The objective of this study was to explore the conditions necessary
to assign causal status to headache triggers.
The term “headache trigger” is commonly used to label
any stimulus that is assumed to cause headaches. However, the assumptions
required for determining if a given stimulus in fact has a causal-type
relationship in eliciting headaches have not been explicated.
A synthesis and application of Rubin’s Causal Model is
applied to the context of headache causes. From this application the
conditions necessary to infer that one event (trigger) causes another
(headache) are outlined using basic assumptions and examples from relevant
Although many conditions must be satisfied for a causal attribution,
three basic assumptions are identified for determining causality in headache
triggers: 1) constancy of the sufferer; 2) constancy of the trigger effect;
and 3) constancy of the trigger presentation. A valid evaluation of a
potential trigger’s effect can only be undertaken once these three
basic assumptions are satisfied during formal or informal studies of
Evaluating these assumptions is extremely difficult or infeasible in
clinical practice, and satisfying them during natural experimentation is
unlikely. Researchers, practitioners, and headache sufferers are encouraged
to avoid natural experimentation to determine the causal effects of headache
triggers. Instead, formal experimental designs or retrospective diary
studies using advanced statistical modeling techniques provide the best
approaches to satisfy the required assumptions and inform causal statements
about headache triggers.
headache triggers; causality; research design
Interindividual variability in postoperative pain presents a clinical challenge. Preoperative quantitative sensory testing is useful but time consuming in predicting postoperative pain intensity. The current study was conducted to develop and validate a predictive model of acute postcesarean pain using a simple three-item preoperative questionnaire.
A total of 200 women scheduled for elective cesarean delivery under subarachnoid anesthesia were enrolled (192 subjects analyzed). Patients were asked to rate the intensity of loudness of audio tones, their level of anxiety and anticipated pain, and analgesic need from surgery. Postoperatively, patients reported the intensity of evoked pain. Regression analysis was performed to generate a predictive model for pain from these measures. A validation cohort of 151 women was enrolled to test the reliability of the model (131 subjects analyzed).
Responses from each of the three preoperative questions correlated moderately with 24-h evoked pain intensity (r = 0.24-0.33, P < 0.001). Audio tone rating added uniquely, but minimally, to the model and was not included in the predictive model. The multiple regression analysis yielded a statistically significant model (R2 = 0.20, P < 0.001), whereas the validation cohort showed reliably a very similar regression line (R2 = 0.18). In predicting the upper 20th percentile of evoked pain scores, the optimal cut point was 46.9 (z =0.24) such that sensitivity of 0.68 and specificity of 0.67 were as balanced as possible.
This simple three-item questionnaire is useful to help predict postcesarean evoked pain intensity, and could be applied to further research and clinical application to tailor analgesic therapy to those who need it most.
To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open label study of memantine in frontotemporal dementia (FTD).
We repeated fluoro-deoxyglucose positron emission tomography (PET) after 6 months of drug use and subjected the data to an SPM analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI).
Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia. The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p<0.002) for 5 participants with semantic dementia. The 2–6 month interval revealed a late increase in normalized metabolic activity in the left insula (p<0.013), right insula (p<0.009), and left anterior cingulate (p<0.005). The right anterior cingulate showed both an initial increase and a delayed, further increase (2–6 month, p<0.016). FBI scores worsened by 43.3%. One participant with semantic dementia opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases.
Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Since one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure.
frontotemporal dementia; metabolism; PET scan; semantic dementia
A number of addictions have been linked with decreased striatal dopamine (DA) receptor availability and DA release. Stress has a key role in cannabis craving, as well as in modulation of dopaminergic signaling. The present study aimed to assess DA release in response to a laboratory stress task with [11C]-(+)-PHNO positron emission tomography in cannabis users (CU). Thirteen healthy CU and 12 healthy volunteers (HV) were scanned during a sensorimotor control task (SMCT) and under a stress condition using the validated Montreal imaging stress task (MIST). The simplified reference tissue model (SRTM) was used to obtain binding potential (BPND) in striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Stress-induced DA release (indexed as a percentage of reduction in [11C]-(+)-PHNO BP ND) between CU and HV was tested with analysis of variance. SMCT BPND was significantly higher in CU compared with HV in the AST (F=10.38, p=0.003), LST (F=4.95, p=0.036), SMST (F=4.33, p=0.048), and whole striatum (F=9.02, p=0.006). Percentage of displacement (change in BPND between SMCT and MIST PET scans) was not significantly different across groups in any brain region, except in the GP (−5.03±14.6 in CU, compared with 6.15±12.1 in HV; F=4.39, p=0.049). Duration of cannabis use was significantly associated with stress-induced [11C]-(+)-PHNO displacement by endogenous DA in the LST (r=0.566, p=0.044), with no effect in any other brain region. In conclusion, despite an increase in striatal BPND observed during the control task, chronic cannabis use is not associated with alterations in stress-induced DA release.
psychosocial stress; dopamine; cannabis use disorder; positron emission tomography; [11C]-(+)-PHNO; [11C]-(+)-PHNO; Addiction & Substance Abuse; Cannabinoids; Cannabis use disorder; Dopamine; Imaging; Clinical or Preclinical; Positron emission tomography; Psychosocial stress
Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [11C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [11C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90 minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation (COV) of the net influx constant Ki and the composite parameter λk3 (λ=K1/k2) <5%, and COV(k3)<10%). Reducing scan time to 60 minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with Ki, but not with k3 or λk3. Our data suggest that λk3 is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [11C]CURB. Simulations showed that [11C]CURB binding in healthy subjects is far from a flow-limited uptake.
[11C]CURB; endocannabinoid; FAAH; fatty acid amide hydrolase; kinetic modeling; PET; positron emission tomography
In vivo imaging of translocator protein 18 kDa (TSPO) has received significant attention as potential biomarker of microglia activation. Several radioligands have been designed with improved properties. Our group recently developed an 18F-labeled TSPO ligand, [18F]-FEPPA, and confirmed its reliability with a 2-tissue compartment model. Here, we extended, in a group of healthy subjects, its suitability for use in voxel-based analysis with the newly proposed graphical analysis approach, Relative-Equilibrium-Gjedde-Patlak (REGP) plot. The REGP plot successfully replicated the total distribution volumes estimated by the 2-tissue compartment model. We also showed its proof-of-concept in a patient with possible meningioma showing increased [18F]-FEPPA total distribution volume.
inflammation; kinetic modeling; microglia; neurooncology; positron emission tomography
Chronic pain after surgery occurs in 10-40% of individuals, including 5-20% of women after cesarean delivery in previous reports. Pain and depression 2 months after childbirth are independently associated with more severe acute post-delivery pain. Here we examine other predictors of pain at 2 months and determine the incidence of pain at 6 and 12 months after childbirth.
Following Institutional Review Board approval, 1228 women were interviewed within 36 hr of delivery. Of these, 937 (76%) were successfully contacted by telephone at 2 months, and, if they had pain, at 6 and 12 months after delivery. The primary outcome measure was presence of pain which began at the time of delivery. We also generated a model of severity of acute post-delivery pain and 2 month pain and depression.
Pain which began at the time of delivery was remarkably rare 6 and 12 months later (1.8% and 0.3% [upper 95% confidence limit, 1.2%], respectively). Past history of pain and degree of tissue damage at delivery accounted for 7.0% and 16.7%, respectively of one aspect in the variability in acute post-delivery pain. Neither of these factors was associated with incidence of pain 2 months later.
Using a definition of new onset pain from delivery, we show a remarkably low incidence of pain 1 year after childbirth, including those with surgical delivery. Additionally, degree of tissue trauma and history of chronic pain, risk factors for pain 2 months after other surgery, were unimportant to pain 2 months after cesarean or vaginal delivery.
Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored.
We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined.
Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2–3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban.
These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.
The collagen meshwork plays a central role in the functioning of a range of tissues including cartilage, tendon, arteries, skin, bone and ligament. Because of its importance in function, it is of considerable interest for studying development, disease and regeneration processes. Here, we have used second harmonic generation (SHG) to image human tissues on the hundreds of micron scale, and developed a numerical model to quantitatively interpret the images in terms of the underlying collagen structure on the tens to hundreds of nanometer scale. Focusing on osteoarthritic changes in cartilage, we have demonstrated that this combination of polarized SHG imaging and numerical modeling can estimate fibril diameter, filling fraction, orientation and bundling. This extends SHG microscopy from a qualitative to quantitative imaging technique, providing a label-free and non-destructive platform for characterizing the extracellular matrix that can expand our understanding of the structural mechanisms in disease.
(170.0170) Medical optics and biotechnology; (190.0190) Nonlinear optics
The objective of this study was to evaluate the time-series relationships between stress, sleep duration, and headache pain among patients with chronic headaches. Sleep and stress have long been recognized as potential triggers of episodic headache (< 15 headache days/month), though prospective evidence is inconsistent and absent in patients diagnosed with chronic headaches (≥ 15 days/month). We reanalyzed data from a 28-day observational study of chronic migraine (n = 33) and chronic tension-type headache (n = 22) sufferers. Patients completed the Daily Stress Inventory and recorded headache and sleep variables using a daily sleep/headache diary. Stress ratings, duration of previous nights' sleep, and headache severity were modeled using a series of linear mixed models with random effects to account for individual differences in observed associations. Models were displayed using contour plots. Two consecutive days of either high stress or low sleep were strongly predictive of headache, whereas two days of low stress or adequate sleep were protective. When patterns of stress or sleep were divergent across days, headache risk was increased only when the earlier day was characterized by high stress or poor sleep. As predicted, headache activity in the combined model was highest when high stress and low sleep occurred concurrently during the prior 2 days denoting an additive effect. Future research is needed to expand on current findings among chronic headache patients and to develop individualized models that account for multiple simultaneous influences of headache trigger factors.
Stress; Sleep; Headache; Time-series; Headache trigger factors; Headache precipitants
This study tested a modified Cognitive Processing Therapy intervention (MCPT) designed as a more flexible administration of the protocol. Number of sessions was determined by client progress toward a priori defined end-state criteria, “stressor sessions” were inserted when necessary, and therapy was conducted by novice CPT clinicians.
A randomized, controlled, repeated measures, semi-crossover design was utilized to 1) test the relative efficacy of the MCPT intervention compared to a Symptom-Monitoring Delayed Treatment (SMDT) condition and 2) to assess within-group variation in change with a sample of 100 male and female interpersonal trauma survivors with posttraumatic stress disorder (PTSD).
Hierarchical linear modeling analyses revealed that MCPT evidenced greater improvement on all primary (PTSD and depression) and secondary (guilt, quality of life, general mental health, social functioning, and health perceptions) outcomes compared with SMDT. After the conclusion of SMDT, participants crossed over to MCPT, resulting in a Combined MCPT sample (n = 69). Of the 50 participants who completed MCPT, 58% reached end-state criteria prior to the 12th session, 8% at session 12, and 34% between sessions 12-18. Maintenance of treatment gains was found at the 3-month follow-up, with only two of the treated sample meeting criteria for PTSD. The use of stressor sessions did not result in poorer treatment outcomes.
Findings suggest that individuals respond at a variable rate to CPT, with significant benefit from additional therapy when indicated and excellent maintenance of gains. The insertion of stressor sessions did not alter the efficacy of the therapy.
posttraumatic stress disorder; treatment outcome; cognitive processing therapy; effectiveness; interpersonal assault
The 4-Isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.
A patient’s experience with headache is influenced, not only by the frequency and pain of the attacks, but also by the patient’s perception of the controllability of the attacks, their willingness to engage in activities despite attacks and their attitude towards the medications used to treat the headaches. Clinicians are often aware of the need to evaluate their patients for the existence of comorbid psychiatric disorders but may be less aware of the importance of these nonpathological beliefs/attitudes that are present to some degree in every headache sufferer. This article gives an overview (by no means exhaustive) of several important psychological constructs, with an emphasis on how these constructs can be assessed in headache patients using freely available paper–pencil questionnaires.
The administration of injections has become an increasingly common addition to pharmacists’ scope of practice. Four Canadian provinces, all US states and a number of other countries have regulations allowing pharmacists to administer injections. However, the extent to which such services are remunerated is unknown.
We contacted regulatory and advocacy organizations within those jurisdictions where pharmacists are authorized to administer injections to identify publicly funded programs that pay pharmacists for these services, as well as details of the eligible drugs/vaccines. Patient or private insurer payment programs were excluded.
Of the 281 organizations we contact-ed, 104 provided information on a total of 34 pharmacist vaccination programs throughout Canada, the United States, England, Wales and Ireland. Converted to 2013 Canadian dollars, remuneration averages $13.12 (SD $4.63) per injection (range, $4.14-$21.21). All regions allow pharmacists to bill for administration of the influenza vaccine, while some states allow for a number of other vaccines. Alberta has the broadest range of injections eligible for remuneration.
Despite evidence of increased vaccination rates in areas allowing pharmacist administration of injections, the availability of publicly funded remuneration programs and the fee offered vary by more than 5-fold across North America and the United Kingdom.
Pharmacist-administered injections have great public health potential. The range of injections eligible for remuneration should be expanded to include a wide range of vaccines and other injectable drugs, and remuneration should be sufficient to encourage more pharmacists to provide this service.
The revolution in DNA sequencing technology continues unabated, and is affecting all aspects of the biological and medical sciences. The training and recruitment of the next generation of researchers who are able to use and exploit the new technology is severely lacking and potentially negatively influencing research and development efforts to advance genome biology. Here we present a cross-disciplinary course that provides undergraduate students with practical experience in running a next generation sequencing instrument through to the analysis and annotation of the generated DNA sequences.
Many labs across world are installing next generation sequencing technology and we show that the undergraduate students produce quality sequence data and were excited to participate in cutting edge research. The students conducted the work flow from DNA extraction, library preparation, running the sequencing instrument, to the extraction and analysis of the data. They sequenced microbes, metagenomes, and a marine mammal, the Californian sea lion, Zalophus californianus. The students met sequencing quality controls, had no detectable contamination in the targeted DNA sequences, provided publication quality data, and became part of an international collaboration to investigate carcinomas in carnivores.
Students learned important skills for their future education and career opportunities, and a perceived increase in students’ ability to conduct independent scientific research was measured. DNA sequencing is rapidly expanding in the life sciences. Teaching undergraduates to use the latest technology to sequence genomic DNA ensures they are ready to meet the challenges of the genomic era and allows them to participate in annotating the tree of life.
Undergraduate education; DNA sequencing; Sea lion; Metagenome
Geometric morphometrics comprises tools for measuring and analyzing shape as captured by an entire set of landmark configurations. Many interesting questions in evolutionary, genetic, and developmental research, however, are only meaningful at a local level, where a focus on “parts” or “traits” takes priority over properties of wholes. To study variational properties of such traits, current approaches partition configurations into subsets of landmarks which are then studied separately. This approach is unable to fully capture both variational and spatial characteristics of these subsets because interpretability of shape differences is context-dependent. Landmarks omitted from a partition usually contain information about that partition’s shape. We present an interpolation-based approach that can be used to model shape differences at a local, infinitesimal level as a function of information available globally. This approach belongs in a large family of methods that see shape differences as continuous “fields” spanning an entire structure, for which landmarks serve as reference parameters rather than as data. We show, via analyses of simulated and real data, how interpolation models provide a more accurate representation of regional shapes than partitioned data. A key difference of this interpolation approach from current morphometric practice is that one must assume an explicit interpolation model, which in turn implies a particular kind of behavior of the regions between landmarks. This choice presents novel methodological challenges, but also an opportunity to incorporate and test biomechanical models that have sought to explain tissue-level processes underlying the generation of morphological shape.
Geometric morphometrics; Thin-plate splines; Shape variables; Interpolation; Local shape variation; Modularity; Biomechanical models
Background Household characteristics are important influences on the risk of child death. However, little is known about this influence in HIV-endemic areas. We describe the effects of household characteristics on children’s risk of dying in rural South Africa.
Methods We use data describing the mortality of children younger than 5 years living in the Agincourt health and socio-demographic surveillance system study population in rural northeast South Africa during the period 1994–2008. Using discrete time event history analysis we estimate children’s probability of dying by child characteristics and household composition (other children and adults other than parents) (N = 924 818 child-months), and household socio-economic status (N = 501 732 child-months).
Results Children under 24 months of age whose subsequent sibling was born within 11 months experience increased odds of dying (OR 2.5; 95% CI 1.1–5.7). Children also experience increased odds of dying in the period 6 months (OR 2.1; 95% CI 1.2–3.6), 3–5 months (OR 3.0; 95% CI 1.5–5.9), and 2 months (OR 11.8; 95% CI 7.6–18.3) before another household child dies. The odds of dying remain high at the time of another child’s death (OR 11.7; 95% CI 6.3–21.7) and for the 2 months following (OR 4.0; 95% CI 1.9–8.6). Having a related but non-parent adult aged 20–59 years in the household reduces the odds (OR 0.6; 95% CI 0.5–0.8). There is an inverse relationship between a child’s odds of dying and household socio-economic status.
Conclusions This detailed household profile from a poor rural setting where HIV infection is endemic indicates that children are at high risk of dying when another child is very ill or has recently died. Short birth intervals and additional children in the household are further risk factors. Presence of a related adult is protective, as is higher socio-economic status. Such evidence can inform primary health care practice and facilitate targeting of community health worker efforts, especially when covering defined catchment areas.
Child mortality; socio-economic status; HIV; birth spacing; household; health and demographic surveillance system; rural; South Africa
The main pattern of cognitive impairments seen in early to moderate stages of Parkinson’s disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [11C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [11C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [11C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [11C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.
PMID: 22331665 CAMSID: cams2380
FLB-457; positron emission tomography; set-shifting; cognition; mesocortical dopamine
Decision making is a cognitive function relaying on a complex neural network. In particular, the right dorsolateral prefrontal cortex (DLPFC) plays a key role within this network. We used positron emission tomography (PET) combined with continuous theta burst transcranial magnetic stimulation (cTBS) to investigate neuronal and behavioral changes in normal volunteers while performing a delay discounting (DD) task. We aimed to test whether stimulation of right DLPFC would modify the activation pattern of the neural circuit underlying decision making during the DD task and influence discounting behavior.
We found that cTBS of the right DLPFC influenced decision making by reducing impulsivity and inducing participants to favor large but delayed rewards instead of immediate but small rewards. Stimulation also affected activation in several prefrontal areas associated with DD. In particular, we observed a reduced regional cerebral blood flow (rCBF) in the ipsilateral DLPFC (BA 46) extending into the rostral part of the prefrontal cortex (BA 10) as well as a disrupted relationship between impulsivity (k-value) and rCBF in these and other prefrontal areas.
These findings suggest that transcranial magnetic stimulation of the DLPFC influences the neural network underlying impulsive decision making behavior.
PMID: 22494829 CAMSID: cams3170
rTMS; Theta burst stimulation; Dorsolateral prefrontal cortex; Decision making; Impulsivity; Delay discounting task
[18F]-FEPPA binds to the 18-kDa translocator protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of the PET signal with new generation TSPO PET radioligands are confounded by large interindividual variability in binding affinity. This presents as a trimodal distribution, reflecting high-affinity binders (HABs), low-affinity binder (LAB), and mixed-affinity binders (MABs). Here, we show that one polymorphism (rs6971) located in exon 4 of the TSPO gene, which results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein, predicts [18F]-FEPPA total distribution volume in human brains. In addition, [18F]-FEPPA exhibits clearly different features in the shape of the time activity curves between genetic groups. Testing for the rs6971 polymorphism may allow quantitative interpretation of TSPO PET studies with new generation of TSPO PET radioligands.
genetics; inflammation; microglia; mitochondria; positron emission tomography