Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE).

OBJECTIVE: To evaluate the safety and efficacy of cholecalciferol in patients with relapsing-remitting MS (RRMS). METHODS: In this double-blind, placebo-controlled parallel-group, 2-year study, 181 patients with RRMS were randomized 1:1. Key inclusion criteria were a low serum 25-hydroxy vitamin D (25OHD) concentration (<75 nmol/L), a treatment with interferon beta-1a 44 µg (SC 3 times per week) 4 months ± 2 months before randomization, and at least one documented relapse during the previous 2 years. Patients received high-dose oral cholecalciferol 100,000 IU or placebo every other week for 96 weeks. Primary outcome measure was the change in the annualized relapse rate (ARR) at 96 weeks. Secondary objectives included safety and tolerability of cholecalciferol and efficacy assessments (ARR, MRI parameters, and Expanded Disability Status Scale [EDSS]). RESULTS: The primary end point was not met. In patients who completed the 2-year follow-up (45 with cholecalciferol and 45 with placebo), all efficacy parameters favored cholecalciferol with an ARR reduction (p = 0.012), less new hypointense T1-weighted lesions (p = 0.025), a lower volume of hypointense T1-weighted lesions (p = 0.031), and a lower progression of EDSS (p = 0.026). The overall rate of adverse events was well balanced between groups. CONCLUSIONS: Although the primary end point was not met, these data suggest a potential treatment effect of cholecalciferol in patients with RRMS already treated with interferon beta-1a and low serum 25OHD concentration. Together with the good safety profile, these data support the exploration of cholecalciferol treatment in such patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01198132. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and low serum 25OHD, cholecalciferol did not significantly affect ARRs.

Five-year outcome in the copaxone observatory: a nationwide cohort of patients with multiple sclerosis starting treatment with glatiramer acetate in France.

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing-remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator's normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39-0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9-47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials.

Vitamin D and multiple sclerosis: An update.

The most recent findings linking exposure to sun and vitamin D insufficiency to multiple sclerosis (MS) are reviewed. Due to insufficient sunshine and changing lifestyles, hypovitaminosis D is widespread in temperate countries. Numerous epidemiological studies have strongly suggested that sunshine and vitamin D insufficiency contributes to MS risk in these countries. Moreover, several large genetic studies in MS patients have recently stated unequivocally that diverse abnormalities involving vitamin D metabolism are related to the risk of the disease. The important implications of such results are discussed here. Then, the interactions of hypovitaminosis D with the other genetic and environmental protective and risk factors, such as the allele HLA DRB1*1501, Epstein-Barr virus infection, obesity, smoking and sexual hormones, are summarized. Vitamin D insufficiency and sufficiency could be a risk and a protective factor, respectively, among many other factors possibly continuously modulating the global MS risk from the mother's pregnancy to the triggering of MS in adulthood. However, many interactions between these different factors occur more particularly between conception and the end of adolescence, which corresponds to the period of maturation of the immune system and thymus and may be related to the dysimmune nature of the disease. The main mechanisms of action of vitamin D in MS appear to be immunomodulatory, involving the various categories of T and B lymphocytes in the general immune system, but neuroprotector and neurotrophic mechanisms could also be exerted at the central nervous system level. Furthermore, several controlled immunological studies performed in MS patients have recently confirmed that vitamin D supplementation has multiple beneficial immunomodulatory effects. However, there is still an enduring absence of major conclusive randomized clinical trials testing vitamin D supplementation in MS patients because of the quasi-insurmountable practical difficulties that exist nowadays in conducting and completing over several years such studies involving the use of a vitamin. Nevertheless, it should be noted that similar robust statistical models used in five different association studies have already predicted a favorable vitamin D effect reducing relapses by 50-70%. If there is now little doubt that vitamin D exerts a beneficial action on the inflammatory component of MS, the results are as yet much less clear for the progressive degenerative component. Lastly, until more information becomes available, vitamin D supplementation of MS patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended.

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis.

The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.

Real time identification of drug-induced liver injury (DILI) through daily screening of ALT results: a prospective pilot cohort study.

OBJECTIVE: Identification of drug-induced liver disease (DILI) is difficult, even among hospitalized patients. The aim of this pilot study was to assess the impact of a specific strategy for DILI screening. DESIGN: We prospectively compared the number of acute DILI cases identified in one week of a proactive strategy based on centralized elevated ALT values to those identified with a standard of care strategy for 24-week period based on referral cases to the hepatology unit. In the centralized strategy, a designated study biochemist identified patients with ALT greater than 3 times the upper limit of normal values (ULN) and notified the designated hepatologists, who then went to the patients' wards, analyzed the charts, and if necessary, interviewed the identified patients. During these two periods, patients with possible DILI were included after signing an informed consent in an ongoing European diagnostic study (SAFE-T consortium). RESULTS: During the 24-week period of the standard strategy, 12 (0.04%) patients out of a total of 28,145 were identified as having possible DILI, and 11 of these accepted to be included in the protocol. During the one-week proactive period, 7 patients out of a total of 1407 inpatients (0.498%) [odds ratio vs. standard = 12.1 (95% CI, 3.9-32.3); P<0.0001] were identified with possible DILI, and 5 were included in the protocol. CONCLUSION: A simple strategy based on the daily analysis of cases with ALT >3 ULN by designated biochemists and hepatologists identified 12 times more acute cases of drug-induced liver disease than the standard strategy. This pilot cohort is registered on the number AP-HP P110201/1/08-03-2011 and AFSSAPS B110346-70.

Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation.

BACKGROUND: Vitamin D could play a protective role in multiple sclerosis. METHODS: In an observational, uncontrolled study, vitamin D3 supplementation (3010 IU/day on average) was given to 156 consecutive patients with relapsing-remitting multiple sclerosis, under first-line immunomodulatory therapy and with initial 25-OH-D serum level lower than 100 nmol/l (40 ng/ml). Relapses were determined for 29.1 ± 8.4 months during vitamin D and 29.8 ± 10.1 months before supplementation. The 25-OH-D level was measured before supplementation and several times during supplementation. The incidence rate of relapses before and during supplementation was estimated using negative binomial regression models with follow-up durations as offset terms. The incidence rate and incidence rate ratio of relapses at various 25-OH-D levels were also calculated using negative binomial regression models. RESULTS: In 76 patients, immunomodulatory therapy preceded vitamin D supplementation (by 4.2 ± 2.7 years) and in 80 patients both treatments were started simultaneously. Under supplementation, the 25-OH-D level increased from 49 ± 22 nmol/l to 110 ± 26 nmol/l on average. Pooling data collected before and during supplementation, we found a significant strong inverse relationship between the relapse incidence rate and the 25-OH-D level (p < 0.0001), suggesting that vitamin D did indeed influence the relapse rate. Results of univariate, bivariate and multivariate analyses were analogous: in the multivariate model adjusted for age, disease duration and previous use of immunomodulatory therapy, every 10 nmol increase in 25-OH-D level was associated with a reduction in the relapse incidence rate of 13.7%. Dividing iteratively the population made up of pooled periods into two subgroups according to the 25-OH-D levels, the relapse incidence rate ratio decreased as the 25-OH-D level increased up to 110 nmol/l, but a plateau effect was observed beyond this limit. CONCLUSION: Further studies are warranted for accurate quantification of the vitamin D effect.

When should we measure vitamin D concentration in clinical practice?

The many recently published data on vitamin D have raised much interest in the medical community. One of the consequences has been a great increase in the prescription of vitamin D concentration measurements in clinical practice. It must be reminded that only the measurement of 25-hydroxyvitamin D (25(OH)D) concentration is indicated to evaluate vitamin D status. Furthermore, since vitamin D insufficiency is so common, since treatment is inexpensive and has a large safety margin, and since we already have much data suggesting that besides its classic effects on bone and mineral metabolism, vitamin D may potentially be helpful for the prevention/management of several diseases, perhaps should it be prescribed to everyone without prior testing? In our opinion, there are however groups of patients in whom estimation of vitamin D status is legitimate and may be recommended. This includes patients in whom a "reasonably" evidence-based target concentration (i.e., based on randomized clinical trials when possible) should be achieved and/or maintained such as patients with rickets/osteomalacia, osteoporosis, chronic kidney disease and kidney transplant recipients, malabsorption, primary hyperparathyroidism, granulomatous disease, and those receiving treatments potentially inducing bone loss. Other patients in whom vitamin D concentration may be measured are those with symptoms compatible with a severe vitamin D deficiency or excess persisting without explanation such as those with diffuse pain, or elderly individuals who fall, or those receiving treatments which modify vitamin D metabolism such as some anti-convulsants. Measurement of Vitamin D concentrations should also be part of any exploration of calcium/phosphorus metabolism which includes measurement of serum calcium, phosphate and PTH.

Nuclear, internuclear, and supranuclear ocular motor disorders.

In the brainstem, lateral and vertical eye movements are controlled by separate structures, the former mainly in the pons and the latter in the midbrain. The abducens nucleus (VI) in the pons controls all ipsilateral eye movements, i.e., ipsilateral saccades as well as the horizontal vestibulo-ocular reflex (VOR). This nucleus contains the abduction motoneurons, but also the internuclear neurons involved in adduction, passing through the contralateral medial longitudinal fasciculus (MLF) before relaying in the third-nerve nucleus in the midbrain. Lesions affecting the abducens nucleus result in complete ipsilateral eye movement paralysis, and lesions damaging the MLF result in internuclear ophthalmoplegia, whereas an association of these two lesions leads to the "one-and-a-half" syndrome. Ipsilateral saccades are controlled by the ipsilateral paramedian pontine reticular formation located close to the sixth nucleus, whereas the ipsilateral VOR is controlled by the contralateral medial vestibular nucleus. Vertical eye movements are controlled by the third- and fourth-nerve nuclei in the midbrain. A lesion unilaterally affecting the third-nerve nucleus results in an ipsilateral third-nerve paralysis and a contralateral upgaze paralysis because of the decussation of the superior rectus motoneurons, at the level of the third-nerve nuclei. Vertical saccades are controlled by the rostral interstitial nucleus of the MLF (riMLF) located close to the third-nerve nucleus. Downward and upward saccade paralysis results from bilateral riMLF damage whereas upgaze paralysis usually results from a unilateral lesion affecting the region of the posterior commissure, suggesting that the suprareticular control of these two types of vertical saccade is distinct.

Widespread vitamin D insufficiency: A new challenge for primary prevention, with particular reference to multiple sclerosis.

In the past 10 years, our knowledge of vitamin D has been revolutionized on two main points. Firstly, this vitamin is not only crucial for bone and calcium metabolism but also exerts major hormonal actions via its active metabolite (calcitriol) and specific receptors in almost all organs. The diverse non-classical actions of vitamin D-i.e. anti-inflammatory, immunomodulatory, antiproliferative and as a neurotransmitter-could have protective and preventive effects for a wide variety of pathologies, such as autoimmune diseases, cancer, infections and cardiovascular affections. Secondly, daily vitamin D requirements have been redefined thanks to many recent metabolic and pathological studies and are about 10 times higher than the amount considered sufficient until a few years ago. The fact that sunshine is the essential natural source of vitamin D and is limited in temperate and Nordic countries, coupled with the fact that modern lifestyle increasingly removes people from exposure to the sun, could explain why a great majority of the general population in these countries are in a state of vitamin D insufficiency. A lack of vitamin D can therefore also be observed in all pathologies but it may play a pathogenic role only in some of them. The incrimination of hypovitaminosis D as a risk factor is a reasonable assumption when several different research approaches used in a given pathology have consistently concluded that vitamin D is likely involved in that pathology. In multiple sclerosis, taken here as a prime example, there is a substantial rationale for vitamin D involvement, based on the findings of different experimental, epidemiological, genetic and immunological studies. Possible curative effects of vitamin D, in addition to a preventive action, are currently being tested but have not yet been demonstrated in most pathologies. However, these two questions appear to be clearly distinct and may involve notably different mechanisms. Lastly, since vitamin D insufficiency exists in most people living in mid- or high-latitude countries, vitamin D could exert multiple major preventive actions, simple supplementation is both safe and inexpensive and, for a vitamin-hormone, supplementation seems obligatory from a general preventive medical point of view alone, it follows that vitamin D supplementation should be organized in these countries to treat all those currently in a state of insufficiency, patients and 'normal' subjects alike, without further delay.

Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice.

BACKGROUND: There is increasing evidence that, in addition to the well-known effects on musculoskeletal health, vitamin D status may be related to a number of non-skeletal diseases. An international expert panel formulated recommendations on vitamin D for clinical practice, taking into consideration the best evidence available based on published literature today. In addition, where data were limited to smaller clinical trials or epidemiologic studies, the panel made expert-opinion based recommendations. METHODS: Twenty-five experts from various disciplines (classical clinical applications, cardiology, autoimmunity, and cancer) established draft recommendations during a 2-day meeting. Thereafter, representatives of all disciplines refined the recommendations and related texts, subsequently reviewed by all panelists. For all recommendations, panelists expressed the extent of agreement using a 5-point scale. RESULTS AND CONCLUSION: Recommendations were restricted to clinical practice and concern adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. The panel reached substantial agreement about the need for vitamin D supplementation in specific groups of patients in these clinical areas and the need for assessing their 25-hydroxyvitamin D (25(OH)D) serum levels for optimal clinical care. A target range of at least 30 to 40 ng/mL was recommended. As response to treatment varies by environmental factors and starting levels of 25(OH)D, testing may be warranted after at least 3 months of supplementation. An assay measuring both 25(OH)D(2) and 25(OH)D(3) is recommended. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.

Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis?

The role of hypovitaminosis D as a possible risk factor for multiple sclerosis is reviewed. First, it is emphasized that hypovitaminosis D could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. Secondly, the classical physiological notions about vitamin D have recently been challenged and the main new findings are summarized. This vitamin could have an important immunological role involving a number of organs and pathologies, including autoimmune diseases and multiple sclerosis. Furthermore, human requirements for this vitamin are much higher than previously thought, and in medium- or high-latitude countries, they might not be met in the majority of the general population due to a lack of sunshine and an increasingly urbanized lifestyle. Thereafter, the different types of studies that have helped to implicate hypovitaminosis D as a risk factor for multiple sclerosis are reviewed. In experimental autoimmune encephalomyelitis, vitamin D has been shown to play a significant immunological role. Diverse epidemiological studies suggest that a direct chain of causality exists in the general population between latitude, exposure to the sun, vitamin D status and the risk of multiple sclerosis. New epidemiological analyses from France support the existence of this chain of links. Recently reported immunological findings in patients with multiple sclerosis have consistently shown that vitamin D significantly influences regulatory T lymphocyte cells, whose role is well known in the pathogenesis of the disease. Lastly, in a number of studies on serum levels of vitamin D in multiple sclerosis, an insufficiency was observed in the great majority of patients, including at the earliest stages of the disease. The questionable specificity and significance of such results is detailed here. Based on a final global analysis of the cumulative significance of these different types of findings, it would appear likely that hypovitaminosis D is one of the risk factors for multiple sclerosis.

Clinical implications of a possible role of vitamin D in multiple sclerosis.

Hypovitaminosis D is currently one of the most studied environmental risk factors for multiple sclerosis (MS) and is potentially the most promising in terms of new clinical implications. These practical consequences, which could be applied to MS patients without further delay, constitute the main purpose of this review. Vitamin D is involved in a number of important general actions, which were not even suspected until quite recently. In particular, this vitamin could play an immunomodulatory role in the central nervous system. Many and varied arguments support a significant role for vitamin D in MS. In animal studies, vitamin D prevents and improves experimental autoimmune encephalomyelitis. Epidemiologically, latitude, past exposure to sun and the serum level of vitamin D influence the risk of MS, with, furthermore, significant links existing between these different factors. Clinically, most MS patients have low serum levels of vitamin D and are in a state of insufficiency or even deficiency compared to the international norm, which has been established on a metabolic basis. Large therapeutic trials using vitamin D are still lacking but the first results of phase I/II studies are promising. In the meantime, while awaiting the results of future therapeutic trials, it can no longer be ignored that many MS patients have a lack of vitamin D, which could be detected by a serum titration and corrected using an appropriate vitamin D supplementation in order to restore their serum level to within the normal range. From a purely medical point of view, vitamin D supplementation appears in this light to be unavoidable in order to improve the general state of these patients. Furthermore, it cannot currently be ruled out that this supplementation could also be neurologically beneficial.

Upbeat nystagmus from a demyelinating lesion in the caudal pons.

A 51-year-old man developed positional vertigo, ataxia, dysgeusia, diplopia, and oscillopsia. Eye movement examination and video-oculographic recording disclosed primary position upbeat nystagmus (PPUN) and a right internuclear ophthalmoplegia. Brain MRI showed a small focal lesion in the right dorsal tegmentum of the caudal pons with signal characteristics consistent with a primary demyelinating central nervous system disease. PPUN has not been described previously with a lesion in such a location. Clinicoanatomic correlation in this patient suggests that a lesion of the superior vestibular nucleus and its efferent crossing ventral tegmental tract could be responsible for the PPUN. This case report contributes to a better understanding of the role of this pathway in humans.

New insights into the upward vestibulo-oculomotor pathways in the human brainstem.

The brainstem vestibulo-oculomotor pathways are not yet fully known. Three different excitatory tracts could be involved in the transmission of upward vestibular eye movement (VEM) signals and upward eye position (EP) signals to the oculomotor nucleus (III): the medial longitudinal fasciculus (MLF), the brachium conjunctivum (BC), and the crossing ventral tegmental tract (CVTT). The involvement of the MLF pathway originating in the medial vestibular nucleus (MVN) in this transmission is experimentally and clinically well established whereas a role of the BC appears to be questionable. Furthermore, there is now accumulating evidence that the CVTT pathway emerging from the superior vestibular nucleus (SVN) also plays an important role in the mediation of excitatory upward EP and VEM signals to the III. This duplication of pathways (MVN-MLF and SVN-CVTT) could be explained by a supplementary and relatively specific function performed by the SVN-CVTT pathway to counteract the gravity pull in the upward eye movement system. Various arguments in support of this hypothesis are reviewed.

Nicotine-induced nystagmus correlates with midpontine activation.

The pathomechanism of nicotine-induced nystagmus (NIN) is unknown. The aim of this study was to delineate brain structures that are involved in NIN generation. Eight healthy volunteers inhaled nicotine in darkness during a functional magnetic resonance imaging (fMRI) experiment; eye movements were registered using video-oculography. NIN correlated with blood oxygen level-dependent (BOLD) activity levels in a midpontine site in the posterior basis pontis. NIN-induced midpontine activation may correspond to activation of the dorsomedial pontine nuclei and the nucleus reticularis tegmenti pontis, structures known to participate in the generation of multidirectional saccades and smooth pursuit eye movements.

Lateralized parietal activity during decision and preparation of saccades.

The posterior parietal cortex is involved in numerous visuospatial tasks, but little is known about the lateralization of these functions. We used functional magnetic resonance imaging to map the posterior parietal areas involved in saccades. Cerebral activation was studied during three different steps of saccadic elaboration: internal Decision of where to direct a horizontal saccade, motor Preparation and saccade Execution. These steps activated distinct areas: Decision and Preparation selectively activated the left posterior parietal cortex (left deep posterior intraparietal sulcus and left medial posterior intraparietal sulcus), whereas Execution activated only the right posterior parietal cortex (right medial posterior intraparietal sulcus). In humans, left but not right posterior parietal cortex might be specifically related to decision making and preparation of forthcoming ocular saccades.

Inhibitory control of the human dorsolateral prefrontal cortex during the anti-saccade paradigm--a transcranial magnetic stimulation study.

In the anti-saccade paradigm, subjects are instructed not to make a reflexive saccade to an appearing lateral target but to make an intentional saccade to the opposite side instead. The inhibition of reflexive saccade triggering is under the control of the dorsolateral prefrontal cortex (DLPFC). The critical time interval at which this inhibition takes place during the paradigm, however, is not exactly known. In the present study, we used single-pulse transcranial magnetic stimulation (TMS) to interfere with DLPFC function in 15 healthy subjects. TMS was applied over the right DLPFC either 100 ms before the onset of the visual target (i.e. -100 ms), at target onset (i.e. 0 ms) or 100 ms after target onset (i.e. +100 ms). Stimulation 100 ms before target onset significantly increased the percentage of anti-saccade errors to both sides, while stimulation at, or after, target onset had no significant effect. All three stimulation conditions had no significant influence on saccade latency of correct or erroneous anti-saccades. These findings show that the critical time interval at which the DLPFC controls the suppression of a reflexive saccade in the anti-saccade paradigm is before target onset. In addition, the results suggest the view that the triggering of correct anti-saccades is not under direct control of the DLPFC.

Prefrontal cortex is involved in internal decision of forthcoming saccades.

Deciding where to look is mandatory to explore the visual world. To study the neural correlates subserving the cognitive phase of self-initiated eye movements in humans, we tested 12 healthy participants, using event-related functional MRI. Changes in the frontal-cortical activity preceding voluntary saccades were studied when the participants freely decided the direction of a forthcoming saccade, compared with a condition in which they had only to prepare an externally cued saccade. Self-initiation of saccades, before their execution, was specifically associated with frontal-lobe activation in the dorsolateral prefrontal cortex, and in the right presupplementary eye field and frontal eye fields, suggesting the roles of these areas in the decision process of where to look when facing two possible visual targets.