Empathy and aversion: the neural signature of mentalizing in Tourette syndrome.

BACKGROUND: Previous studies suggest that adults with Tourette syndrome (TS) can respond unconventionally on tasks involving social cognition. We therefore hypothesized that these patients would exhibit different neural responses to healthy controls in response to emotionally salient expressions of human eyes. METHOD: Twenty-five adults with TS and 25 matched healthy controls were scanned using fMRI during the standard version of the Reading the Mind in the Eyes Task which requires mental state judgements, and a novel comparison version requiring judgements about age. RESULTS: During prompted mental state recognition, greater activity was apparent in TS within left orbitofrontal cortex, posterior cingulate, right amygdala and right temporo-parietal junction (TPJ), while reduced activity was apparent in regions including left inferior parietal cortex. Age judgement elicited greater activity in TS within precuneus, medial prefrontal and temporal regions involved in mentalizing. The interaction between group and task revealed differential activity in areas including right inferior frontal gyrus. Task-related activity in the TPJ covaried with global ratings of the urge to tic. CONCLUSIONS: While recognizing mental states, adults with TS exhibit greater activity than controls in brain areas involved in the processing of negative emotion, in addition to reduced activity in regions associated with the attribution of agency. In addition, increased recruitment of areas involved in mental state reasoning is apparent in these patients when mentalizing is not a task requirement. Our findings highlight differential neural reactivity in response to emotive social cues in TS, which may interact with tic expression.

History of migraine with aura and cortical spreading depression from 1941 and onwards.

Several personal descriptions of migraine with aura from 1870 onwards reported a slow, gradual progression of symptoms. Lashley in 1941 meticulously chartered his own auras and concluded that the symptomatology reflected a cortical process progressing with a speed of 3 mm/min across the primary visual cortex. Leão described cortical spreading depression (CSD) in rabbits in 1944 and noticed its similarity to the migraine aura. Despite these scattered pieces of evidence, the prevailing theory was that the migraine aura was caused by a vasospasm and cortical ischaemia. The advent of a technique for measurements of regional cerebral blood flow (rCBF) in 1974 made it possible to detect spreading oligaemia during migraine aura. Between 1981 and 1990 a series of studies of rCBF during migraine attacks showed reduced brain blood flow posteriorly spreading slowly and contiguously anteriorly and crossing borders of supply of major cerebral arteries. These observations refuted the ischaemic hypothesis. The human studies showed initial hyperaemia followed by prolonged hypoperfusion. The relation between aura and CSD was known to cause short-lasting, and therefore not obvious vasodilation and it was considerably strengthened by the demonstration of a long-lasting oligaemia in rats in the wake of CSD. In the primates CSD is not easily elicited, but it has in recent years been clearly demonstrated in patients with brain trauma and stroke. Finally, mutations for familial hemiplegic migraine have been expressed in mice and lower the threshold for CSD. The seminal papers on rCBF and CSD published in the 1980s caused a dramatic shift in our concepts of migraine aura. They moved attention from ischaemia to CSD and thereby to the brain itself, and paved the way for subsequent discoveries of brainstem mechanisms.

Abnormal thalamocortical dynamics may be altered by deep brain stimulation: using magnetoencephalography to study phantom limb pain.

Deep brain stimulation (DBS) is used to alleviate chronic pain. Using magnetoencephalography (MEG) to study the mechanisms of DBS for pain is difficult because of the artefact caused by the stimulator. We were able to record activity over the occipital lobe of a patient using DBS for phantom limb pain during presentation of a visual stimulus. This demonstrates that MEG can be used to study patients undergoing DBS provided control stimuli are used to check the reliability of the data. We then asked the patient to rate his pain during and off DBS. Correlations were found between these ratings and power in theta (6-9) and beta bands (12-30). Further, there was a tendency for frequencies under 25 Hz to correlate with each other after a period off stimulation compared with immediately after DBS. The results are interpreted as reflecting abnormal thalamocortical dynamics, previously implicated in painful syndromes.

History of methysergide in migraine.

Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.

History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward.

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.

Modulation of saccadic intrusions by exogenous and endogenous attention.

Primary gaze fixation in healthy individuals is frequently interrupted by microsaccades and saccadic intrusions (SI). The neural systems responsible for the control of attention and eye movements are believed to overlap and in line with this, the behaviour of microsaccades appears to be affected by exogenous and endogenous attention shifts. In the current work we wished to establish whether SI would also be influenced by attention in order to provide evidence that SI and microsaccades exhibit similar behaviour and further investigate the extent of overlap between attention and eye movement systems. Twelve participants performed a cue-target task where they were cued exogenously or endogenously and had to respond to the appearance of a peripheral target with either a button press or saccade. Our results replicate earlier microsaccade research, indicating that SI are also influenced by exogenous and endogenous attention. In all conditions, SI frequency initially decreased following the cue, then rose to a maximum before falling to below baseline levels. Following the exogenous cue, SI were more frequently directed away from the cue as predicted by inhibition of return. Additionally, SI direction following the endogenous cue was biased towards the cue for the saccadic response mode only, suggesting that the degree to which the eye movement and attention systems overlap depends on whether an eye movement is required. In summary, our findings indicate that SI characteristics are modulated by exogenous and endogenous attention and in a similar way to microsaccades, suggesting that SI and microsaccades may lie on a continuum of fixational instabilities. Furthermore, as with microsaccades, SI are likely to provide additional insights into the relationship between attention and the oculomotor systems.

Do 'clumsy' children have visual deficits.

Visual processing by 10-year-old children diagnosed on the basis of standardised tests as having developmental 'clumsiness' syndrome, and by a control group of children without motor difficulties, was tested using three different psychophysical tasks. The tasks comprised a measure of global motion processing using a dynamic random dot kinematogram, a measure of static global pattern processing where the position of the target was randomised, and a measure of static global pattern processing in which the target position was fixed. The most striking finding was that the group of clumsy children, who were diagnosed solely on the basis of their motor difficulties, were significantly less sensitive than the control group on all three tasks of visual sensitivity. Clumsy children may have impaired visual sensitivity in both the dorsal and ventral streams in addition to their obvious problems with motor control. These results support the existence of generalised visual anomalies associated with impairments of cerebellar function.

Auditory frequency discrimination in adult developmental dyslexics.

Developmental dyslexics reportedly discriminate auditory frequency poorly. A recent study found no such deficit. Unlike its predecessors, however, it employed multiple exposures per trial to the standard stimulus. To investigate whether this affects frequency discrimination in dyslexics, a traditional two-interval same-different paradigm (2I_1A_X) and a variant with six A-stimuli per trial (2I_6A_X) were used here. Frequency varied around 500 Hz; interstimulus interval (ISI) ranged between 0 and 1,000 msec. Under 2I_1A_X, dyslexics always had larger just noticeable differences (JNDs) than did controls. Dyslexic and control JNDs were equal at shorter ISIs under 2I_6A_X, but dyslexics became worse than controls at longer ISIs. Signal detection analysis suggests that both sensory variance and trace variance are larger in dyslexics than in controls.

Detection of audio-visual integration sites in humans by application of electrophysiological criteria to the BOLD effect.

Electrophysiological studies in nonhuman primates and other mammals have shown that sensory cues from different modalities that appear at the same time and in the same location can increase the firing rate of multisensory cells in the superior colliculus to a level exceeding that predicted by summing the responses to the unimodal inputs. In contrast, spatially disparate multisensory cues can induce a profound response depression. We have previously demonstrated using functional magnetic resonance imaging (fMRI) that similar indices of crossmodal facilitation and inhibition are detectable in human cortex when subjects listen to speech while viewing visually congruent and incongruent lip and mouth movements. Here, we have used fMRI to investigate whether similar BOLD signal changes are observable during the crossmodal integration of nonspeech auditory and visual stimuli, matched or mismatched solely on the basis of their temporal synchrony, and if so, whether these crossmodal effects occur in similar brain areas as those identified during the integration of audio-visual speech. Subjects were exposed to synchronous and asynchronous auditory (white noise bursts) and visual (B/W alternating checkerboard) stimuli and to each modality in isolation. Synchronous and asynchronous bimodal inputs produced superadditive BOLD response enhancement and response depression across a large network of polysensory areas. The most highly significant of these crossmodal gains and decrements were observed in the superior colliculi. Other regions exhibiting these crossmodal interactions included cortex within the superior temporal sulcus, intraparietal sulcus, insula, and several foci in the frontal lobe, including within the superior and ventromedial frontal gyri. These data demonstrate the efficacy of using an analytic approach informed by electrophysiology to identify multisensory integration sites in humans and suggest that the particular network of brain areas implicated in these crossmodal integrative processes are dependent on the nature of the correspondence between the different sensory inputs (e.g. space, time, and/or form).

Are dyslexics' visual deficits limited to measures of dorsal stream function?

We tested the hypothesis that the differences in performance between developmental dyslexics and controls on visual tasks are specific for the detection of dynamic stimuli. We found that dyslexics were less sensitive than controls to coherent motion in dynamic random dot displays. However, their sensitivity to control measures of static visual form coherence was not significantly different from that of controls. This dissociation of dyslexics' performance on measures that are suggested to tap the sensitivity of different extrastriate visual areas provides evidence for an impairment specific to the detection of dynamic properties of global stimuli, perhaps resulting from selective deficits in dorsal stream functions.

Visual motion sensitivity in dyslexia: evidence for temporal and energy integration deficits.

In addition to poor literacy skills, developmental dyslexia has been associated with multisensory deficits for dynamic stimulus detection. In vision these deficits have been suggested to result from impaired sensitivity of cells within the retino-cortical magnocellular pathway and extrastriate areas in the dorsal stream to which they project. One consequence of such selectively reduced sensitivity is a difficulty in extracting motion coherence from dynamic noise, a deficit associated with both developmental dyslexia and persons with extrastriate, dorsal stream lesions. However the precise nature of the mechanism(s) underlying these perceptual deficits in dyslexia remain unknown. In this study, we obtained motion detection thresholds for 10 dyslexic and 10 control adults while varying the spatial and temporal parameters of the random dot kinematogram (RDK) stimuli. In Experiment 1 stimulus duration was manipulated to test whether dyslexics are specifically impaired for detecting short duration, rather than longer stimuli. Dot density was varied in Experiment 2 to examine whether dyslexics' reduced motion sensitivity was affected by the amount of motion energy present in the RDKs. Dyslexics were consistently less sensitive to coherent motion than controls in both experiments. Increasing stimulus duration did not improve dyslexics' performance, whereas increasing dot density did. Thus increasing motion energy assisted the dyslexics, suggesting that their motion detectors have a lower signal to noise ratio, perhaps due to spatial undersampling.

Dynamic sensory sensitivity and children's word decoding skills.

The relationship between sensory sensitivity and reading performance was examined to test the hypothesis that the orthographic and phonological skills engaged in visual word recognition are constrained by the ability to detect dynamic visual and auditory events. A test battery using sensory psychophysics, psychometric tests, and measures of component literacy skills was administered to 32 unselected 10-year-old primary school children. The results suggest that children's sensitivity to both dynamic auditory and visual stimuli are related to their literacy skills. Importantly, after controlling for intelligence and overall reading ability, visual motion sensitivity explained independent variance in orthographic skill but not phonological ability, and auditory FM sensitivity covaried with phonological skill but not orthographic skill. These results support the hypothesis that sensitivity at detecting dynamic stimuli influences normal children's reading skills. Vision and audition separately may affect the ability to extract orthographic and phonological information during reading.

Dynamics of letter string perception in the human occipitotemporal cortex.

The inferior occipitotemporal brain areas, especially in the left hemisphere, have been shown to be involved in the processing of written words and letter strings. This processing probably occurs within 200 ms after presentation of the letter string. It has also been suggested that this activation may differ between fluent and dyslexic readers. Using whole-head magnetoencephalography, we studied the spatiotemporal dynamics of brain processes evoked by visually presented letter strings in 12 healthy adult subjects. Our achromatic stimuli consisted of rectangular patches in which single letters, two-letter syllables, four-letter words, or symbol strings of equal length were embedded and to which variable noise was added. This manipulation dissociated three different response patterns. The first of these patterns took place approximately 100 ms after stimulus onset, originated in areas surrounding the V1 cortex and was distributed along the ventral visual stream, extending laterally as far as V4v. This response was systematically modulated by noise but was insensitive to the stimulus content, suggesting involvement in early visual analysis. The second pattern took place approximately 150 ms after stimulus onset and was concentrated in the inferior occipitotemporal region with left-hemisphere dominance. This activation showed a preference for letter strings, and its strength and timing correlated with the speed at which the subjects were able to read words aloud. The third pattern also occurred in the time window approximately 150 ms after stimulus onset, but originated mainly in the right occipital area. Like the second pattern, it was modulated by string length, but showed no preference for letters compared with symbols. The present data strongly support the special role of the left inferior occipitotemporal cortex in visual word processing within 200 ms after stimulus onset.

Dissociation of normal feature analysis and deficient processing of letter-strings in dyslexic adults.

Neuroimaging studies have revealed that the functional organization of reading differs between developmentally dyslexic and non-impaired individuals. However, it is not clear how early in the reading process the differences between fluent and dyslexic readers start to emerge. We studied cortical activity of ten dyslexic adults using magnetoencephalography (MEG), as they silently read words or viewed symbol-strings which were clearly visible or degraded with Gaussian noise. This method has previously been used to dissociate between analysis of local features and pre-lexical word processing in fluent adult readers. Signals peaking around 100 ms after stimulus onset and originating in the postero-medial extrastriate cortex were associated with increasing local luminance contrast in the noise patches. These early visual responses were similar in dyslexic and non-impaired readers. In contrast, the letter-string-specific responses peaking around 150 ms predominantly in the left inferior occipito-temporal cortex in fluent readers were undetectable in dyslexic readers. Thus, while the early visual processing seems intact in dyslexic adults, the pattern of cortical activation starts to differ from that of fluent readers at the point where letter-string-specific signals first emerge during reading.

Can sensitivity to auditory frequency modulation predict children's phonological and reading skills?

Understanding how letter units represent particular speech sounds is a crucial skill for developing competent reading skills. However it is not known whether such phonological ability is constrained by basic auditory capacities such as those necessary for detecting the frequency modulations characteristic of many phonemes. Here we show that nearly 40% of the variability in normal children's phonological and reading skills can be predicted from their sensitivity to 2 Hz frequency modulated (FM) tones. This relationship does not hold for sensitivity to 240 Hz FM. Because lower but not higher rates of FM provide information important for speech comprehension, dynamic auditory sensitivity is likely to play an important role in children's phonological and reading skill development.

Coherent motion detection and letter position encoding.

We identified 24 'good' and 24 'poor' coherent motion detectors from an unselected sample of young adults. The two groups were matched for reading ability, age and IQ. All subjects carried out two tasks in which optimal performance depended on accurate letter position encoding: a lexical decision task and a primed reaction time task. We found that accurate letter position encoding was predicted by performance in the motion detection task. Since coherent motion detection depends on input from the magnocellular pathway, these findings suggest that information carried by the magnocellular system may be required for encoding letter position. Furthermore, these results may have implications for reading disability which is said to be associated with magnocellular dysfunction.

Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers.

BACKGROUND: Developmental dyslexia is a specific disorder of reading and spelling that affects 3-9% of school-age children and adults. Contrary to the view that it results solely from deficits in processes specific to linguistic analysis, current research has shown that deficits in more basic auditory or visual skills may contribute to the reading difficulties of dyslexic individuals. These might also have a crucial role in the development of normal reading skills. Evidence for visual deficits in dyslexia is usually found only with dynamic and not static stimuli, implicating the magnocellular pathway or dorsal visual stream as the cellular locus responsible. Studies of such a dissociation between the processing of dynamic and static auditory stimuli have not been reported previously. RESULTS: We show that dyslexic individuals are less sensitive both to particular rates of auditory frequency modulation (2 Hz and 40 Hz but not 240 Hz) and to dynamic visual-motion stimuli. There were high correlations, for both dyslexic and normal readers, between their sensitivity to the dynamic auditory and visual stimuli. Nonword reading, a measure of phonological awareness believed crucial to reading development, was also found to be related to these sensory measures. CONCLUSIONS: These results further implicate neuronal mechanisms that are specialised for detecting stimulus timing and change as being dysfunctional in many dyslexic individuals. The dissociation observed in the performance of dyslexic individuals on different auditory tasks suggests a sub-modality division similar to that already described in the visual system. These dynamic tests may provide a non-linguistic means of identifying children at risk of reading failure.

Magnocellular visual function and children's single word reading.

Recent research has shown that reading disabled children find it unusually difficult to detect flickering or moving visual stimuli, consistent with impaired processing in the magnocellular visual stream. Yet, it remains controversial to suggest that reduced visual sensitivity of this kind might affect children's reading. Here we suggest that when children read, impaired magnocellular function may degrade information about where letters are positioned with respect to each other, leading to reading errors which contain sounds not represented in the printed word. We call these orthographically inconsistent nonsense errors "letter" errors. To test this idea we assessed magnocellular function in a sample of 58 unselected children by using a coherent motion detection task. We then gave these children a single word reading task and found that their "letter" errors were best explained by independent contributions from motion detection (i.e., magnocellular function) and phonological awareness (assessed by a spoonerism task). This result held even when chronological age, reading ability, and IQ were controlled for. These findings suggest that impaired magnocellular visual function, as well as phonological deficits may affect how children read.

Effect of time and frequency manipulation on syllable perception in developmental dyslexics.

Many people with developmental dyslexia have difficulty perceiving stop consonant contrasts as effectively as other people and it has been suggested that this may be due to perceptual limitations of a temporal nature. Accordingly, we predicted that perception of such stimuli by listeners with dyslexia might be improved by stretching them in time-equivalent to speaking slowly. Conversely, their perception of the same stimuli ought to be made even worse by compressing them in time-equivalent to speaking quickly. We tested 15 children with dyslexia on their ability to identify correctly consonant-vowel-consonant (CVC) stimuli that had been stretched or compressed in the time domain. We also tested their perception of the same CVC stimuli after the formant transitions had been stretched or compressed in the frequency domain. Contrary to our predictions, we failed to find any systematic improvement in their performance with either manipulation. We conclude that simple manipulations in the time and frequency domains are unlikely to benefit the ability of people with dyslexia to discriminate between CVCs containing stop consonants.

Analysis of perceptual confusions between nine sets of consonant-vowel sounds in normal and dyslexic adults.

It is widely accepted that most developmental dyslexics perform poorly on tasks which assess phonological awareness. One reason for this association might be that the early or "input" phonological representations of speech sounds are distorted or noisy in some way. We have attempted to test this hypothesis directly. In Experiment 1, we measured the confusions that adult dyslexics and controls made when they listened to nine randomly presented consonant-vowel (CV) segments [sequence: see text] under four conditions of increasing white noise masking. Subjects could replay stimuli and were under no obligation to respond quickly. Responses were selected with a computer mouse from a set of nine letter-strings, corresponding to the auditory stimuli, presented on a VDU. While the overall pattern of confusions made by dyslexics and controls was very similar for this stimulus set, dyslexics confused [sequence: see text] significantly more than did controls. In Experiment 2, subjects heard each stimulus once only and were forced to respond as quickly as possible. Under these timed conditions, the pattern of confusions made by dyslexics and controls was the same as before, but dyslexics took longer to respond than controls. The slower responses of dyslexics in Experiment 2 could have arisen because: (a) they were slower at processing the auditory stimuli than controls, (b) they had worse visual pattern memory for letter strings than controls, (c) they were slower than controls at using the computer mouse. In Experiments 3, 4 and 5 subjects carried out control tasks which eliminated each of these possibilities and confirmed that the results from the auditory tasks genuinely reflected subjects' speech perception. We propose that the fine structure of dyslexics' input phonological representations should be further explored with this confusion paradigm by using other speech sounds containing VCs, CCVs and VCCs.