Phytocannabinoids for the Treatment of Neuropathic Pain: A Scoping Review of Randomised Controlled Trials Published Between 2012 and 2023.

PURPOSE OF REVIEW: Neuropathic pain (NP) remains a challenge to treat, with 50% of patients experiencing limited efficacy from current treatments. Medicinal cannabis, which contains tetrahydrocannabinol (THC), cannabidiol (CBD) and other minor cannabinoids, is garnering attention as an alternative treatment for NP. This paper reviews the clinical evidence for phytocannabinoid treatment of NP. RECENT FINDINGS: Seventeen randomised controlled trials (RCT) were identified for inclusion in this review. Of these, ten studies using phytocannabinoid preparations containing THC alone had the most evidence for pain relief. Four studies investigating THC/CBD combinations showed some reductions in pain scores, although not all findings were statistically significant, whereas studies investigating CBD (two studies) or cannabidivarin (one study) showed no analgesic effect over placebo. However, CBD studies were of small sample size when compared to other studies in the review and short duration. Results for treatment of diabetic peripheral neuropathy patients with THC showed better improvements over those for NP induced by chemotherapy and multiple sclerosis, with these trials using vaporised whole plant cannabis. This formulation may have trace amounts of other minor cannabinoids, compared with synthetic cannabinoids such as dronabinol or nabilone that were investigated in other studies. This review provides an overview of RCTs that have investigated phytocannabinoid use for the treatment of NP. There appears to be evidence to necessitate further high quality RCTs into novel formulations of phytocannabinoids for the treatment of NP.

Using automation to manage donor engagement and fine-tune supply and demand during the first year of the COVID-19 pandemic.

BACKGROUND: COVID-19 disrupted blood center operations starting March 2020 and continues to affect donor presentation and blood availability today. The industry mobilized significant resources to collect COVID-19 convalescent plasma (CCP) to treat COVID-19 patients. At the same time, blood centers continued to collect platelets, plasma, and red blood cells (RBCs) to meet the needs of non-COVID-19 patients. The purpose of this study was to quantify how automation was used to fine-tune supply and demand and increase donor engagement during the first year of the pandemic. METHODS: This was a single-center retrospective study of blood collection and donor presentation at a mid-sized US blood center. Data was evaluated from January 1, 2020 through March 31, 2021. Parameters evaluated included donor presentation, platelets per procedure, concurrent RBC and plasma collections per procedure, operator compliance, total donor appointment count, and donor frequency. RESULTS: With the cancelation of mobile blood drives, fixed sites increased total apheresis procedures by 37% and increased turns per bed by 46% whereas less products were collected per donor. By collecting only what was needed, platelet expiration rate decreased from 6.8% (pre-pandemic) to less than 4%. Donor engagement as measured by donor frequency increased from 1.6 in January 2020 to 1.8 in March 2021. CONCLUSIONS: Using technological advances such as automated blood collection and information systems, the blood center improved donor engagement and avoided collecting a surplus of any one type of blood product over the course of the pandemic.

Changes in plasma unit distributions to hospitals over a 10-year period.

BACKGROUND: There are many influences on a hospital's demand for plasma. Pharmaceuticals are now being administered for many indications instead of plasma, although trauma resuscitation now emphasizes increased and early intervention with plasma. This multinational study evaluated changes in blood center plasma unit distributions over a 10-year period. STUDY DESIGN AND METHODS: Data on the total number and the ABO groups of plasma unit distributions were obtained from nine American blood collectors (ABCs) and nine national or provincial blood services (NPBS) from 2007 through 2016. Plasma distributions to trauma hospitals by five ABCs and four NPBS were also analyzed. RESULTS: The overall number of plasma unit distributions from ABCs decreased by 23.1% from 2007 to 2016, but the relative proportion of distributed AB plasma units increased during the same period. The NPBS (excluding the Japanese Red Cross [JRC]) also had a 35.4% decrease in the overall number of plasma unit distributions with an increase in the relative proportion of AB plasma distributions between 2007 and 2016. The JRC, however, reported an increase in the overall number of plasma distributions by 13.5% in 2016 compared to 2007. The proportion of low-titer A plasma distributions increased to 1.6% of total plasma distributions by ABCs in 2016. There was a trend of distributing increasing proportions of group AB plasma units to trauma hospitals over the 10-year period. CONCLUSION: Although the number of plasma unit distributions has decreased at many blood collectors over time, the proportion of AB units has increased at both ABCs and NPBS.

Addiction and the Brain: Development, Not Disease.

I review the brain disease model of addiction promoted by medical, scientific, and clinical authorities in the US and elsewhere. I then show that the disease model is flawed because brain changes in addiction are similar to those generally observed when recurrent, highly motivated goal seeking results in the development of deep habits, Pavlovian learning, and prefrontal disengagement. This analysis relies on concepts of self-organization, neuroplasticity, personality development, and delay discounting. It also highlights neural and behavioral parallels between substance addictions, behavioral addictions, normative compulsive behaviors, and falling in love. I note that the short duration of addictive rewards leads to negative emotions that accelerate the learning cycle, but cortical reconfiguration in recovery should also inform our understanding of addiction. I end by showing that the ethos of the disease model makes it difficult to reconcile with a developmental-learning orientation.

Maternal Regulation of Daughters' Emotion During Conflicts From Early to Mid-Adolescence.

Primary caregivers play an important role in emotion socialization. Real-time mother-daughter emotion socialization was examined in 45 mother-daughter dyads with early-adolescent daughters (age M = 11.80, SD = .27) at the first observation point. Maternal supportive emotion regulation and daughters' emotions were coded during two conflict discussions, 2 years apart. With multilevel survival analysis, the likelihood of maternal supportiveness was predicted both over time, between early and mid-adolescence, and by daughters' pubertal status. Mothers were more likely to respond to daughters' negative and positive emotions with supportiveness for daughters whose pubertal maturation occurred relatively early. Results suggest that mothers adjust their socialization of daughters' emotions according to their daughters' pubertal development.

Hypervalent Activation as a Key Step for Dehydrogenative ortho C-C Coupling of Iodoarenes.

Building on earlier results, a direct metal-free α-arylation of substituted cyclic 1,3-diones using ArI(O2CCF3)2 reagents has been developed; unlike other arylative approaches, the arylated products retain the iodine substituent ortho to the newly formed C-C bond. The mechanism is explored by using DFT calculations, which show a vanishingly small activation barrier for the C-C bond-forming step. In fact, taking advantage of an efficient in situ hypervalent activation, the iodoarenes are shown to undergo a cross-dehydrogenative C-C coupling at the C-H ortho to the iodine. When Oxone is used as terminal oxidant, the process is found to benefit from a rapid initial formation of the hypervalent ArI(OR)2 species and the sulfate-accelerated final coupling with a ketone. This method complements the ipso selectivity obtained in the metal-catalyzed α-arylation of carbonyl compounds.

Interobserver Reliability of Quantitative Muscle Sonographic Analysis in the Critically Ill Population.

OBJECTIVES: There is growing interest in the use of quantitative high-resolution neuromuscular sonography to evaluate skeletal muscles in patients with critical illness. There is currently considerable methodological variability in the measurement technique of quantitative muscle analysis. The reliability of muscle parameters using different measurement techniques and assessor expertise levels has not been examined in patients with critical illness. The primary objective of this study was to determine the interobserver reliability of quantitative sonographic measurement analyses (thickness and echogenicity) between assessors of different expertise levels and using different techniques for selecting the region of interest. METHODS: We conducted a cross-sectional observational study in neurocritical care and mixed surgical-medical intensive care units from 2 tertiary referral hospitals. RESULTS: Twenty diaphragm and 20 quadriceps images were evaluated. Images were obtained by using standardized imaging acquisition techniques. Quantitative sonographic measurements included muscle thickness and echogenicity analysis (either by the trace or square technique). All images were analyzed twice independently by 4 assessors of differing expertise levels. Excellent interobserver reliability was obtained for all measurement techniques regardless of expertise level (intraclass correlation coefficient, >0.75 for all comparisons). There was less variability between assessors for echogenicity values when the square technique was used for the quadriceps muscle and the trace technique for the diaphragm. CONCLUSIONS: Excellent interobserver reliability exists regardless of expertise level for quantitative analysis of muscle parameters on sonography in the critically ill population. On the basis of these findings, it is recommended that echogenicity analysis be performed using the square technique for the quadriceps and the trace technique for the diaphragm.

Dietary nitrate supplementation improves exercise performance and decreases blood pressure in COPD patients.

Dietary nitrate (NO3(-)) supplementation via beetroot juice has been shown to increase the exercise capacity of younger and older adults. The purpose of this study was to investigate the effects of acute NO3(-) ingestion on the submaximal constant work rate exercise capacity of COPD patients. Fifteen patients were assigned in a randomized, single-blind, crossover design to receive one of two treatments (beetroot juice then placebo or placebo then beetroot juice). Submaximal constant work rate exercise time at 75% of the patient's maximal work capacity was the primary outcome. Secondary outcomes included plasma NO3(-) and nitrite (NO2(-)) levels, blood pressure, heart rate, oxygen consumption (VO2), dynamic hyperinflation, dyspnea and leg discomfort. Relative to placebo, beetroot ingestion increased plasma NO3(-) by 938% and NO2(-) by 379%. Median (+interquartile range) exercise time was significantly longer (p = 0.031) following the ingestion of beetroot versus placebo (375.0 + 257.0 vs. 346.2 + 148.0 s, respectively). Compared with placebo, beetroot ingestion significantly reduced iso-time (p = 0.001) and end exercise (p = 0.008) diastolic blood pressures by 6.4 and 5.6 mmHg, respectively. Resting systolic blood pressure was significantly reduced (p = 0.019) by 8.2 mmHg for the beetroot versus the placebo trial. No other variables were significantly different between the beetroot and placebo trials. These results indicate that acute dietary NO3(-) supplementation can elevate plasma NO3(-) and NO2(-) concentrations, improve exercise performance, and reduce blood pressure in COPD patients.

Developmental change in EEG theta activity in the medial prefrontal cortex during response control.

Cognitive control functions continue to improve from infancy until early adulthood, allowing flexible adaptation to a complex environment. However, it remains controversial how this development in cognitive capabilities is mediated by changes in cortical activity: both age-related increases and decreases of mediofrontal neural activity have been observed and interpreted as neural underpinnings of this functional development. To better understand this developmental process, we examined EEG theta activity in the mediofrontal region using a Go/No-go response control task. We found that both pre-stimulus baseline theta-power and theta-power during the response control task, without baseline-correction, decreased with age. Conversely, when task-related theta-power was baseline corrected (using a ratio method), it exhibited a positive developmental trajectory. The age-related theta-power increase was source-localized to the anterior cingulate cortex. This increase in theta activity also partially mediated age-related improvements in response control and was greatest in a condition that demanded greater effort. Theta activity in older children also showed greater temporal reliability across trials as measured by inter-trial phase-coherence. Interestingly, directly subtracting baseline activity from task-related activity did not yield significant developmental effects, which highlights the necessity of separating and contrasting the pre-stimulus baseline with task-related processing in the understanding of neurodevelopmental changes.

Neurophysiological markers that predict and track treatment outcomes in childhood anxiety.

The present study examined the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli, before and after anxious children participated in a cognitive behavioral therapy program. Electroencephalographic activity was recorded from anxious children (n = 24, 8 males) and comparison children (n = 16, 7 males) at pre-and post-treatment sessions. The change in anxiety T-scores from pre- to post-treatment was used to signify clinical improvement among anxious children (Improvers: n = 11 vs. Non-improvers: n = 13). Event-related potential components were recorded while children performed a Go/No-go task using emotional facial expressions. For the P1 component, believed to reflect attention and/or arousal processes, Non-improvers had greater activation levels relative to Improver and comparison groups at both sessions. Greater P1 amplitudes at pre-treatment predicted non-improvement following treatment. For the frontal N2 component, thought to reflect cognitive control processing, Improvers recruited greater activation from pre- to post-treatment, a change in activation that was predictive of treatment outcome. Non-improvers showed increased cortical activation within the time window of the P1, whether at pre- or post-treatment. These data suggest that heightened perceptual vigilance may have led to poorer outcomes. Improvers showed increased prefrontal activation within the time window of the N2 from pre- to post-treatment. These data suggest that increased cognitive control may have led to improved treatment outcomes. In sum, P1 activation may serve as a predictor of treatment outcome, while N2 activation may serve as an indicator of treatment response.

Improving the thermal, radial, and temporal accuracy of the analytical ultracentrifuge through external references.

Sedimentation velocity (SV) is a method based on first principles that provides a precise hydrodynamic characterization of macromolecules in solution. Due to recent improvements in data analysis, the accuracy of experimental SV data emerges as a limiting factor in its interpretation. Our goal was to unravel the sources of experimental error and develop improved calibration procedures. We implemented the use of a Thermochron iButton temperature logger to directly measure the temperature of a spinning rotor and detected deviations that can translate into an error of as much as 10% in the sedimentation coefficient. We further designed a precision mask with equidistant markers to correct for instrumental errors in the radial calibration that were observed to span a range of 8.6%. The need for an independent time calibration emerged with use of the current data acquisition software (Zhao et al., Anal. Biochem., 437 (2013) 104-108), and we now show that smaller but significant time errors of up to 2% also occur with earlier versions. After application of these calibration corrections, the sedimentation coefficients obtained from 11 instruments displayed a significantly reduced standard deviation of approximately 0.7%. This study demonstrates the need for external calibration procedures and regular control experiments with a sedimentation coefficient standard.

Neural mechanisms of emotion regulation in childhood anxiety.

BACKGROUND: The present study was designed to examine the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli in anxious children. METHODS: Electroencephalographic (EEG) activity was recorded from clinically anxious children (n = 29) and typically developing children (n = 34). Event-related potential components were recorded while children performed a go/no-go task using facial stimuli depicting angry, calm, and happy expressions. RESULTS: Anxious children had significantly greater posterior P1 and frontal N2 amplitudes, components associated with attention/arousal and cognitive control, respectively, than typically developing children. Anxious children also had significantly greater error-related negativities and correct-response negativities relative to typically developing children. For the anxious group only, there were no differences in neural activation between face (emotion) types or trial (Go vs. No-go) types. A regression analysis revealed that No-go N2 amplitudes for calm faces predicted self-reported anxiety levels. CONCLUSIONS: Anxious children appeared to show increased cortical activation regardless of the emotional content of the stimuli. Anxious children also showed greater medial-frontal activity regardless of task demands and response accuracy. Taken together, these findings suggest indiscriminate cortical processes that may underlie the hypervigilant regulatory style seen in clinically anxious individuals.

Emotion regulation in children with behavior problems: linking behavioral and brain processes.

Past studies have shown that aggressive children exhibit rigid (rather than flexible) parent-child interactions; these rigid repertoires may provide the context through which children fail to acquire emotion-regulation skills. Difficulties in regulating emotion are associated with minimal activity in dorsal systems in the cerebral cortex, for example, the anterior cingulate cortex. The current study aimed to integrate parent-child and neurocognitive indices of emotion regulation and examine their associations for the first time. Sixty children (8-12 years old) referred for treatment for aggression underwent two assessments. Brain processes related to emotion regulation were assessed using dense-array EEG with a computerized go/no-go task. The N2 amplitudes thought to tap inhibitory control were recorded, and a source analysis was conducted. In the second assessment, parents and children were videotaped while trying to solve a conflict topic. State space grids were used to derive two dynamic flexibility parameters from the coded videotapes: (a) the number of transitions between emotional states and (b) the dispersion of emotional states, based on proportional durations in each state. The regression results showed that flexibility measures were not related to N2 amplitudes. However, flexibility measures were significantly associated with the ratio of dorsal to ventral source activation: for transitions, ΔR 2 = .27, F (1, 34) = 13.13, p = .001; for dispersion, ΔR 2 = .29, F (1, 35) = 14.76, p < .001. Thus, in support of our main hypothesis, greater dyadic flexibility was associated with a higher ratio of dorsomedial to ventral activation, suggesting that children with more flexible parent-child interactions are able to recruit relatively more dorsomedial activity in challenging situations.

Withholding response in the face of a smile: age-related differences in prefrontal sensitivity to Nogo cues following happy and angry faces.

The modulation of control processes by stimulus salience, as well as associated neural activation, changes over development. We investigated age-related differences in the influence of facial emotion on brain activation when an action had to be withheld, focusing on a developmental period characterized by rapid social-emotional and cognitive change. Groups of kindergarten and young school-aged children and a group of young adults performed a modified Go/Nogo task. Response cues were preceded by happy or angry faces. After controlling for task performance, left orbitofrontal regions discriminated trials with happy vs. angry faces in children but not in adults when a response was withheld, and this effect decreased parametrically with age group. Age-related changes in prefrontal responsiveness to facial expression were not observed when an action was required, nor did this region show age-related activation changes with the demand to withhold a response in general. Such results reveal age-related differences in prefrontal activation that are specific to stimulus valence and depend on the action required.

Magnitude and chronometry of neural mechanisms of emotion regulation in subtypes of aggressive children.

Emotion regulation is a key social skill and children who fail to master it are at risk for clinical disorders. Specific styles of emotion regulation have been associated with particular patterns of prefrontal activation. We investigated whether anxious aggressive children would reveal a different pattern of cortical activation than non-anxious aggressive children and normally-developing children. We examined the magnitude and timing of source activation underlying the N2-an ERP associated with inhibitory control-during a go/nogo task with a negative emotion induction component (loss of earned points). We estimated cortical activation for two regions of interest-a ventral prefrontal and a dorsomedial prefrontal region-for three 100-ms windows over the range of the N2 (200-500 ms). Anxious aggressive children showed high ventral prefrontal activation in the early window; non-anxious aggressive children showed high ventral prefrontal activation in the late window, but only for the duration of the emotion induction; and normally-developing children showed low ventral prefrontal activation throughout. There were no group differences in dorsomedial prefrontal activation. These results suggest that anxious aggressive children recruit ventral prefrontal activation quickly and indiscriminately, possibly giving rise to their rigid, threat-oriented approach to conflict. The late ventral prefrontal activation seen for non-anxious aggressive children may underlie a more delayed, situation-specific, but ineffective response to frustration.

Neural changes associated with treatment outcome in children with externalizing problems.

BACKGROUND: The current study directly investigated whether changes in the neural correlates of self-regulation (SR) are associated with the effectiveness of treatment for the externalizing problems of children. METHODS: Seventy-one children 8-12 years of age with clinical levels of externalizing behavior and their families completed a 3-month cognitive behavioral therapy program with a parent management training component. Electroencephalogram correlates of SR were evaluated before and after treatment with a go/no-go task requiring inhibitory control. RESULTS: Results showed that neural markers of SR, such as the N2 and frontal P3 event-related potential magnitudes, differed between the clinical sample and a matched comparison group before treatment: the clinical sample had larger N2 magnitudes and smaller frontal P3 magnitudes. Children who improved with treatment demonstrated a marked decrease in the magnitude of the N2 in comparison with children who did not improve. For improvers only, source analyses during the time period of the N2 estimated activation decreases in medial and ventral prefrontal cortex as well as the anterior medial temporal lobe. CONCLUSIONS: A decrease in N2 magnitudes and corresponding source activation in children who improved with treatment might reflect improved efficiency in the neural mechanisms of SR.

The changing face of emotion: age-related patterns of amygdala activation to salient faces.

The present study investigated age-related differences in the amygdala and other nodes of face-processing networks in response to facial expression and familiarity. fMRI data were analyzed from 31 children (3.5-8.5 years) and 14 young adults (18-33 years) who viewed pictures of familiar (mothers) and unfamiliar emotional faces. Results showed that amygdala activation for faces over a scrambled image baseline increased with age. Children, but not adults, showed greater amygdala activation to happy than angry faces; in addition, amygdala activation for angry faces increased with age. In keeping with growing evidence of a positivity bias in young children, our data suggest that children find happy faces to be more salient or meaningful than angry faces. Both children and adults showed preferential activation to mothers' over strangers' faces in a region of rostral anterior cingulate cortex associated with self-evaluation, suggesting that some nodes in frontal evaluative networks are active early in development. This study presents novel data on neural correlates of face processing in childhood and indicates that preferential amygdala activation for emotional expressions changes with age.

Transient coordinated activity within the developing brain's default network.

The concept of a brain default network postulates that specific brain regions are more active when a person is engaged in introspective mental activity. Transient functional coordination between groups of neurons is thought to be necessary for information processing. Since children develop introspection as they mature, regions of the default network may establish increasing functional coordination with age, resulting in fewer fluctuations in synchronization patterns. We investigated the transient coordinated activity in regions of the default network in seventeen children aged 11 months to 17 years of age using EEG recordings while subjects were resting quietly with eyes closed. The temporal and spatial fluctuations in the phase synchrony patterns were estimated across sites associated with the default network pattern and compared to other regions. Lower variability of the spatio-temporal patterns of phase synchronization associated with the default network was observed in the older group as compared to the younger group. This indicates that functional coordination increases among regions of the default network as children develop.