefficient (ICC) and a repeated measures analysis of variance. The shear wave speed was measured and used to estimate Young's modulus using the Supersonics Imagine Aixplorer. The median Young's modulus measured through the inter-costal space was 5.55 ± 0.74 kPa. The intra-operator reliability was better for same-day evaluations (ICC = 0.91) than the inter-operator reliability (ICC = 0.78). Intra-observer agreement decreased when scans were repeated on a different day. Inter-session repeatability was between 3.3% and 9.9% for intra-day repeated scans, compared with to 6.5%–12% for inter-day repeated scans. No significant difference was observed in subjects with a body mass index greater or less than 25 kg/m².     

Evaluation of the Effect of Naloxegol on Cardiac Repolarization: A Randomized,Placebo- and Positive-Controlled Crossover Thorough QT/QTc Study in Healthy Volunteers

Background

Opioid-induced constipation (OIC) is a common adverse effect associated with opioid use. Naloxegol is a PEGylated derivative of naloxone in clinical development as a once-daily oral treatment of OIC.

Objectives

A thorough QT/QTc study was conducted, according to International Conference on Harmonisation E14 guidelines, to characterize the effect of naloxegol on cardiac repolarization.

Methods

In this randomized, positive- and placebo-controlled crossover study, healthy men received a single dose of naloxegol 25 mg (therapeutic dose), naloxegol 150 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 sequences (Williams Latin square design). The washout time between treatment periods was at least 5 days. Digital 12-lead ECGs were recorded at baseline and at 10 time points over 24 hours after dosing in each treatment period. QT intervals were corrected for heart rate using the Fridericia formula (QTcF) and the Bazett formula (QTcB).

Results

A total of 52 subjects were enrolled (mean age, 28 years), and 45 received all 4 treatments. The placebo-corrected, baseline-adjusted, mean increases in QTcF with naloxegol 25 and 150 mg were both <5 msec at each time point, and all upper limits of the 2-sided 90% CI were <10 msec. Similar findings were observed using QTcB; the upper limits of the 2-sided 90% CI were <10 msec at all time points after dosing with naloxegol 25 or 150 mg. With moxifloxacin 400 mg, mean QTcF was increased by a maximum of 11.1 msec (90% CI, 9.3–12.9 msec), supporting assay sensitivity.

Conclusion

Naloxegol at 25 and 150 mg was not associated with QT/QTc interval prolongation in these healthy men, and at the proposed therapeutic dose of 25 mg/d, naloxegol is not expected to have a clinically relevant effect on cardiac repolarization in patients with OIC. ClinicalTrials.gov identifier: NCT01325415.     

Pharmacokinetics and Safety of Subcutaneous Pasireotide and Intramuscular Pasireotide Long-acting Release in Chinese Male Healthy Volunteers: A Phase I,Single-center,Open-label,Randomized Study

Purpose

The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).

Methods

In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, C_max, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.

Findings

Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70–1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (C_max in single-dose SC administration) or significantly decreased (C_min,ss in multiple BID SC doses and first peak C_max in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.

Implications

The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.