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1.  Line bisection performance in patients with generalized anxiety disorder and treatment-resistant depression 
Background and Objectives The line bisection error to the left of the true center has been interpreted as a relative right hemisphere activation, which might relate to the subject's emotional state. Considering that patients with generalized anxiety disorder (GAD) or treatment-resistant depression (TRD) often have negative emotions, we hypothesized that these patients would bisect lines significantly leftward. Methods We tried the line bisection task in the right-handed healthy volunteers (n = 56), GAD (n = 47) and TRD outpatients (n = 52). Subjects also completed the Zuckerman - Kuhlman Personality Questionnaire, the Zuckerman Sensation Seeking Scales, and the Plutchik-van Praag Depression Inventory. Results GAD patients scored highest on the Neuroticism-Anxiety trait, TRD patients scored highest on depression, and both patients scored lower on the Sociability trait. Patients with GAD also bisected lines significantly leftward compared to the healthy subjects. The Frequency of the bisection error was negatively correlated with Disinhibition-Seeking in the healthy subjects, and with Total sensation-seeking and Experience-Seeking in GAD patients, while the Magnitude of the line bisection error was negatively correlated with depression in TRD patients. Conclusions The study suggests a stronger right hemispheric activation, a weaker left activation, or both in the GAD, instead of TRD patients.
PMCID: PMC2899451  PMID: 20617126
Generalized Anxiety Disorder; hemispheric activation; line bisection; treatment-resistant depression
2.  Headache, anxiety and depressive disorders: the HADAS study 
The Journal of Headache and Pain  2010;11(2):141-150.
The objective of this paper was to assess prevalence and characteristics of anxiety and depression in migraine without aura and tension-type headache, either isolated or in combination. Although the association between headache and psychiatric disorders is undisputed, patients with migraine and/or tension-type headache have been frequently investigated in different settings and using different tests, which prevents meaningful comparisons. Psychiatric comorbidity was tested through structured interview and the MINI inventory in 158 adults with migraine without aura and in 216 persons with tension-type headache or migraine plus tension-type headache. 49 patients reported psychiatric disorders: migraine 10.9%, tension-type headache 12.8%, and migraine plus tension-type headache 21.4%. The MINI detected a depressive episode in 59.9, 67.0, and 69.6% of cases. Values were 18.4, 19.3, and 18.4% for anxiety, 12.7, 5.5, and 14.2%, for panic disorder and 2.3, 1.1 and 9.4% (p = 0.009) for obsessive–compulsive disorder. Multivariate analysis showed panic disorder prevailing in migraine compared with the other groups (OR 2.9; 95% CI 1.2–7.0). The association was higher (OR 6.3; 95% CI 1.4–28.5) when migraine (with or without tension-type headache) was compared to pure tension-type headache. This also applied to obsessive–compulsive disorder (OR 4.8; 95% CI 1.1–20.9) in migraine plus tension-type headache. Psychopathology of primary headache can reflect shared risk factors, pathophysiologic mechanisms, and disease burden.
doi:10.1007/s10194-010-0187-2
PMCID: PMC3452290  PMID: 20108021
Migraine; Tension-type headache; Depression; Anxiety; Prevalence
3.  Anger and emotional distress in patients with migraine and tension–type headache 
The Journal of Headache and Pain  2005;6(5):392-399.
The objective was to evaluate the prevalence and the characteristics of anger and emotional distress in migraine and tension– type headache patients. Two hundred and one headache patients attending the Headache Center of the University of Turin were selected for the study and divided into 5 groups: (1) migraine, (2) episodic tension–type headache, (3) chronic tension–type headache, (4) migraine associated with episodic tension–type headache and (5) migraine associated with chronic tension–type headache. A group of 45 healthy subjects served as controls. All the subjects completed the State–Trait Anger Expression Inventory, the Beck's Depression Inventory and the Cognitive Behavioral Assessment. Anger control was significantly lower in all headache patients (p<0.05) except in migraineurs. Patients with migraine and tension–type headache showed a significantly higher level of angry temperament and angry reaction (p<0.05). In addition, chronic tension–type headache and migraine associated with tension–type headache patients reported a higher level of anxiety (p<0.05), depression (p<0.001), phobias (p<0.001) and obsessive–compulsive symptoms (p<0.01), emotional liability (p<0.001) and psychophysiological disorders (p<0.001). Our study shows that chronic tension–type headache and migraine associated with tension–type headache patients present a significant impairment of anger control and suggests a connection between anger and the duration of headache experience.
doi:10.1007/s10194-005-0240-8
PMCID: PMC3452065  PMID: 16362712
Migraine; Tension–type headache; Anger; Depression
4.  Individual differences in drug abuse vulnerability: d-Amphetamine and sensation-seeking status 
Psychopharmacology  2006;189(1):17-25.
Rationale
While the personality dimensions of novelty seeking and sensation seeking are associated with drug abuse vulnerability, the mechanisms associated with this vulnerability remain obscure.
Objective
This study examined the behavioral effects of d-amphetamine in healthy volunteers scoring in the upper and lower quartiles based on age- and gender-adjusted population norms on the impulsive Sensation-Seeking Scale (SSS) of the Zuckerman–Kuhlman personality questionnaire (ZKPQ).
Method
Participants completed 7-day outpatient studies examining the subjective, performance, and cardiovascular effects of d-amphetamine (0, 7.5, and 15 mg/70 kg, p.o.) under double-blind conditions according to a randomized block design. Performance tasks included behavioral measures of impulsivity, including attention, inhibition, and risk-taking behavior.
Results
No differences in baseline performance or d-amphetamine effects on measures of attention, inhibition, and risk-taking behavior were observed. High impulsive sensation seekers reported greater increases on several subjective report measures associated with drug abuse potential, including visual analog scales feel drug, like drug, and high.
Conclusions
Healthy adults scoring in the top quartile on the population of the impulsive SSS of the ZKPQ may be vulnerable to the abuse potential of d-amphetamine.
doi:10.1007/s00213-006-0487-z
PMCID: PMC3188427  PMID: 16972106
d-amphetamine; Sensation-seeking status; Vulnerability; Subjective effects; Performance effects; Abuse potential
5.  Neuroimaging for the Evaluation of Chronic Headaches 
Executive Summary
Objective
The objectives of this evidence based review are:
i) To determine the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) scans in the evaluation of persons with a chronic headache and a normal neurological examination.
ii) To determine the comparative effectiveness of CT and MRI scans for detecting significant intracranial abnormalities in persons with chronic headache and a normal neurological exam.
iii) To determine the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Clinical Need: Condition and Target Population
Headaches disorders are generally classified as either primary or secondary with further sub-classifications into specific headache types. Primary headaches are those not caused by a disease or medical condition and include i) tension-type headache, ii) migraine, iii) cluster headache and, iv) other primary headaches, such as hemicrania continua and new daily persistent headache. Secondary headaches include those headaches caused by an underlying medical condition. While primary headaches disorders are far more frequent than secondary headache disorders, there is an urge to carry out neuroimaging studies (CT and/or MRI scans) out of fear of missing uncommon secondary causes and often to relieve patient anxiety.
Tension type headaches are the most common primary headache disorder and migraines are the most common severe primary headache disorder. Cluster headaches are a type of trigeminal autonomic cephalalgia and are less common than migraines and tension type headaches. Chronic headaches are defined as headaches present for at least 3 months and lasting greater than or equal to 15 days per month. The International Classification of Headache Disorders states that for most secondary headaches the characteristics of the headache are poorly described in the literature and for those headache disorders where it is well described there are few diagnostically important features.
The global prevalence of headache in general in the adult population is estimated at 46%, for tension-type headache it is 42% and 11% for migraine headache. The estimated prevalence of cluster headaches is 0.1% or 1 in 1000 persons. The prevalence of chronic daily headache is estimated at 3%.
Neuroimaging
Computed Tomography
Computed tomography (CT) is a medical imaging technique used to aid diagnosis and to guide interventional and therapeutic procedures. It allows rapid acquisition of high-resolution three-dimensional images, providing radiologists and other physicians with cross-sectional views of a person’s anatomy. CT scanning poses risk of radiation exposure. The radiation exposure from a conventional CT scanner may emit effective doses of 2-4mSv for a typical head CT.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used to aid diagnosis but unlike CT it does not use ionizing radiation. Instead, it uses a strong magnetic field to image a person’s anatomy. Compared to CT, MRI can provide increased contrast between the soft tissues of the body. Because of the persistent magnetic field, extra care is required in the magnetic resonance environment to ensure that injury or harm does not come to any personnel while in the environment.
Research Questions
What is the effectiveness of CT and MRI scanning in the evaluation of persons with a chronic headache and a normal neurological examination?
What is the comparative effectiveness of CT and MRI scanning for detecting significant intracranial abnormality in persons with chronic headache and a normal neurological exam?
What is the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Research Methods
Literature Search
Search Strategy
A literature search was performed on February 18, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January, 2005 to February, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Systematic reviews, randomized controlled trials, observational studies
Outpatient adult population with chronic headache and normal neurological exam
Studies reporting likelihood ratio of clinical variables for a significant intracranial abnormality
English language studies
2005-present
Exclusion Criteria
Studies which report outcomes for persons with seizures, focal symptoms, recent/new onset headache, change in presentation, thunderclap headache, and headache due to trauma
Persons with abnormal neurological examination
Case reports
Outcomes of Interest
Primary Outcome
Probability for intracranial abnormality
Secondary Outcome
Patient relief from anxiety
System service use
System costs
Detection rates for significant abnormalities in MRI and CT scans
Summary of Findings
Effectiveness
One systematic review, 1 small RCT, and 1 observational study met the inclusion and exclusion criteria. The systematic review completed by Detsky, et al. reported the likelihood ratios of specific clinical variables to predict significant intracranial abnormalities. The RCT completed by Howard et al., evaluated whether neuroimaging persons with chronic headache increased or reduced patient anxiety. The prospective observational study by Sempere et al., provided evidence for the pre-test probability of intracranial abnormalities in persons with chronic headache as well as minimal data on the comparative effectiveness of CT and MRI to detect intracranial abnormalities.
Outcome 1: Pre-test Probability.
The pre-test probability is usually related to the prevalence of the disease and can be adjusted depending on the characteristics of the population. The study by Sempere et al. determined the pre-test probability (prevalence) of significant intracranial abnormalities in persons with chronic headaches defined as headache experienced for at least a 4 week duration with a normal neurological exam. There is a pre-test probability of 0.9% (95% CI 0.5, 1.4) in persons with chronic headache and normal neurological exam. The highest pre-test probability of 5 found in persons with cluster headaches. The second highest, that of 3.7, was reported in persons with indeterminate type headache. There was a 0.75% rate of incidental findings.
Likelihood ratios for detecting a significant abnormality
Clinical findings from the history and physical may be used as screening test to predict abnormalities on neuroimaging. The extent to which the clinical variable may be a good predictive variable can be captured by reporting its likelihood ratio. The likelihood ratio provides an estimate of how much a test result will change the odds of having a disease or condition. The positive likelihood ratio (LR+) tells you how much the odds of having the disease increases when a test is positive. The negative likelihood ratio (LR-) tells you how much the odds of having the disease decreases when the test is negative.
Detsky et al., determined the likelihood ratio for specific clinical variable from 11 studies. There were 4 clinical variables with both statistically significant positive and negative likelihood ratios. These included: abnormal neurological exam (LR+ 5.3, LR- 0.72), undefined headache (LR+ 3.8, LR- 0.66), headache aggravated by exertion or valsalva (LR+ 2.3, LR- 0.70), and headache with vomiting (LR+ 1.8, and LR- 0.47). There were two clinical variables with a statistically significant positive likelihood ratio and non significant negative likelihood ratio. These included: cluster-type headache (LR+ 11, LR- 0.95), and headache with aura (LR+ 12.9, LR- 0.52). Finally, there were 8 clinical variables with both statistically non significant positive and negative likelihood ratios. These included: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, and migraine type headache.
Outcome 2: Relief from Anxiety
Howard et al. completed an RCT of 150 persons to determine if neuroimaging for headaches was anxiolytic or anxiogenic. Persons were randomized to receiving either an MRI scan or no scan for investigation of their headache. The study population was stratified into those persons with a Hospital Anxiety and Depression scale (HADS) > 11 (the high anxiety and depression group) and those < 11 (the low anxiety and depression) so that there were 4 groups:
Group 1: High anxiety and depression, no scan group
Group 2: High anxiety and depression, scan group
Group 3: Low anxiety and depression, no scan group
Group 4: Low anxiety and depression, scan group
Anxiety
There was no evidence for any overall reduction in anxiety at 1 year as measured by a visual analogue scale of ‘level of worry’ when analysed by whether the person received a scan or not. Similarly, there was no interaction between anxiety and depression status and whether a scan was offered or not on patient anxiety. Anxiety did not decrease at 1 year to any statistically significant degree in the high anxiety and depression group (HADS positive) compared with the low anxiety and depression group (HADS negative).
There are serious methodological limitations in this study design which may have contributed to these negative results. First, when considering the comparison of ‘scan’ vs. ‘no scan’ groups, 12 people (16%) in the ‘no scan group’ actually received a scan within the follow up year. If indeed scanning does reduce anxiety then this contamination of the ‘no scan’ group may have reduced the effect between the groups results resulting in a non significant difference in anxiety scores between the ‘scanned’ and the ‘no scan’ group. Second, there was an inadequate sample size at 1 year follow up in each of the 4 groups which may have contributed to a Type II statistical error (missing a difference when one may exist) when comparing scan vs. no scan by anxiety and depression status. Therefore, based on the results and study limitations it is inconclusive as to whether scanning reduces anxiety.
Outcome 3: System Services
Howard et al., considered services used and system costs a secondary outcome. These were determined by examining primary care case notes at 1 year for consultation rates, symptoms, further investigations, and contact with secondary and tertiary care.
System Services
The authors report that the use of neurologist and psychiatrist services was significantly higher for those persons not offered as scan, regardless of their anxiety and depression status (P<0.001 for neurologist, and P=0.033 for psychiatrist)
Outcome 4: System Costs
System Costs
There was evidence of statistically significantly lower system costs if persons with high levels of anxiety and depression (Hospital Anxiety and Depression Scale score >11) were provided with a scan (P=0.03 including inpatient costs, and 0.047 excluding inpatient costs).
Comparative Effectiveness of CT and MRI Scans
One study reported the detection rate for significant intracranial abnormalities using CT and MRI. In a cohort of 1876 persons with a non acute headache defined as any type of headache that had begun at least 4 weeks before enrolment Sempere et al. reported that the detection rate was 19/1432 (1.3%) using CT and 4/444 (0.9%) using MRI. Of 119 normal CT scans 2 (1.7%) had significant intracranial abnormality on MRI. The 2 cases were a small meningioma, and an acoustic neurinoma.
Summary
The evidence presented can be summarized as follows:
Pre-test Probability
Based on the results by Sempere et al., there is a low pre-test probability for intracranial abnormalities in persons with chronic headaches and a normal neurological exam (defined as headaches experiences for a minimum of 4 weeks). The Grade quality of evidence supporting this outcome is very low.
Likelihood Ratios
Based on the systematic review by Detsky et al., there is a statistically significant positive and negative likelihood ratio for the following clinical variables: abnormal neurological exam, undefined headache, headache aggravated by exertion or valsalva, headache with vomiting. Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al. there is a statistically significant positive likelihood ratio but non statistically significant negative likelihood ratio for the following clinical variables: cluster headache and headache with aura. The Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al., there is a non significant positive and negative likelihood ratio for the following clinical variables: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, migraine type headache. The Grade quality of evidence supporting this outcome is very low.
Relief from Anxiety
Based on the RCT by Howard et al., it is inconclusive whether neuroimaging scans in persons with a chronic headache are anxiolytic. The Grade quality of evidence supporting this outcome is low.
System Services
Based on the RCT by Howard et al. scanning persons with chronic headache regardless of their anxiety and/or depression level reduces service use. The Grade quality of evidence is low.
System Costs
Based on the RCT by Howard et al., scanning persons with a score greater than 11 on the High Anxiety and Depression Scale reduces system costs. The Grade quality of evidence is moderate.
Comparative Effectiveness of CT and MRI Scans
There is sparse evidence to determine the relative effectiveness of CT compared with MRI scanning for the detection of intracranial abnormalities. The Grade quality of evidence supporting this is very low.
Economic Analysis
Ontario Perspective
Volumes for neuroimaging of the head i.e. CT and MRI scans, from the Ontario Health Insurance Plan (OHIP) data set were used to investigate trends in the province for Fiscal Years (FY) 2004-2009.
Assumptions were made in order to investigate neuroimaging of the head for the indication of headache. From the literature, 27% of all CT and 13% of all MRI scans for the head were assumed to include an indication of headache. From that same retrospective chart review and personal communication with the author 16% of CT scans and 4% of MRI scans for the head were for the sole indication of headache. From the Ministry of Health and Long-Term Care (MOHLTC) wait times data, 73% of all CT and 93% of all MRI scans in the province, irrespective of indication were outpatient procedures.
The expenditure for each FY reflects the volume for that year and since volumes have increased in the past 6 FYs, the expenditure has also increased with a pay-out reaching 3.0M and 2.8M for CT and MRI services of the head respectively for the indication of headache and a pay-out reaching 1.8M and 0.9M for CT and MRI services of the head respectively for the indication of headache only in FY 08/09.
Cost per Abnormal Finding
The yield of abnormal finding for a CT and MRI scan of the head for the indication of headache only is 2% and 5% respectively. Based on these yield a high-level estimate of the cost per abnormal finding with neuroimaging of the head for headache only can be calculated for each FY. In FY 08/09 there were 37,434 CT and 16,197 MRI scans of the head for headache only. These volumes would generate a yield of abnormal finding of 749 and 910 with a CT scan and MRI scan respectively. The expenditure for FY 08/09 was 1.8M and 0.9M for CT and MRI services respectively. Therefore the cost per abnormal finding would be $2,409 for CT and $957 for MRI. These cost per abnormal finding estimates were limited because they did not factor in comparators or the consequences associated with an abnormal reading or FNs. The estimates only consider the cost of the neuroimaging procedure and the yield of abnormal finding with the respective procedure.
PMCID: PMC3377587  PMID: 23074404
6.  New daily persistent headache 
Annals of Indian Academy of Neurology  2012;15(Suppl 1):S62-S65.
New daily persistent headache (NDPH) is a chronic headache developing in a person who does not have a past history of headaches. The headache begins acutely and reaches its peak within 3 days. It is important to exclude secondary causes, particularly headaches due to alterations in cerebrospinal fluid (CSF) pressure and volume. A significant proportion of NDPH sufferers may have intractable headaches that are refractory to treatment. The condition is best viewed as a syndrome rather than a diagnosis. The headache can mimic chronic migraine and chronic tension-type headache, and it is also important to exclude secondary causes, particularly headaches due to alterations in CSF pressure and volume. A large proportion of NDPH sufferers have migrainous features to their headache and should be managed with treatments used for treating migraine. A small group of NDPH sufferers may have intractable headaches that are refractory to treatment.
doi:10.4103/0972-2327.100011
PMCID: PMC3444222  PMID: 23024565
Chronic daily headache; new daily persistent headache; intractable headache
7.  Psychosocial Correlates and Impact of Chronic Tension-type Headaches 
Headache  2000;40(1):3-16.
Objectives
To examine the psychosocial correlates of chronic tension-type headache and the impact of chronic tension-type headache on work, social functioning, and well-being.
Methods
Two hundred forty-five patients (mean age=37.0 years) with chronic tension-type headache as a primary presenting problem completed an assessment protocol as part of a larger treatment outcome study. The assessment included a structured diagnostic interview, the Medical Outcomes Study Short Form, Disability Days/Impairment Ratings, Recurrent Illness Impact Profile, Beck Depression Inventory, State-Trait Anxiety Inventory—Trait Form, Primary Care Evaluation for Mental Disorders, and the Hassles Scale Short Form. Comparisons were made with matched controls (N=89) and, secondarily, with Medical Outcomes Study data for the general population, arthritis, and back problem samples.
Results
About two thirds of those with chronic tension-type headache recorded daily or near daily (≥25 days per month) headaches with few (12%) recording headaches on less than 20 days per month. Despite the fact that patients reported that their headaches had occurred at approximately the present frequency for an average of 7 years, chronic tension-type headache sufferers were largely lapsed consulters (54% of subjects) or current consulters in primary care (81% of consulters).
Significant impairments in functioning and well-being were evident in chronic tension-type headache and were captured by each of the assessment devices. Although headache-related disability days were reported by 74% of patients (mean=7 days in previous 6 months), work or social functioning was severely impaired in only a small minority of patients. Sleep, energy level, and emotional well-being were frequently impaired with about one third of patients recording impairments in these areas on 10 or more days per month. Most patients with chronic tension-type headache continued to carry out daily life responsibilities when in pain, although role performance at times was clearly impaired by headaches and well-being was frequently impaired.
Chronic tension-type headache sufferers were 3 to 15 times more likely than matched controls to receive a diagnosis of an anxiety or mood disorder with almost half of the patients exhibiting clinically significant levels of anxiety or depression. Affective distress and severity of headaches (Headache Index) were important determinants of headache impact/impairment.
Conclusions
Chronic tension-type headache has a greater impact on individuals' lives than has generally been realized, with affective distress being an important correlate of impairment. If treatment is to remedy impairment in functioning, affective distress, as well as pain, thus needs to be addressed.
PMCID: PMC2128255  PMID: 10759896
chronic tension-type headache; disability; impairment; affective distress
8.  Clinical features of headache patients with fibromyalgia comorbidity 
The Journal of Headache and Pain  2011;12(6):629-638.
Our previous study assessed the prevalence of fibromyalgia (FM) syndrome in migraine and tension-type headache. We aimed to update our previous results, considering a larger cohort of primary headache patients who came for the first time at our tertiary headache ambulatory. A consecutive sample of 1,123 patients was screened. Frequency of FM in the main groups and types of primary headaches; discriminating factor for FM comorbidity derived from headache frequency and duration, age, anxiety, depression, headache disability, allodynia, pericranial tenderness, fatigue, quality of life and sleep, and probability of FM membership in groups; and types of primary headaches were assessed. FM was present in 174 among a total of 889 included patients. It prevailed in the tension-type headache main group (35%, p < 0.0001) and chronic tension-type headache subtype (44.3%, p < 0.0001). Headache frequency, anxiety, pericranial tenderness, poor sleep quality, and physical disability were the best discriminating variables for FM comorbidity, with 81.2% sensitivity. Patients presenting with chronic migraine and chronic tension-type headache had a higher probability of sharing the FM profile (Bonferroni test, p < 0.01). A phenotypic profile where headache frequency concurs with anxiety, sleep disturbance, and pericranial tenderness should be individuated to detect the development of diffuse pain in headache patients.
doi:10.1007/s10194-011-0377-6
PMCID: PMC3208047  PMID: 21847547
Primary headache; Fibromyalgia; Comorbidity
9.  Clinical features of headache patients with fibromyalgia comorbidity 
The Journal of Headache and Pain  2011;12(6):629-638.
Our previous study assessed the prevalence of fibromyalgia (FM) syndrome in migraine and tension-type headache. We aimed to update our previous results, considering a larger cohort of primary headache patients who came for the first time at our tertiary headache ambulatory. A consecutive sample of 1,123 patients was screened. Frequency of FM in the main groups and types of primary headaches; discriminating factor for FM comorbidity derived from headache frequency and duration, age, anxiety, depression, headache disability, allodynia, pericranial tenderness, fatigue, quality of life and sleep, and probability of FM membership in groups; and types of primary headaches were assessed. FM was present in 174 among a total of 889 included patients. It prevailed in the tension-type headache main group (35%, p < 0.0001) and chronic tension-type headache subtype (44.3%, p < 0.0001). Headache frequency, anxiety, pericranial tenderness, poor sleep quality, and physical disability were the best discriminating variables for FM comorbidity, with 81.2% sensitivity. Patients presenting with chronic migraine and chronic tension-type headache had a higher probability of sharing the FM profile (Bonferroni test, p < 0.01). A phenotypic profile where headache frequency concurs with anxiety, sleep disturbance, and pericranial tenderness should be individuated to detect the development of diffuse pain in headache patients.
doi:10.1007/s10194-011-0377-6
PMCID: PMC3208047  PMID: 21847547
Primary headache; Fibromyalgia; Comorbidity
10.  Topo–kinesthetic memory in chronic headaches. A new test for chronic patients: preliminary report 
The Journal of Headache and Pain  2005;6(6):448-454.
The objective of this study was to establish if chronic headaches with medication overuse can modify a topo–kinesthetic memory test. Nineteen patients with medication overuse headache (MOH), 13 patients with chronic tension–type headache (CTTH) without medication use and a group of "normal" subjects underwent a topo–kinesthetic memory test at T0 and after one month (T1); a control group of healthy volunteers was also tested to establish the baseline in our experimental setting. After one month, in the MOH patients there was a reduction of medication overuse from 3.3±2.65 to 1.1±2.23 (p<0.01), but no significant reduction in headache frequency and severity index, quality of life, anxiety and depression scores. The navigation time at T0 was 14.3±4.97, 27.9±10.12, 34.3±15.38 and 7.5±2.33, 10.1±2.95, 11.4±3.21 for control, MOH and CTTH with closed and open eyes, respectively (p<0.02). At T1, the MOH patients reached performances with open eyes similar to the healthy controls, while with closed eyes the navigation test reached times similar to those of CTTH patients. The topokinesthetic memory test seems both able to discriminate MOH and CTTH from healthy volunteers and to be related to pain scores but is not influenced by the use of drugs.
doi:10.1007/s10194-005-0248-0
PMCID: PMC3452299  PMID: 16388339
Topo–kinesthetic test; Chronic tension–type headache; MOH
11.  Concepts leading to the definition of the term cervicogenic headache: a historical overview 
The Journal of Headache and Pain  2005;6(6):462-466.
The idea that headache may originate from a problem at the neck or cervical spine level has fascinated and stimulated researchers for centuries. Contributions and reports seeking to clarify this issue have multiplied in the past 80 or 90 years. Bärtschi–Rochaix reported what seems to have been the first clinical description of cervicogenic headache, but it was not until 1983 that Sjaastad and his school defined diagnostic criteria for this sydrome. The current, revised International Headache Society Classification (ICHD–II) includes the term cervicogenic headache, but the diagnostic criteria it gives differ from those of the International Association for the Study of Pain (IASP), and also from the most recent Cervicogenic Headache International Study Group (CHISG) definition (1998).
doi:10.1007/s10194-005-0250-6
PMCID: PMC3452304  PMID: 16388342
Cervicogenic headache; History of headache; Cervical spine; Anaesthetic blockade
12.  Clinical Efficacy of Radiofrequency Cervical Zygapophyseal Neurotomy in Patients with Chronic Cervicogenic Headache 
Journal of Korean Medical Science  2007;22(2):326-329.
The purpose of the present study was to assess the clinical efficacy of radiofrequency (RF) cervical zygapophyseal joint neurotomy in patients with cervicogenic headache. A total of thirty consecutive patients suffering from chronic cervicogenic headaches for longer than 6 months and showing a pain relief by greater than 50% from diagnostic/prognostic blocks were included in the study. These patients were treated with RF neurotomy of the cervical zygapophyseal joints and were subsequently assessed at 1 week, 1 month, 6 months, and at 12 months following the treatment. The results of this study showed that RF neurotomy of the cervical zygapophyseal joints significantly reduced the headache severity in 22 patients (73.3%) at 12 months after the treatment. In conclusion, RF cervical zygapophyseal joint neurotomy has shown to provide substantial pain relief in patients with chronic cervicogenic headache when carefully selected.
doi:10.3346/jkms.2007.22.2.326
PMCID: PMC2693602  PMID: 17449944
Cervicogenic Headache; Zygapophyseal Joint; Radiofrequency Neurotomy
13.  Functioning styles of personality disorders and five-factor normal personality traits: a correlation study in Chinese students 
BMC Psychiatry  2003;3:11.
Background
Previous studies show that both the categorical and dimensional descriptors of personality disorders are correlated with normal personality traits. Recently, a 92-item inventory, the Parker Personality Measure (PERM) was designed as a more efficient and precise first-level assessment of personality disorders. Whether the PERM constructs are correlated with those of the five-factor models of personality needs to be clarified.
Methods
We therefore invited 913 students from poly-technical schools and colleges in China to answer the PERM, the Five-Factor Nonverbal Personality Questionnaire (FFNPQ), and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ).
Results
Most personality constructs had satisfactory internal alphas. PERM constructs were loaded with FFNPQ and ZKPQ traits clearly on four factors, which can be labelled as Dissocial, Emotional Dysregulation, Inhibition and Compulsivity, as reported previously. FFNPQ Openness to Experience, Conscientiousness and Extraversion formed another Factor, named Experience Hunting, which was not clearly covered by PERM or ZKPQ.
Conclusion
The PERM constructs were loaded in a predictable way on the disordered super-traits, suggesting the PERM might offer assistance measuring personality function in clinical practice.
doi:10.1186/1471-244X-3-11
PMCID: PMC212553  PMID: 13129438
14.  Physical and psychological correlates of primary headache in young adulthood: A 26 year longitudinal study 
Objectives: To determine if physical and/or psychological risk factors could differentiate between subtypes of primary headache (migraine, tension-type headache (TTH), and coexisting migraine and TTH (combined)) among members of a longitudinal birth cohort study.
Methods: At age 26, the headache status of members of the Dunedin Multidisciplinary Health and Development Study (DMHDS) was determined using International Headache Society criteria. Headache history and potential physical and psychological correlates of headache were assessed. These factors included perinatal problems and injuries sustained to age 26; and behavioural, personality, and psychiatric disorders assessed between ages 5 to 21.
Results: The 1 year prevalences for migraine, TTH, and combined headache at the age of 26 were 7.2%, 11.1%, and 4.3%, respectively. Migraine was related to maternal headache, anxiety symptoms in childhood, anxiety disorders during adolescence and young adulthood, and the stress reactivity personality trait at the age of 18. TTH was significantly associated with neck or back injury in childhood (before the age of 13). Combined headache was related to maternal headache and anxiety disorder at 18 and 21 only among women with a childhood history of headache. Headache status at the age of 26 was unrelated to a history of perinatal complication, neurological disorder, or mild traumatic head injury.
Conclusions: Migraine and TTH seem to be distinct disorders with different developmental characteristics. Combined headache may also have a distinct aetiology.
doi:10.1136/jnnp.72.1.86
PMCID: PMC1737678  PMID: 11784831
15.  Genome-wide association study of personality traits in bipolar patients 
Psychiatric genetics  2011;21(4):190-194.
Objective
Genome-wide association study was carried out on personality traits among bipolar patients as possible endophenotypes for gene discovery in bipolar disorder.
Methods
The subscales of Cloninger’s Temperament and Character Inventory (TCI) and the Zuckerman–Kuhlman Personality Questionnaire (ZKPQ) were used as quantitative phenotypes. The genotyping platform was the Affymetrix 6.0 SNP array. The sample consisted of 944 individuals for TCI and 1007 for ZKPQ, all of European ancestry, diagnosed with bipolar disorder by Diagnostic and Statistical Manual of Mental Disorders-IV criteria.
Results
Genome-wide significant association was found for two subscales of the TCI, rs10479334 with the ‘Social Acceptance versus Social Intolerance’ subscale (Bonferroni P = 0.014) in an intergenic region, and rs9419788 with the ‘Spiritual Acceptance versus Rational Materialism’ subscale (Bonferroni P = 0.036) in PLCE1 gene. Although genome-wide significance was not reached for ZKPQ scales, lowest P values pinpointed to genes, RXRG for Sensation Seeking, GRM7 and ITK for Neuroticism Anxiety, and SPTLC3 gene for Aggression Hostility.
Conclusion
After correction for the 25 subscales in TCI and four scales plus two subscales in ZKPQ, phenotype-wide significance was not reached.
doi:10.1097/YPG.0b013e3283457a31
PMCID: PMC3125400  PMID: 21368711
bipolar; genome-wide association study; GRM7; personality; RXRG; Temperament and Character Inventory; Zuckerman–Kuhlman Personality Questionnaire
16.  Chronic daily headaches 
Annals of Indian Academy of Neurology  2012;15(Suppl 1):S40-S50.
Chronic Daily Headache is a descriptive term that includes disorders with headaches on more days than not and affects 4% of the general population. The condition has a debilitating effect on individuals and society through direct cost to healthcare and indirectly to the economy in general. To successfully manage chronic daily headache syndromes it is important to exclude secondary causes with comprehensive history and relevant investigations; identify risk factors that predict its development and recognise its sub-types to appropriately manage the condition. Chronic migraine, chronic tension-type headache, new daily persistent headache and medication overuse headache accounts for the vast majority of chronic daily headaches. The scope of this article is to review the primary headache disorders. Secondary headaches are not discussed except medication overuse headache that often accompanies primary headache disorders. The article critically reviews the literature on the current understanding of daily headache disorders focusing in particular on recent developments in the treatment of frequent headaches.
doi:10.4103/0972-2327.100002
PMCID: PMC3444216  PMID: 23024563
Chronic daily headache; chronic migraine; chronic tension type headache; hemicrania continua; new daily persistent headache
17.  A CASE STUDY OF CHRONIC HEADACHES 
The following paper is a case study of a patient with a history of chronic headaches (originally diagnosed as migraine without aura) who was being treaded at the Macquarie University Chiropractic Outpatients Clinic for cervical spine dysfunction. The treatments successfully reduced the upper neck and thoracic pain that the patient was experiencing and for which they had initially presented at the clinic. During the treatments, the patient also showed a significant subjective reduction in prevalence and intensity of headaches over a four month period. Analysis of the outcome is complicated by the fact that it is not clear whether the patient’s headaches were initially misdiagnosed as common migraine when in fact, they were cervicogenic. There may be some overlap between the two conditions, and a possible causative relationship between cervical spine dysfunction and common migraine. Furthermore, this case study discusses the validity of chiropractic treatment of organic disorders such as chronic headache or migraine.
PMCID: PMC2050613  PMID: 17987139
Chiropractic; headache.
18.  Magnetic resonance imaging of craniovertebral structures: clinical significance in cervicogenic headaches 
This paper aims to investigate the relevance of morphological changes in the main stabilizing structures of the craniocervical junction in persons with cervicogenic headache (CEH). A case control study of 46 consecutive persons with CEH, 22 consecutive with headache attributed to whiplash associated headache (WLaH) and 19 consecutive persons with migraine. The criteria of the Cervicogenic Headache International Study Group (CHISG) were used for diagnosing CEH; otherwise the criteria of the International Classification of Headache Disorders (ICHD II) were applied. All participants had a clinical interview, and physical and neurological examination. Proton weighted magnetic resonance imaging (MRI) of the craniovertebral junction, and the alar and transverse ligaments were evaluated and blinded to clinical information. The MRI of the craniovertebral and the cervical junctions, the alar and transverse ligaments disclosed no significant differences between those with CEH, WLaH and or migraine. The site of CEH pain was not correlated with the site of signal intensity changes of the alar and transverse ligaments. In fact, very few had moderate or severe signal intensity changes in their ligaments. MRI shows no specific changes of cervical discs or craniovertebral ligaments in CEH.
doi:10.1007/s10194-011-0387-4
PMCID: PMC3253147  PMID: 21947945
Cervicogenic headache; Alar ligaments; Transverse ligaments; Craniovertebral junction; Cervical junction; MRI
19.  Magnetic resonance imaging of craniovertebral structures: clinical significance in cervicogenic headaches 
This paper aims to investigate the relevance of morphological changes in the main stabilizing structures of the craniocervical junction in persons with cervicogenic headache (CEH). A case control study of 46 consecutive persons with CEH, 22 consecutive with headache attributed to whiplash associated headache (WLaH) and 19 consecutive persons with migraine. The criteria of the Cervicogenic Headache International Study Group (CHISG) were used for diagnosing CEH; otherwise the criteria of the International Classification of Headache Disorders (ICHD II) were applied. All participants had a clinical interview, and physical and neurological examination. Proton weighted magnetic resonance imaging (MRI) of the craniovertebral junction, and the alar and transverse ligaments were evaluated and blinded to clinical information. The MRI of the craniovertebral and the cervical junctions, the alar and transverse ligaments disclosed no significant differences between those with CEH, WLaH and or migraine. The site of CEH pain was not correlated with the site of signal intensity changes of the alar and transverse ligaments. In fact, very few had moderate or severe signal intensity changes in their ligaments. MRI shows no specific changes of cervical discs or craniovertebral ligaments in CEH.
doi:10.1007/s10194-011-0387-4
PMCID: PMC3253147  PMID: 21947945
Cervicogenic headache; Alar ligaments; Transverse ligaments; Craniovertebral junction; Cervical junction; MRI
20.  Primary headaches in patients with generalized anxiety disorder 
The Journal of Headache and Pain  2011;12-12(3):331-338.
Although anxiety disorders and headaches are comorbid conditions, there have been no studies evaluating the prevalence of primary headaches in patients with generalized anxiety disorder (GAD). The aim of this study was to analyze the lifetime prevalence of primary headaches in individuals with and without GAD. A total of 60 individuals were evaluated: 30 GAD patients and 30 controls without mental disorders. Psychiatric assessments and primary headache diagnoses were made using structured interviews. Among the GAD patients, the most common diagnosis was migraine, which was significantly more prevalent among the GAD patients than among the controls, as were episodic migraine, chronic daily headache and aura. Tension-type headache was equally common in both groups. Primary headaches in general were significantly more common and more severe in GAD patients than in controls. In anxiety disorder patients, particularly those with GAD, accurate diagnosis of primary headache can improve patient management and clinical outcomes.
doi:10.1007/s10194-010-0290-4
PMCID: PMC3094648  PMID: 21298316
Migraine; Anxiety disorders; Generalized anxiety disorder; Comorbidity
21.  Primary headaches in patients with generalized anxiety disorder 
The Journal of Headache and Pain  2011;12(3):331-338.
Although anxiety disorders and headaches are comorbid conditions, there have been no studies evaluating the prevalence of primary headaches in patients with generalized anxiety disorder (GAD). The aim of this study was to analyze the lifetime prevalence of primary headaches in individuals with and without GAD. A total of 60 individuals were evaluated: 30 GAD patients and 30 controls without mental disorders. Psychiatric assessments and primary headache diagnoses were made using structured interviews. Among the GAD patients, the most common diagnosis was migraine, which was significantly more prevalent among the GAD patients than among the controls, as were episodic migraine, chronic daily headache and aura. Tension-type headache was equally common in both groups. Primary headaches in general were significantly more common and more severe in GAD patients than in controls. In anxiety disorder patients, particularly those with GAD, accurate diagnosis of primary headache can improve patient management and clinical outcomes.
doi:10.1007/s10194-010-0290-4
PMCID: PMC3094648  PMID: 21298316
Migraine; Anxiety disorders; Generalized anxiety disorder; Comorbidity
22.  The validity of questionnaire-based diagnoses: the third Nord-Trøndelag Health Study 2006–2008 
The Nord-Trøndelag Health Study (HUNT 3) performed in 2006–2008 is a replication of the cross-sectional survey from 1995 to 1997 (HUNT 2). The aim of the present study was to assess the sensitivity and specificity of questionnaire-based headache diagnoses using a personal interview by a neurologist as a gold standard. For the questionnaire-based status as headache sufferer, a sensitivity of 88%, a specificity of 86%, and a kappa statistic of 0.70 were found. Chronic headache, chronic tension-type headache (TTH), and medication overuse headache (MOH) were diagnosed with a specificity of ≥99%, and a kappa statistic of ≥0.73. Lower figures were found for the diagnoses of migraine and TTH. For individuals with headache ≥1 day per month, a sensitivity of 58% (migraine) and 96% (TTH), a specificity of 91 and 69%, and a kappa statistic of 0.54 and 0.44 were found, respectively. The specificity for migraine with aura was 95%. In conclusion, the HUNT 3-questionnaire is a valid tool for identifying headache sufferers, and diagnosing patients with chronic headache, including chronic TTH and MOH. The more moderate sensitivity for migraine and TTH makes the questionnaire-based diagnoses of migraine and TTH suboptimal for determining the prevalence. However, the high specificity of the questionnaire-based diagnosis of migraine, in particular for migraine with aura, makes the questionnaire a valid tool for diagnosing patients with migraine for genetic studies.
doi:10.1007/s10194-009-0174-7
PMCID: PMC3452179  PMID: 19946790
Headache; Migraine; Questionnaire; Survey; Population
23.  Diagnosing cervicogenic headache 
The Journal of Headache and Pain  2006;7(3):145-148.
The notion that disorders of the cervical spine can cause headache is more than a century old, yet there is still a great deal of debate about cervicogenic headache (CEH) in terms of its underlying mechanisms, its signs and symptoms, and the most appropriate treatments for it. CEH is typically a unilateral headache that can be provoked by neck movement, awkward head positions or pressure on tender points in the neck. The headaches can last hours or days, and the pain is usually described as either dull or piercing. Convergence of the upper cervical roots on the nucleus caudalis of the trigeminal tract is the most commonly accepted neurophysiological explanation for CEH. In most cases, CEH is caused by pathology in the upper aspect of the cervical spine, but the type and exact location of the pathology varies substantially among individual cases.
Anaesthetic blocks may be necessary to confirm the diagnosis of CEH, showing that the source of pain is in the neck. Differential diagnosis is sometimes a challenge because CEH can be mistaken for other forms of unilateral headache, especially unilateral migraine without aura.
Neuroimaging and kinematic analysis of neck motion may aid in diagnosing difficult CEH.
doi:10.1007/s10194-006-0277-3
PMCID: PMC3451567  PMID: 16575502
Cervicogenic headache; Neck pain; Headache
24.  Classification and clinical features of headache patients: an outpatient clinic study from China 
The Journal of Headache and Pain  2011;12(5):561-567.
This study aimed to analyze and classify the clinical features of headache in neurological outpatients. A cross-sectional study was conducted consecutively from March to May 2010 for headache among general neurological outpatients attending the First Affiliated Hospital of Chongqing Medical University. Personal interviews were carried out and a questionnaire was used to collect medical records. Diagnosis of headache was according to the International classification of headache disorders, 2nd edition (ICHD-II). Headache patients accounted for 19.5% of the general neurology clinic outpatients. A total of 843 (50.1%) patients were defined as having primary headache, 454 (27%) secondary headache, and 386 (23%) headache not otherwise specified (headache NOS). For primary headache, 401 (23.8%) had migraine, 399 (23.7%) tension-type headache (TTH), 8 (0.5%) cluster headache and 35 (2.1%) other headache types. Overall, migraine patients suffered (1) more severe headache intensity, (2) longer than 6 years of headache history and (3) more common analgesic medications use than TTH ones (p < 0.001).TTH patients had more frequent episodes of headaches than migraine patients, and typically headache frequency exceeded 15 days/month (p < 0.001); 22.8% of primary headache patients were defined as chronic daily headache. Almost 20% of outpatient visits to the general neurology department were of headache patients, predominantly primary headache of migraine and TTH. In outpatient headaches, more attention should be given to headache intensity and duration of headache history for migraine patients, while more attention to headache frequency should be given for the TTH ones.
doi:10.1007/s10194-011-0360-2
PMCID: PMC3173628  PMID: 21744226
Outpatient; Headache; Cross-sectional study; Clinical feature; Migraine
25.  Classification and clinical features of headache patients: an outpatient clinic study from China 
The Journal of Headache and Pain  2011;12(5):561-567.
This study aimed to analyze and classify the clinical features of headache in neurological outpatients. A cross-sectional study was conducted consecutively from March to May 2010 for headache among general neurological outpatients attending the First Affiliated Hospital of Chongqing Medical University. Personal interviews were carried out and a questionnaire was used to collect medical records. Diagnosis of headache was according to the International classification of headache disorders, 2nd edition (ICHD-II). Headache patients accounted for 19.5% of the general neurology clinic outpatients. A total of 843 (50.1%) patients were defined as having primary headache, 454 (27%) secondary headache, and 386 (23%) headache not otherwise specified (headache NOS). For primary headache, 401 (23.8%) had migraine, 399 (23.7%) tension-type headache (TTH), 8 (0.5%) cluster headache and 35 (2.1%) other headache types. Overall, migraine patients suffered (1) more severe headache intensity, (2) longer than 6 years of headache history and (3) more common analgesic medications use than TTH ones (p < 0.001).TTH patients had more frequent episodes of headaches than migraine patients, and typically headache frequency exceeded 15 days/month (p < 0.001); 22.8% of primary headache patients were defined as chronic daily headache. Almost 20% of outpatient visits to the general neurology department were of headache patients, predominantly primary headache of migraine and TTH. In outpatient headaches, more attention should be given to headache intensity and duration of headache history for migraine patients, while more attention to headache frequency should be given for the TTH ones.
doi:10.1007/s10194-011-0360-2
PMCID: PMC3173628  PMID: 21744226
Outpatient; Headache; Cross-sectional study; Clinical feature; Migraine

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