The three dimensions of headache impact: pain, disability and affective distress

It is increasingly recognized that pain measures alone provide incomplete information about the impact of pain on functioning or quality-of-life. A wide range of measures that promise to provide additional information about the impact of pain on people's lives are thus coming into use. In order to clarify the construct of headache impact, we attempted to identify the dimensions assessed by a set of 22 headache-impact measures and to identify the specific measures that best assessed each of these headache-impact dimensions. Adults (n=329) with frequent benign headache disorders completed a comprehensive assessment battery that included 22 headache-impact measures. Factor analysis was then used to identify dimensions underlying the headache-impact measures. Three factors labeled Affective Distress, Pain Density and Disability best accounted for correlations among headache-impact measures. Interfactor correlations ranged between 0.37 and 0.20, suggesting three correlated but separable impact dimensions. These results suggest the construct of headache impact needs to be broadened beyond pain and disability to include affective distress. An adequate assessment of the impact of recurrent headache disorders in clinical trials and other research may require measures from all three of the headache-impact dimensions identified here.     

Responsibility modulates neural mechanisms of outcome processing: an ERP study

The role of personal responsibility in decision-making and its influence on the outcome evaluation process have been investigated relatively rarely in cognitive neuroscience. The present event-related brain potential (ERP) study manipulated the subjective sense of responsibility by modifying outcome controllability in a gambling task. Participants reported a higher sense of responsibility and produced a larger fERN when they were told that the game was 'controllable' compared with when they were told that the game was 'uncontrollable.' In addition, fERN amplitude was correlated with individual self-reports of personal responsibility over the outcomes. These results indicate that self-attribution of responsibility associated with different degrees of controllability affects the outcome evaluation process and fERN amplitude.     

Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease

Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease. Classical Menkes disease is an X‐linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1‐q21. ATP7A encodes a copper‐transporting P‐type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X‐autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three‐generation family in which a severe ATP7A mutation, a 5.5‐kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long‐range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at‐risk females in the family for this junction fragment and analyzed their X‐inactivation patterns using the human androgen‐receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at‐risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X‐inactivation was observed in all non‐carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X‐inactivation patterns in female carriers of other X‐linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A‐related distal motor neuropathy.     

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

Electrophysiological measures of conflict and reward processing are associated with decisions to engage in physical effort

Anterior cingulate cortex (ACC), a key brain region involved in cognitive control and decision making, is suggested to mediate effort- and value-based decision making, but the specific role of ACC in this process remains debated. Here we used frontal midline theta (FMT) and the reward positivity (RewP) to examine ACC function in a value-based decision making task requiring physical effort. We investigated whether (1) FMT power is sensitive to the difficulty of the decision or to selecting effortful actions, and (2) RewP is sensitive to the subjective value of reward outcomes as a function of effort investment. On each trial, participants chose to execute a low-effort or a high-effort behavior (that required squeezing a hand-dynamometer) to obtain smaller or larger rewards, respectively, while their brainwaves were recorded. We replicated prior findings that tonic FMT increased over the course of the hour-long task, which suggests increased application of control in the face of growing fatigue. RewP amplitude also increased following execution of high-effort compared to low-effort behavior, consistent with increased valuation of reward outcomes by ACC. Although neither phasic nor tonic FMT were associated with decision difficulty or effort selection per se, an exploratory analysis revealed that the interaction of phasic FMT and expected value of choice predicted effort choice. This interaction suggests that phasic FMT increases specifically under situations of decision difficulty when participants ultimately select a high-effort choice. These results point to a unique role for ACC in motivating and persisting at effortful behavior when decision conflict is high.     

To tell or not to tell – what to do about p.C282Y heterozygotes identified by HFE screening

Hereditary hemochromatosis (HH) is a common preventable disorder of iron overload that can result in liver cirrhosis and reduced lifespan. Most HH is due to homozygosity for the HFE p.C282Y substitution. We conducted a study of screening for p.C282Y in high schools where p.C282Y heterozygotes (CY) individuals were informed of their genotype by letter. We studied whether these individuals understood the implications of their genotype, whether this resulted in anxiety or reduced health perception and whether cascade testing was higher in families of CY than wild‐type homozygous (CC) individuals. We found 586 of 5757 (1 in 10) screened individuals were CY. One month after receiving their result, 83% correctly answered that they have one copy of p.C282Y. There was no adverse change in anxiety or health perception from prior to screening to 1 month after receiving results. Significantly more family members of CY individuals than CC individuals were informed about HH and had testing for HH. In conclusion, we found that informing CY individuals of their genotype does not increase anxiety and the implications are generally well understood. This leads to cascade testing in a minority of families. CY individuals should be informed of their genetic status when identified by population screening.