Luca Latini Corazzini

A systematic review of adverse events in placebo groups of anti-migraine clinical trials

ABSTRACT In analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. Interestingly, patients who receive the placebo often report a high frequency of adverse events, but little is understood about the nature of these negative effects. In the present study, we compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti‐migraine drugs: NSAIDs, triptans and anticonvulsants. We identified 73 clinical trials in 69 studies describing adverse events in placebo groups: 8 were clinical trials with NSAIDs, 56 were trials with triptans, and 9 were trials with anticonvulsants. Studies were selected of all Medline/PubMed or CENTRAL referenced trials published until 2007. Adverse event profiles of the three classes were compared using a systematic review approach. We found that the rate of adverse events in the placebo arms of trials with anti‐migraine drugs was high. In addition, and most interestingly, the adverse events in the placebo arms corresponded to those of the anti‐migraine medication against which the placebo was compared. For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti‐migraine medications depend on the adverse events of the active medication against which the placebo is compared. These findings are in accordance with the expectation theory of placebo and nocebo effects.

Collicular vision guides nonconscious behavior

Following destruction or deafferentation of primary visual cortex (area V1, striate cortex), clinical blindness ensues, but residual visual functions may, nevertheless, persist without perceptual consciousness (a condition termed blindsight). The study of patients with such lesions thus offers a unique opportunity to investigate what visual capacities are mediated by the extrastriate pathways that bypass V1. Here we provide evidence for a crucial role of the collicular–extrastriate pathway in nonconscious visuomotor integration by showing that, in the absence of V1, the superior colliculus (SC) is essential to translate visual signals that cannot be consciously perceived into motor outputs. We found that a gray stimulus presented in the blind field of a patient with unilateral V1 loss, although not consciously seen, can influence his behavioral and pupillary responses to consciously perceived stimuli in the intact field (implicit bilateral summation). Notably, this effect was accompanied by selective activations in the SC and in occipito-temporal extrastriate areas. However, when instead of gray stimuli we presented purple stimuli, which predominantly draw on S-cones and are thus invisible to the SC, any evidence of implicit visuomotor integration disappeared and activations in the SC dropped significantly. The present findings show that the SC acts as an interface between sensory and motor processing in the human brain, thereby providing a contribution to visually guided behavior that may remain functionally and anatomically segregated from the geniculo-striate pathway and entirely outside conscious visual experience.

Functional asymmetry and interhemispheric cooperation in the perception of emotions from facial expressions

The present study used the redundant target paradigm on healthy subjects to investigate functional hemispheric asymmetries and interhemispheric cooperation in the perception of emotions from faces. In Experiment 1 participants responded to checkerboards presented either unilaterally to the left (LVF) or right visual half field (RVF), or simultaneously to both hemifields (BVF), while performing a pointing task for the control of eye movements. As previously reported (Miniussi et al. in J Cogn Neurosci 10:216–230, 1998), redundant stimulation led to shorter latencies for stimulus detection (bilateral gain or redundant target effect, RTE) that exceeded the limit for a probabilistic interpretation, thereby validating the pointing procedure and supporting interhemispheric cooperation. In Experiment 2 the same pointing procedure was used in a go/no-go task requiring subjects to respond when seeing a target emotional expression (happy or fearful, counterbalanced between blocks). Faster reaction times to unilateral LVF than RVF emotions, regardless of valence, indicate that the perception of positive and negative emotional faces is lateralized toward the right hemisphere. Simultaneous presentation of two congruent emotional faces, either happy or fearful, produced an RTE that cannot be explained by probability summation and suggests interhemispheric cooperation and neural summation. No such effect was present with BVF incongruent facial expressions. In Experiment 3 we studied whether the RTE for emotional faces depends on the physical identity between BVF stimuli, and we set a second BVF congruent condition in which there was only emotional but not physical or gender identity between stimuli (i.e. two different faces expressing the same emotion). The RTE and interhemispheric cooperation were present also in this second BVF congruent condition. This shows that emotional congruency is the sufficient condition for the RTE to take place in the intact brain and that the cerebral hemispheres can interact in spite of physical differences between stimuli.

Spatial navigation in large-scale virtual environments: Gender differences in survey tasks

Most of the studies on gender differences in spatial abilities have focused on traditional paper and pencil cognitive tests, while these differences have been less investigated in navigational tasks carried out in complex virtual environments (VEs). The aim of the present study has been to evaluate gender differences in route and survey knowledge by means of specific tasks (route-learning, pointing, landmark-placing) carried out in two separate VEs. In addition the male and female participants were subjected to a battery of spatial abilities tests and specific self-report questionnaires. The results showed a significant difference favouring males in the survey tasks, as well as in the spatial abilities tests; on the contrary, no gender differences were found in the route task. Moreover, a different pattern of correlations among the measures were found in the male and female sub-groups.

Mental number line disruption in a right-neglect patient after a left-hemisphere stroke

A right-neglect patient with focal left-hemisphere damage to the posterior superior parietal lobe was assessed for numerical knowledge and tested on the bisection of numerical intervals and visual lines. The semantic and verbal knowledge of numbers was preserved, whereas the performance in numerical tasks that strongly emphasize the visuo-spatial layout of numbers (e.g. number bisection) was impaired. The behavioral pattern of error in the two bisection tasks mirrored the one previously described in left-neglect patients. In other words, our patient misplaced the subjective midpoint (numerical or visual) to the left as function of the interval size. These data, paired with the patients lesion site are strictly consistent with the tripartite organization of number-related processes in the parietal lobes as proposed by Dehaene and colleagues. According to these authors, the posterior superior parietal lobe on both hemispheres underpins the attentional orientation on the putative mental number line, the horizontal segment of the intraparietal sulcus is bilaterally related to the semantic of the numerical domain, whereas the left angular gyrus subserves the verbal knowledge of numbers. In summary, our results suggest that the processes involved in the navigation along the mental number line, which are related to the parietal mechanisms for spatial attention, and the processes involved in the semantic and verbal knowledge of numbers, are dissociable.

Effects of emotional face cueing on line bisection in neglect: A single case study

One patient with left neglect (FM) and four right brain-damaged controls were tested on a line bisection task with pictures of neutral and emotional faces as unilateral cues. We thus manipulated the attentional salience of the cues (higher for emotional and lower for neutral faces) while keeping constant their physical dimensions. Our findings showed that left emotional faces were more effective than left neutral faces in reducing bisection errors only in FM. These data indicate that in the neglected hemispace cues bias attention rather than simply altering the perceptual point of balance of the line in the horizontal plane.

Acceleration perception and spatial distortion in a left unilateral neglect patient

To explain relative leftward overextension in a line extension task by left unilateral neglect subjects, Bisiach et al. (1998) suggested that the representation of space is distorted--i.e., dilated towards the left side. If perception of the velocity of a moving stimulus is due to a calculation of the distance covered per unit time in representational space, then a stimulus with uniform linear motion should be perceived as decelerating when moving leftwards in the visual field of a subject with left unilateral neglect. We investigated the perception of acceleration in a patient with left unilateral neglect and spatial distortion (revealed as relative left overextension in a line extension task) using a task in which the stimuli were right and left moving targets with variable acceleration. The patients ability to perceive acceleration was much lower (higher acceleration threshold) for leftward movements than rightward movements. Fourteen months later unilateral neglect had improved, and the relative left overextension and decreasing acceleration threshold for leftward movements were reduced. By contrast, alterations in the perception of acceleration for leftward movements were not found in a patient with left unilateral neglect and left underextension and in a patient with right brain damage and left hemianopia. These findings in one patient with left spatial unilateral neglect and a relative left overextension in a line extension task are consistent with the hypothesis that representational space is distorted, with a disproportionate leftward expansion, that affects perception of movement.

Differentiated forgetting rates of spatial knowledge in humans in the absence of repeated testing

Spatial knowledge, necessary for efficient navigation, comprises route knowledge (memory of the landmarks along a route) and survey knowledge (map-like). Available data on the retention in humans of spatial knowledge show that this does not decline systematically over months or years. Here, two groups of participants elaborated route and survey knowledge during navigation in a complex virtual environment before performing route and survey tasks. Both groups were tested 5 minutes after learning and 3 months later, while one group was also tested 1 week and 1 month later (repeated testing). Performance was similar in both groups on the first testing session, remained stable in the repeated tested group, but decreased in the non-repeated tested group, especially on route tasks. These results are the first to reveal a substantial and selective decline of spatial knowledge, occurring only if there is no possibility of reactivating knowledge along repeated testing.

Visual acceleration and spatial distortion in right brain-damaged patients

A subset of right brain-damaged patients shows leftward overextension in the line extension task. It has been argued that this deficit can be attributed to a distortion of the metric structure of perceived space (spatial anisometry). We investigated whether spatial distortion of static stimuli is associated with a corresponding misperception of perceived acceleration of moving stimuli. Seven right brain-damaged patients with spatial anisometry and two control groups were presented with stimuli moving leftwards or rightwards along the horizontal axis at different rates of acceleration. They were asked to estimate whether the target accelerated or decelerated. The anisometric group judged the perceived acceleration of leftward motions as less than that of rightward motions. The magnitude of the misperception of acceleration correlated positively with relative left overextension in the line extension task and with rightward displacement error in the line bisection task. This directional difference is in line with the predictions of the spatial anisometry hypothesis.

Forgetting rate of topographical memory in a virtual environment.

It is well admitted that spatial knowledge of large-scale environments is organized into route or survey representations (Thorndyke and Hayes-Roth 1982; Montello 1998; Allen 1999). The route representation consists in the memory trace of the sequence of landmarks encountered along a specific route and of the turns associated with each landmark. The survey representation is considered as being map-like, allowing direct access to the global layout of an environment. While extensive research has been devoted to the retention of verbal knowledge, very little is known about the retention of spatial knowledge. The available data show no systematic decline of performance in topographical memory for a long-term period. However, these data were gathered through a limited set of tasks (mainly tapping survey-type memory) performed in real-world environments, which were not entirely controlled from a methodological point of view. For these reasons, in the present study the forgetting rate of route and survey memory was investigated in a virtual environment.