Anticonvulsants in migraine prophylaxis: a Cochrane review.

Several trials have asserted that some anticonvulsant drugs seem to be useful for the prophylaxis of migraine, but systematic reviews are sparse. We independently searched PubMed, EMBASE and the Cochrane Central Register of Controlled Trials until 2005, as well as Headache and Cephalalgia through April 2006, for prospective, controlled trials of anticonvulsant drugs. Data were calculated and pooled across studies and expressed as standardized mean differences, odds ratios and numbers-needed-to-treat. Anticonvulsants, considered as a class, reduce migraine frequency by about 1.3 attacks per 28 days compared with placebo, and more than double the number of patients for whom migraine frequency is reduced by > or = 50% relative to placebo. Sodium valproate/divalproex sodium and topiramate were better than placebo, whereas acetazolamide, clonazepam, lamotrigine and vigabatrin were not; gabapentin, in particular, needs further evaluation. Trials designed with sufficient power to compare different drugs are also necessary.

Objective assessment of cortical excitability in migraine with and without aura.

Recent progress in the genetics of migraine has refocused attention on cortical dysfunction as an important component of the pathophysiology of this disorder. In previous work, we have demonstrated functional changes in the visual cortex of migraine patients, using an objective transcranial magnetic stimulation technique, termed magnetic suppression of perceptual accuracy (MSPA). This study aimed to replicate previous findings in migraine with aura (MA) and to use the technique to examine migraine without aura (MoA). Eight MA patients, 14 MoA patients and 13 migraine-free controls participated. MSPA assessments were undertaken using a standardized protocol in which computer-presented letter targets were followed at a variable delay interval by a single magnetic pulse delivered over the occiput. MSPA performance is expressed as a profile of response accuracy across target-pulse delay intervals. The profiles of migraine-free controls exhibited a normal U-shape. MA patients had significantly shallower profiles, showing little or no suppression at intermediate delay intervals. MoA patients had profiles that were similar to controls. Recent animal evidence strongly indicates that the U-shape of the normal MSPA function is caused by preferential activation of inhibitory neurons. Shallower MPSA profiles in MA patients are therefore likely to indicate a functional hyperexcitability caused by impaired inhibition. The finding of normal MPSA profiles in MoA patients is novel and will require further investigation.

Cognitive function is not impaired in people with a long history of migraine: a blinded study.

Little is known about the long-term consequences of migraine for cognitive functioning. This study compared older migraine patients with matched controls on four measures of cognitive ability, in a blinded design. Migraine patients and case-matched controls were recruited from the database records of a pre-existing study of ageing. Data were available from four tests of cognitive ability: verbal/arithmetic problem solving, spatial problem solving, processing speed, and vocabulary. There were no significant differences between the mean scores of migraine and control groups on any of the four cognitive tests. In addition, there were no significant differences between migraine and control groups in the effect of age on any of the four tests. A long history of migraine does not compromise scores on the four cognitive tests used in this study. These tests are predictive of memory and executive functioning in cognitive ageing, but it remains possible that lower-level cognitive processes, particularly as assessed by visual tasks, may be vulnerable to migraine.

A computational perspective on migraine aura.

The classical visual aura of migraine is characterized by a unilateral hallucination, composed of a zigzag fortification pattern followed by a trailing scotoma. This pattern usually starts in central vision, expands and spreads to the periphery, and then disappears. We review a number of historical attempts to explain the migraine aura in terms of brain events, then summarize recent theories of the pathophysiology of the aura. We describe an approach to the computational modeling of migraine aura, based on the principles of (a) cortical organization, and (b) active wave propagation in an excitable medium. We demonstrate correspondences between properties of the model system and aspects of the pathophysiology of the aura. The simulations produced by the model are in agreement with descriptions and drawings of visual aura from migraine patients. We outline several testable predictions stemming from the implementation of the model, and explain how model-based empirical research has the capacity to (a) improve recording of the phenomena of the visual aura, (b) improve understanding of the spatio-temporal dynamics of other types of aura, in particular somatosensory and dysphasic aurae, and (c) clarify the theoretical requirements for the initiation of aura in the brain.

Visual cortex excitability in migraine before and after valproate prophylaxis: a pilot study using TMS.

We examined the effect of standard migraine prophylaxis with sodium valproate on repeated measures of occipital excitability using transcranial magnetic stimulation (TMS). We predicted that, comparing pre- and post-treatment assessments, a reduction in clinical migraine parameters would be paralleled by a decrease in excitability measurements.A total of 31 migraine patients enrolled in the study, for assessment prior to and 1 month after commencement of sodium valproate prophylaxis. At each assessment, we used a standardized protocol to stimulate the occipital cortex with a 90-mm circular (coil A) and 70 mm figure-of-eight (coil B) coil. We recorded the threshold stimulation intensity at which subjects just perceived phosphenes. Subjects kept detailed records of headache parameters 1 month before and also during the study period. Valproate therapy significantly improved headache indexes, as expected. In MA subjects assessed with coil B, phosphene thresholds were significantly higher post-treatment than pre-treatment, but those for MO did not change. Modest correlations were observed in MA patients between increase in phosphene threshold and decrease in headache index. Although preliminary, the findings with coil B lend some support to the notion that effective migraine prophylaxis may be achieved through lowering cortical excitability by gamma-aminobutyric acid (GABA)-ergic intervention. Further investigation of the effect of sodium valproate or other similarly acting substances on cortical excitability in migraine is warranted.

When insight just won't come: the failure of visual cues in the nine-dot problem.

The nine-dot problem is a classic in the field of human problem solving. Cognitive accounts of the problem's difficulty have been criticized on the grounds that the experimental methods on which they rely for support involve a qualitative change to the task requirements of the problem. The three experiments reported here utilize visual and visual-procedural hints to examine the notion that its difficulty is rooted in a mismatch between problem shape and solution shape. Experiment 1 demonstrated that a perceptual cue to the shape of the solution in the form of shading gave rise to only minimal improvements in performance; an additional hint about the relevance of the shading gave rise to modest, but not statistically significant, improvements. Experiment 2 replicated these findings against an additional control condition in which a solely verbal hint to violate the perceptual boundary of the problem shape was given. Furthermore, when both the verbal and visual hints were provided, performance improved only slightly. Experiment 3 provided participants with experience in producing the shape of the correct solution in problem variants closely related to the nine-dot problem. Performance on the transfer task, the basic nine-dot problem, remained at floor, however. These data suggest that visual constraint relaxation is unlikely to be the sole process by which the insight required to find a solution is achieved. The results are interpreted in terms of a previously proposed computational model of performance.

Visual cortex excitability in migraine with and without aura.

OBJECTIVES: Previous research using transcranial magnetic stimulation has produced equivocal findings concerning thresholds for the generation of visual phosphenes in migraine with aura. These studies were methodologically varied and did not systematically address cortical excitability in migraine without aura. We therefore studied magnetophosphene thresholds in both migraine with aura and migraine without aura compared with headache-free controls. METHODS: Sixteen subjects with migraine with aura and 12 subjects with migraine without aura were studied and compared with 16 sex- and age-matched controls. Using a standardized transcranial magnetic stimulation protocol of the occipital cortex, we assessed the threshold stimulation intensity at which subjects just perceived phosphenes via a method of alternating course and fine-tuning of stimulator output. RESULTS: There were no significant differences across groups in the proportion of subjects seeing phosphenes. However, the mean threshold at which phosphenes were reported was significantly lower in both migraine groups (migraine with aura=47%, migraine without aura=46%) than in controls (66%). Moreover, there was no significant correlation between individual phosphene threshold and the time interval to the closest migraine attack. CONCLUSION: Our findings confirm that the occipital cortex is hyperexcitable in the migraine interictum, both in migraine with and without aura.

Suppression of perception in migraine: evidence for reduced inhibition in the visual cortex.

BACKGROUND: Results from transcranial magnetic stimulation (TMS) studies of visual cortex have confirmed visual cortical hyperexcitability in patients with migraine. It has been speculated that this may be due to deficient intracortical inhibitory tone. However, the TMS induction of phosphenes relies on the reporting of a subjective experience, and may thus be subject to bias. METHODS: Seven migraineurs with visual aura and seven sex- and age-matched controls were studied. Fifty-four different three-letter combinations were briefly displayed and followed by a magnetic pulse at 40, 70, 100, 130, 160, and 190 msec. Subjects were required to report as many letters as they thought they had recognized. RESULTS: In the migraine group, the mean proportion of correctly identified letters was significantly higher at 100 msec, as was the proportion of trials with two or three letters correctly reported. The time window in which perceptual suppression could be introduced was narrower in migraineurs compared to controls. CONCLUSION: These findings suggest that inhibitory systems are activated to a lesser extent by TMS pulses in patients. This observation is in agreement with the hypothesized deficiency of intracortical inhibition of the visual cortex, at least in migraineurs with aura.

Information processing and insight: a process model of performance on the nine-dot and related problems.

The 9-dot problem is widely regarded as a difficult insight problem. The authors present a detailed information-processing model to explain its difficulty, based on maximization and progress-monitoring heuristics with lookahead. In Experiments 1 and 2, the model predicted performance for the 9-dot and related problems. Experiment 3 supported an extension of the model that accounts for insightful moves. Experiments 4 and 5 provided a critical test of model predictions versus those of previous accounts. On the basis of these findings, the authors claim that insight problem solving can be modeled within a means-ends analysis framework. Maximization and progress-monitoring heuristics are the source of problem difficulty, but also create the conditions necessary for insightful moves to be sought. Furthermore, they promote the discovery and retention of promising states that meet the progress-monitoring criterion and attenuate the problem space.

Why do we still not know whether refractive error causes headaches? Towards a framework for evidence based practice.

In this paper, we systematically review the available experimental and clinical evidence concerning the causation of headache by refractive error. Despite the apparent belief of both medical and optometric professionals that provision of an appropriate correction may alleviate various types of headache, there is little if any robust evidence in support of this position. We identify four serious methodological and theoretical difficulties with studies to date, which currently render it impossible to assess the relationship between refractive error and headache. The provision by the International Headache Society of the diagnostic category "headache associated with refractive error" is called into question. Five research questions are posited in the form of a framework for the development of evidence-based practice in optometry and the treatment of headache.

Self-reported photophobic symptoms in migraineurs and controls are reliable and predict diagnostic category accurately.

OBJECTIVES: To assess the reliability of self-reported photophobia across different patient populations and to examine how visual stress thresholds and photophobic symptoms may be predictive of diagnosis. BACKGROUND: Relatively little is known about interictal photophobia in migraine. In particular, the variability of photophobia across different patient groups has not previously been studied, and a pathophysiological hypothesis to account for the symptoms is not agreed upon. METHODS AND RESULTS: Study 1 compared 99 self-selected Dutch patients and 101 headache-free controls using survey methods. Patients both with and without aura were significantly more likely to report symptoms, such as the wearing of sunglasses in normal daylight, consistent with interictal photophobia. Study 2 replicated these findings in a series of consecutive referrals to a headache clinic in the United States. Study 3 used a specially designed laboratory test to examine the threshold for visual stress in those patients who had participated in study 2. Visual stress thresholds were significantly lower in patients than in controls. A discriminant function analysis of data from both studies 2 and 3 showed that diagnostic category (migraine; control) could be predicted from photophobic symptoms and visual stress thresholds at a level significantly better than chance. CONCLUSIONS: We suggest that interictal photophobia is common in migraine and similar across different patient populations. One pathophysiological hypothesis is that interictal photophobia is associated with cortical hypersensitivity to stimulation. The predictive validity of interictal photophobic symptoms suggests that clinical diagnosis may be aided by questioning the patient about light sensitivity in the period between attacks.

A model of human performance on the traveling salesperson problem.

A computational model is proposed of how humans solve the traveling salesperson problem (TSP). Tests of the model are reported, using human performance measures from a variety of 10-, 20-, 40-, and 60-node problems, a single 48-node problem, and a single 100-node problem. The model provided a range of solutions that approximated the range of human solutions and conformed closely to quantitative and qualitative characteristics of human performance. The minimum path lengths of subjects and model deviated by average absolute values of 0.0%, 0.9%, 2.4%, 1.4%, 3.5%, and 0.02% for the 10-, 20-, 40-, 48-, 60-, and 100-node problems, respectively. Because the model produces a range of solutions, rather than a single solution, it may find better solutions than some conventional heuristic algorithms for solving TSPs, and comparative results are reported that support this suggestion.

Cortical hyperexcitability is cortical under-inhibition: evidence from a novel functional test of migraine patients.

Recent studies of the visual cortex in patients with migraine have generally concluded that migraine (particularly migraine with aura) is associated with a state of functional cortical hyperexcitability. The mechanisms giving rise to this hyperexcitability have hitherto been unclear. This paper reports two studies that used a novel investigative technique, derived from basic research in vision science, to examine specific deficits of inhibitory processing in primary visual cortex. The technique is termed the metacontrast test, and it examines visual masking under highly specified conditions. In Study 1, 12 migraine with aura patients (MA), 12 age-matched migraine without aura patients (MO) and 12 age- and sex-matched headache-free control subjects (C) were compared using the metacontrast test. MA patients were significantly less susceptible to visual masking in the metacontrast test than both MO and C groups: this result is highly consistent with a deficit in cortical inhibitory processing in MA patients. Study 2 examined MA patients taking a variety of migraine prophylactics, again using the metacontrast test. Test results normalized in those MA patients taking sodium valproate, but not in those taking other prophylactics. Sodium valproate is a GABA-A agonist that is known to cross the blood-brain barrier: GABA-ergic networks act as the primary inhibitory mechanism in visual cortex. Taken together, the results of these studies argue that cortical hyperexcitability, at least in MA patients, is likely to be a result of deficient intracortical inhibitory processes.

Global perceptual processing in problem solving: the case of the traveling salesperson.

The traveling salesperson problem (TSP) consists of finding the shortest tour around a set of locations and is an important task in computer science and operations research. In four experiments, the relationship between processes implicated in the recognition of good figures and the identification of TSP solutions was investigated. In Experiment 1, a linear relationship was found between participants' judgments of good figure and the optimality of solutions to TSPs. In Experiment 2, identification performance was shown to be a function of solution optimality and problem orientation. Experiment 3 replicated these findings with a forced-pace method, suggesting that global processing, rather than a local processing strategy involving point-by-point analysis of TSP solutions, is the primary process involved in the derivation of best figures for the presented TSPs. In Experiment 4, the role of global precedence was confirmed using a priming method, in which it was found that short (100 msec) primes facilitated solution identification, relative to no prime or longer primes. Effects of problem type were found in all the experiments, suggesting that local features of some problems may disrupt global processing. The results are discussed in terms of Sanocki's (1993) global-to-local contingency model. We argue that global perceptual processing may contribute more generally to problem solving and that human performance can complement computational TSP methods.

Spatial and contextual factors in human performance on the travelling salesperson problem.

The travelling salesperson problem (TSP) provides a realistic and practical example of a visuo-spatial problem-solving task. In previous research, we have found that the quality of solutions produced by human participants for small TSPs compares well with solutions from a range of computer algorithms. We have proposed that the ability of participants to find solutions reflects the natural properties of human perception, solutions being found through global perceptual processing of the problem array to extract a best figure from the TSP points. In this paper, we extend the study of human performance on the task in order to understand further how human abilities are utilised in solving real-world TSPs. The results of experiment 1 show that high levels of solution quality are maintained in solving larger TSPs than had been investigated previously with human participants, and that the presence of an implied real-world context in the problems has no effect upon performance. Experiment 2 demonstrated that the presence of regularity in the point layout of a TSP can facilitate performance. This was confirmed in experiment 3, where effects of the internality of point clusters were also found. All three experiments were consistent with a global, perceptually based approach to the problem by participants. We suggest that the role of perceptual processing in spatial problem-solving is an important area for further research in both theoretical and applied domains.

Cognitive processing in migraine: a failure to find facilitation in patients with aura.

Recent interest in cognitive processing in migraine has been based on the assumption that cortical hyperexcitability in migraine with aura may manifest itself in the form of response time advantages in migraine as compared to controls. The study reported here attempted to replicate and extend the findings of Wray and colleagues (Brain 1995;118: 25-35). Using identical cognitive tasks, three experiments failed to find differences between migraine with aura patients and controls: furthermore, an additional group of patients without aura were also statistically indistinguishable from controls with respect to response times. Error rates were consistently high across experiments, indicating that subjects were responding at or near chance levels. These findings cast doubt on the utility of straightforward cognitive psychological methods for the study of cortical hyperexcitability in migraine. Some theoretical difficulties concerning the interpretation of response times in the context of migraine pathophysiology are discussed.

Visual system dysfunction in migraine: a review of clinical and psychophysical findings.

This paper reviews both clinical and experimental literature relating to visual dysfunction in migraine, starting with the eye and progressing via the retina and visual pathways to the visual cortex. Migraine is associated with (i) a pupillary sympathetic hypofunction, and (ii) a cortical hypersensitivity to visual stimuli (perhaps only in migraine with aura), the pathogenesis of which remains to be determined. Various hypotheses are discussed, and it is proposed that the methods of visual psychophysics may represent a useful approach in the future study of cortical hyperexcitability in migraine. Paradoxically, little research has been directed towards understanding (i) the photophobia of migraine attacks, and (ii) how migraine may be triggered by visual stimuli. Research aimed at elucidating the mechanisms of these phenomena may enhance understanding of the pathogenesis of migraine.

Thresholds for detection of a target against a background grating suggest visual dysfunction in migraine with aura but not migraine without aura.

Square-wave gratings with particular spatial characteristics induce visual illusions. Patients with migraine are particularly susceptible to these illusions and report discomfort. Their discomfort tends to be greater when the gratings are illuminated by red light, a tendency not shown by controls. Gratings that induce illusions have been found to impair the recognition of optically superimposed targets in headache-free control subjects. We measured the impairment of target detection under illuminants of various chromaticities in migraineurs with and without aura and in matched controls. Migraineurs with aura had significantly higher thresholds for target detection than either migraineurs without aura or controls; in addition, the effect of chromaticity was slightly more pronounced in both migraine groups than in the control group. These findings are consistent with a recent suggestion that migraine with aura might give rise to subclinical damage to the primary visual cortex.