No effect of auditory -- visual spatial disparity on temporal recalibration It is known that the brain adaptively recalibrates itself to small -LRB- ∼ 100 ms -RRB- auditory -- visual -LRB- AV -RRB- temporal asynchronies so as to maintain intersensory temporal coherence . Here we explored whether spatial disparity between a sound and light affects AV temporal recalibration . Participants were exposed to a train of asynchronous AV stimulus pairs -LRB- sound-first or light-first -RRB- with sounds and lights emanating from either the same or a different location . Following a short exposure phase , participants were tested on an AV temporal order judgement -LRB- TOJ -RRB- task . Temporal recalibration manifested itself as a shift of subjective simultaneity in the direction of the adapted audiovisual lag . The shift was equally big when exposure and test stimuli were presented from the same or different locations . These results provide strong evidence for the idea that spatial co-localisation is not a necessary constraint for intersensory pairing to occur . Introduction In many circumstances people experience external events by a number of different sensory modalities . For example , when someone is talking , there is auditory and visual information that is initially processed by specialized neural pathways . Ultimately , though , the different sensory signals are integrated into a coherent multimodal percept of the speaker . Many behavioural and neurophysiological studies have emphasized the importance of spatial co-localisation and temporal synchrony for intersensory pairing to occur -LRB- e.g. , Welch and Warren 1980 ; Bedford 1989 ; Stein and Meredith 1993 ; Radeau 1994 ; Bertelson 1999 ; Welch 1999 -RRB- . However , there is accumulating evidence that some intersensory phenomena may not require spatial alignment -LRB- Welch et al. 1986 ; Scheier et al. 1999 ; Morein-Zamir et al. 2003 ; Murray et al. 2004 ; Teder-Salejarvi et al. 2005 ; Vroomen and Keetels 2006 ; Keetels et al. 2007 -RRB- . In the present study , we explored the importance of spatial alignment for audio -- visual -LRB- AV -RRB- temporal recalibration . Temporal recalibration refers to the phenomenon that the brain adapts itself to -LRB- small -RRB- temporal asynchronies . In a multi-modal percept , it usually appears that information from different senses arrive at the same time . This occurs , despite the fact that there are natural asynchronies between the senses caused by differences in signal transduction time through air and differences in neural transmission time . At least two options are available to handle these asynchronies : one is concerned with immediate corrections , the other is important for adaptation on a longer time scale . As concerns the immediate effect , several studies have shown that the brain corrects for small AV temporal asynchronies by shifting one or both modalities on the time scale so that the temporal discordance is reduced . For example , when a sound and a light are presented at slightly different onset times -LRB- usually in the order of ∼ 100 ms -RRB- , the temporal asynchrony is reduced by a capturing effect of the light by the sound ; a phenomenon called temporal ventriloquism -LRB- Scheier et al. 1999 ; Fendrich and Corballis 2001 ; Morein-Zamir et al. 2003 ; Vroomen and de Gelder 2004 ; Stekelenburg and Vroomen 2005 ; Vroomen and Keetels 2006 -RRB- . Temporal ventriloquism can , for example , be demonstrated by the use of a visual temporal order judgment -LRB- TOJ -RRB- task in which participants are presented two lights at various stimulus onset asynchronies -LRB- SOAs -RRB- and judge which light came first . By presenting a sound before the first and after the second light , the just noticeable difference -LRB- JND -RRB- improves -LRB- i.e. participants become more sensitive -RRB- , presumably because the two sounds attract the temporal occurrence of the two lights , and thus effectively pull the lights further apart in time -LRB- Scheier et al. 1999 ; Morein-Zamir et al. 2003 ; Vroomen and Keetels 2006 -RRB- . There are also long-term effects reflecting an adaptive change to AV asynchrony , a phenomenon called temporal recalibration -LRB- Fujisaki et al. 2004 ; Vroomen et al. 2004 -RRB- . For example , Vroomen et al. studied temporal recalibration by exposing participants to 3 min of sound and light flashes with a constant time lag , after which an AV TOJ or AV simultaneity task was performed . Following exposure , observers were given AV test stimuli and judged whether the sound or the light came first , or whether the sound and light were simultaneous or successive . The results showed that the point of subjective simultaneity -LRB- PSS -RRB- , the point of perceived temporal alignment between the sound and the light , was shifted in the direction of the exposure lag . So , following exposure to a train of sound-first stimulus pairs , participants perceived sound-first trials as more simultaneous than after light-first exposure . Fujisaki et al. -LRB- 2004 -RRB- demonstrated similar findings and also provided somewhat mixed evidence that temporal recalibration may generalize to different test stimuli than the ones presented during exposure . The authors adapted participants to asynchronous tone-flash stimulus pairs and later tested them on the `` bounce '' illusion -LRB- Sekuler et al. 1997 -RRB- . In this illusion , two visual targets that move across each other can be perceived either to bounce off or to stream through each other . A brief sound presented at the moment that the visual targets coincide generally biases visual perception in favour of a bouncing motion , while without sound observers tend to report a streaming percept . Following exposure to asynchronous sound -- light pairs , the optimal delay for obtaining the bounce illusion was shifted in the same direction , but in other conditions , the magnitude of the after-effect was smaller for some of the cross-adaptation conditions . Temporal recalibration may also occur between other modalities than AV . For example , Navarra et al. -LRB- 2006 -RRB- demonstrated audio -- tactile temporal recalibration by exposing participants to streams of brief auditory and tactile stimuli presented in synchrony , or else with the auditory stimulus leading by 75 ms. Rather than a shift in the PSS , they observed that the JND to resolve audio -- tactile temporal order was larger after exposure to the desynchronized streams than after exposure to the synchronous streams . The authors argued that the temporal window for integration was widened due to audio -- tactile asynchrony . The goal of the present study was to explore whether spatial disparity between a sound and light affects temporal recalibration . According to the `` common notion '' of intersensory pairing , intersensory effects should be bigger when the individual components of a multisensory stimulus come from the same location -LRB- e.g. Welch and Warren 1980 ; Bedford 1989 ; Stein and Meredith 1993 ; Radeau 1994 ; Bertelson 1999 ; Welch 1999 -RRB- . However , Vroomen and Keetels -LRB- 2006 -RRB- demonstrated that , at least for temporal ventriloquism , spatial correspondence between sound and light is not important . In their study , a visual TOJ task was used with a sound presented before the first and after the second light . Temporal ventriloquism manifested itself as an improvement in the JNDs but , crucially , the improvement was unaffected by whether the sounds came from the same or a different position as the lights , whether the sounds were static or moved , or whether the sounds and lights came from the same or opposite sides of fixation . Keetels et al. -LRB- 2007 -RRB- further examined how principles of auditory grouping -LRB- Bregman 1990 -RRB- relate to intersensory pairing . They embedded two sounds that normally enhance sensitivity on the visual temporal order judgement task in a sequence of flanker sounds , which either had the same or different frequency , rhythm , or location . In all experiments , temporal ventriloquism only occurred when the two capture sounds differed from the flankers , thus demonstrating that intramodal grouping of the sounds in the auditory stream took priority over intersensory pairing . By combining principles of auditory grouping with intersensory pairing , they also demonstrated that the capture sounds could , counter-intuitively , be more effective when their locations differed from that of the lights rather than when they came from the same position , thus demonstrating that sound location mattered for auditory grouping , but not intersensory pairing . Here we examined whether , like in temporal ventriloquism , spatial disparity is ignored when temporal recalibration is at stake . Participants were exposed for 3 min to a train of asynchronous sounds and lights that came either from the same or a different location . Following exposure , participants performed an AV TOJ task with sounds and lights from either the same or different location . This design allowed us to address two questions . First , we could test whether temporal recalibration is affected by spatial disparity between the sounds and lights . Recalibration is usually considered to be a low-level perceptual learning phenomenon necessary for re-alignment of the senses -LRB- Bertelson and de Gelder 2004 -RRB- . Observing an after-effect following exposure to spatially disparate sound -- light pairs would provide strong evidence that spatial co-occurrence is , even at this early stage , not necessary for intersensory pairing to occur . Secondly , the use of an exposure -- test design allowed us to introduce a change between the exposure and test stimulus so that we could test whether after-effects generalize to different test stimuli . Here we tested whether spatial similarity between the exposure and test sound affects after-effects . If spatial co-location plays no role in intersensory pairing , one would expect stimulus generalization across space to be complete . Method Participants Thirty students from Tilburg University received course credits for their participation . All reported normal hearing and normal or corrected-to-normal vision . They were tested individually and were unaware of the purpose of the experiment . The study was carried out along the principles laid down in the Helsinki Declaration and informed consent from the participants was obtained . Stimuli Participants sat at a table in a dimly lit and sound-proof booth . Head movements were precluded by a chin-rest . Visual stimuli were presented by a green LED , positioned at central location , at 70 cm from the subject 's eyes -LRB- diameter of 0.5 cm , luminance of 40 cd/m2 -RRB- . Auditory stimuli were 88 dB sound bursts presented by one of two loudspeakers ; one directly behind the green LED and the other placed laterally at 70 cm distance on either the far left or the far right of the subject -LRB- i.e. , 90 degrees of spatial separation between the sound and light -RRB- . See Fig. 1 for a schematic view of the experimental set-up . The sounds and lights each had a duration of 10 ms. A small red LED , placed 2 cm below the green LED , was constantly lit during the experiment and served as fixation point . Fig. 1Schematic illustration of the experimental conditions . In the exposure phase , the subject was exposed to a sound -- light pair with 100 ms temporal offset -LRB- either sound-first or light first -RRB- . During exposure , sounds were either presented from central -LRB- a , c -RRB- or lateral location -LRB- b , d -RRB- . In the test phase , sound -- light pairs were presented with a particular SOA ranging between − 240 and 240 ms , with negative values indicating that the sound was presented first . Sounds of the test-stimulus pair either came from central -LRB- a , b -RRB- or lateral location -LRB- c , d -RRB- Design Three within-subjects factors were used : exposure lag during the exposure phase -LRB- − 100 and +100 ms , with negative values indicating that the sound was presented first -RRB- , location of the sound during exposure -LRB- exposure-sound central or lateral -RRB- and SOA between the sound and light of the test stimuli -LRB- − 240 , − 120 , − 90 , − 60 , − 30 , 0 , +30 , +60 , +90 , +120 , and +240 ms , with negative values indicating that the sound came first -RRB- . The location of the test sound -LRB- central or lateral -RRB- was a between-subjects variable . Half of the participants were tested with central test sounds , the other with lateral test sounds . These factors yielded 44 equi-probable conditions for each location of the test sound -LRB- 2 × 2 × 11 -RRB- , each presented 12 times for a total of 528 trials . Trials were presented in eight blocks of 66 trials each . The exposure lag and the location of the exposure sound were constant within a block , while the SOA between sound and light varied randomly . The order of the blocks was counterbalanced across participants . In half of the blocks with a lateral exposure sound , the sound came from the left , in the other half from the right . The lateral test sounds were presented from the same side as during exposure . Procedure Each block started with an exposure phase consisting of 240 repetitions -LRB- ∼ 3 min -RRB- of a sound -- light stimulus pair -LRB- ISI = 750 ms -RRB- with a constant lag -LRB- − 100 or +100 ms -RRB- between the sound and the light . After a 2,500 ms delay , the first test trial then started . To ensure that participants were fixating the light during exposure , they had to detect the occasional occurrence of the offset -LRB- 150 ms -RRB- of the fixation light -LRB- i.e. , a catch trial -RRB- . Participants then pushed a special button . The test phase consisted of two parts : a short AV re-exposure phase followed by three AV test trials of which the temporal order of the sound and light had to be judged . The re-exposure phase consisted of a train of ten sound-light pairs with the same lag , ISI , and sound location as used during the immediately preceding exposure phase . After 1 s , the three AV test trials were presented with a variable SOA between the sounds and lights . The participant 's task was to judge whether the sound or the light of the test stimulus was presented first . An unspeeded response was made by pressing one of two designated keys on a response box . The next test stimulus was presented 500 ms after a response , and the re-exposure phase of the next trial started 1,000 ms after the response on the third test stimulus . To acquaint participants with the TOJ task , experimental blocks were preceded by four practice blocks in which no exposure preceded the test trials . The first two practice blocks were to acquaint participants with the response buttons , and consisted of 16 trials in which only the largest SOAs were presented -LRB- ± 240 and ± 120 -RRB- . During this part , participants received verbal feedback -LRB- `` correct '' or `` wrong '' -RRB- about whether they gave the correct response or not . The next two practice blocks consisted of 66 trials in which all SOAs were presented 6 times randomly without verbal feedback . Total testing lasted approximately 2.5 h. Results Trials of the practice session were excluded from analyses . The proportion of `` light-first '' responses was for each participant calculated for each combination of exposure lag -LRB- − 100 , +100 ms -RRB- , location of the exposure sound -LRB- central , or lateral -RRB- , location of the test sound -LRB- central , or lateral -RRB- and SOA -LRB- ranging from − 240 to +240 ms -RRB- . Performance on catch trials was flawless , indicating that participants were indeed looking at the fixation light during exposure . For each combination of exposure lag , location of the exposure sound and location of the test sound , an individually determined psychometric function was calculated over the SOAs by fitting a cumulative normal distribution using maximum likelihood estimation . The mean of the resulting distribution -LRB- the interpolated 50 % crossover point -RRB- is the point of subjective simultaneity -LRB- henceforth the PSS -RRB- , and the slope is a measure of the sharpness with which stimuli are distinguished from one another . The slope is inversely related to the just noticeable difference -LRB- JND -RRB- and represents the interval -LRB- absolute SOA -RRB- at which 25 and 75 % visual-first responses were given . The PSS and the JND data are shown in Fig. 2 and Table 1 . Temporal recalibration was expected to manifest itself as a shift of the PSS in the direction of the exposure lag . The temporal recalibration effect -LRB- TRE -RRB- was therefore computed by subtracting the PSS following auditory-first exposure from visual-first exposure . Fig. 2The proportions of visual-first responses -LRB- V-first -RRB- for each exposure lag -LRB- − 100 ms sound-first , 100 ms light-first -RRB- for each combination of location of exposure sound -LRB- central , lateral -RRB- and location of the test sound -LRB- central , lateral -RRB- Table 1Mean points of subjective simultaneity -LRB- PSSs -RRB- in ms , and mean just noticeable differences -LRB- JND -RRB- in parenthesesLocation test sound Location of the exposure soundCentral LateralAV-lag -LRB- ms -RRB- PSS -LRB- JND -RRB- TREPSS -LRB- JND -RRB- TRECentral − 100 − 12.5 -LRB- 39.3 -RRB- 14.5 − 9.9 -LRB- 37.8 -RRB- 6.41002.0 -LRB- 40.8 -RRB- − 3.5 -LRB- 38.6 -RRB- Lateral − 1006.1 -LRB- 38.2 -RRB- 14.2 − 14.3 -LRB- 36.4 -RRB- 16.810020.3 -LRB- 36.1 -RRB- 2.5 -LRB- 42.0 -RRB- Exposure stimulus pairs were presented with an auditory -- visual Lag -LRB- AV-lag -RRB- of − 100 and +100 ms with sounds either central or lateral ; the location of the test stimulus sound was either central or lateral . The temporal recalibration effect -LRB- TRE -RRB- reflects the difference in PSSs between the − 100 and +100 ms audio -- visual lags An overall 2 × 2 × 2 ANOVA with as within-subjects factors exposure lag , location of the exposure sound and as between-subjects factor location of the test sound was run on the JNDs . None of the effects was significant -LRB- all P > 0.08 -RRB- , except for a second-order interaction between exposure lag , exposure location and test location , F -LRB- 1,28 -RRB- = 4.6 , P = 0.041 . Inspection of Table 1 shows that the differences between the JNDs -LRB- on average 38.7 ms -RRB- were rather small and unsystematic . The ANOVA on the TREs only showed a significant effect of exposure lag , F -LRB- 1,28 -RRB- = 23.0 , P < 0.001 , demonstrating , as predicted , that the exposure phase shifted the PSS such that there were more visual-first responses after sound-first exposure than after light-first exposure -LRB- i.e. the TRE -RRB- . The average TRE was 12.9 ms or 6.5 % of the exposure lag . The overall size of this effect corresponds well with previous reports -LRB- Fujisaki et al. obtained an average TRE of 12.5 % ; Vroomen et al. an average TRE of 6.7 % -RRB- . There were , furthermore , no main effects of location of the exposure and test sound , and the crucial interaction between the location of the exposure and test sound was non-significant -LRB- all F < 1 -RRB- . Temporal recalibration thus manifested itself no matter whether exposure sounds came from central or lateral location , and whether the location of the exposure and test sounds was changed or not . Discussion The goal of the present study was to address whether spatially co-located AV asynchronous stimulus pairs induce temporal recalibration as much as spatially dislocated stimuli do , and whether spatial correspondence between the exposure and test sound affects the size of this effect . Results showed that in all cases , there were clear temporal recalibration effects as subjective simultaneity was shifted in the direction of the adapted audiovisual lag . The shift was equally big for spatially separated and spatially co-located exposure stimuli . Apparently , spatial separation between the sound and light did not hinder temporal realignment . Stimulus generalization across space was also complete , as the shift in temporal alignment was equally big for when the exposure and test sound came from the same or different positions . The results therefore support the notion that spatial alignment between the senses is unimportant for AV pairing in the temporal domain . The results are also in line with previous reports on temporal ventriloquism -LRB- Keetels et al. 2007 ; Vroomen and Keetels 2006 -RRB- where it was shown that spatial separation does not affect the capturing effect of a light by a sound . Taken together , these findings provide strong evidence that spatial co-occurrence is , even at early perceptual stages , not a necessary constraint for intersensory pairing . One might object , though , that spatial ventriloquism has diminished the potential effects of spatial discordance . It is well-known that the apparent location of a sound can be shifted towards a visual stimulus that is presented at approximately the same time -LRB- Howard and Templeton 1966 ; Radeau and Bertelson 1978 ; Welch 1978 ; Bertelson and Radeau 1981 ; Bertelson 1994 , 1999 ; Radeau 1994 -RRB- . Could it be , then , that the AV spatial discordance in our set-up was diminished , if not became unnoticeable due to spatial ventriloquism ? If so , one may not observe an effect of spatial separation on temporal recalibration . This argument , though , seems highly unlikely because it is known that spatial ventriloquism dramatically declines whenever spatial separation exceeds approximately 15 degrees -LRB- Slutsky and Recanzone 2001 ; Godfroy et al. 2003 -RRB- . Given that we maximized the spatial separation between the sound and light -LRB- i.e. , at 90 degrees azimuth -RRB- , and that informal testing indeed confirmed that spatial separation was clearly noticeable , it seems safe to assume that spatial ventriloquism did not diminish the effect of spatial discordance . One might also ask whether the visual task as used during the exposure phase -LRB- i.e. , detection of the offset of visual fixation -RRB- resulted in an attentional shift towards the visual modality . According to the `` law of prior entry '' -LRB- Titchener 1908 -RRB- , attending to one sensory modality speeds up the perception of stimuli in that modality , resulting in a change in the PSS -LRB- see also Shore et al. 2001 , 2005 ; Spence et al. 2001 ; Schneider and Bavelier 2003 ; Zampini et al. 2005b -RRB- . Our visual task might thus result in a shift of the PSS towards more `` visual-first '' responses . However , this shift should be uniform for all conditions , and given that temporal recalibration is expressed as a difference in the PSS between exposure lags , the possible role of attention will be subtracted out . A remarkable aspect of the data is that previous studies have demonstrated that AV temporal order judgements become more sensitive -LRB- i.e. smaller JND -RRB- when the sound and light of the test stimuli are spatially separated -LRB- see also Bertelson and Aschersleben 2003 ; Spence et al. 2003 ; Zampini et al. 2003a , b , 2005a ; Keetels and Vroomen 2005 -RRB- . Here , there was a small trend in this direction -LRB- average JND of 39.1 vs. 38.2 ms , for spatially co-located vs. separated test stimuli , respectively -RRB- , but the effect was non-significant . Possibly , we might have picked up this difference if the effect were measured as a within-subjects factor . For the current purpose , though , this was considered to be unpractical because it would have doubled individual testing time . Despite that we did not observe an effect of AV spatial separation on the JNDs , the data speak on the interpretation on this effect . At least two explanations have been brought up for the improved temporal sensitivity when the locations of test sound and light differ . One is that there is more intersensory integration with as a consequence that the temporal discordance is fused ; the other is that there are extra spatial cues that help TOJ performance -LRB- Spence et al. 2003 -RRB- . Given that our results show that intersensory pairing occurs independent of a spatial mismatch -LRB- see also Vroomen and Keetels 2006 ; Keetels et al. 2007 -RRB- , it seems more likely that the previously observed effects of spatial separation on temporal sensitivity were induced by the availability of redundant spatial cues rather than fusion per se . To conclude , our results provide strong evidence for the claim that commonality in space between a sound and light is not relevant for AV pairing in the temporal domain . This may , at first sight , seem unlikely , because after all , most natural multisensory events are spatially and temporally aligned . However , a critical assumption that underlies the idea of spatial correspondence for cross-modal pairing is that space has the same function in vision and audition . This notion , though is arguable , as it has been proposed that the role of space in hearing is to steer vision -LRB- Heffner and Heffner 1992 -RRB- , while in vision it is an indispensable attribute -LRB- Kubovy and Van Valkenburg 2001 -RRB- . If one accepts that auditory spatial perception evolved for steering vision , but not for deciding whether sound and light belong together , there is no reason why cross-modal interactions would require spatial co-localization . Our results therefore have also important implications for designing multimodal devices or creating virtual reality environments , as they show that the brain can ignore cross-modal discordance in space .

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O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

spatial disparity
temporal order judgment
temporal recalibration


Preadolescent presentation of a lumbar chordoma : results of vertebrectomy and fibula strut graft reconstruction at 8 years Chordoma is a tumour of notochordal origin which usually involves the sacrum or skull base presenting in adulthood . Chordoma in a mobile spinal segment is infrequent and the authors report an extremely rare presentation of L3 chordoma in a child aged 7 years . Although a benign tumour , mobile segment chordoma is more locally aggressive , more likely to metastasise and has a poorer 5 year survival than sacral and clival lesions . Wide surgical excision and reconstruction is the treatment of choice in vertebral chordoma . This case was treated with staged vertebrectomy and fibular strut graft reconstruction and the results of clinical and radiological follow up at 8 years are presented . Case report A previously well 7-year old child presented with a 6 month history of right anterior thigh and knee pain . Examination revealed a marked list to the right , painful restriction of spine movements in all directions , an absent right knee jerk with reduced sensation in the right L3 distribution . There was no motor weakness or sphincter disturbance . Back pain restricted straight leg raise bilaterally to 30 ° . No history of weight loss , systemic symptoms and no past medical and family history of relevance . Blood tests were within normal limits . Inflammatory markers were not elevated . Plain radiographs revealed an osteolytic lesion in the posterior body of L3 . MRI of the whole spine identified an isolated lesion at L3 with right pedicle involvement and tumour extension anterior to the dural sac at L4 -LRB- Fig. 1 -RRB- . Isotope bone scan showed no increased uptake . A staging CT of the chest showed no evidence of metastases . Fig. 1Pre-operative MRI scan of lumbar spine showing the lesion involving L3 vertebra Transpedicular biopsy at L3 was performed and histology revealed fragments of remodelling bone , haemorrhage and a myxoid tissue containing strips and ribbons of cohesive , vacuolated cells . These cells had the appearance of notochordal-type tissue . Immunohistochemistry was positive for Cytokeratin S-100 . In view of the histological findings and atypical young age of presentation a radical 360 ° L3 vertebrectomy with pedicle screw stabilization and fusion was planned . At operation the L3 tumour had extended through the lamina and transverse process on the right compromising the right L3 nerve root . There was both cranial and caudal extradural extension of the tumour anterior to the dural sac with tenting from L2 to L4 . A wide decompression was performed with resection of the posterior elements and partial posterior vertebrectomy at L3 . To ensure that the tumour within the spinal canal was completely excised it was necessary to resect the inferior lamina of L2 and most of the lamina at L4 bilaterally . Hence it was felt appropriate to extend the instrumentation inferiorly to L5 . Pedicle screw instrumentation was performed at L2 and L5 bilaterally . Free fat graft was placed over the dura and nerve roots . Bone graft was placed posterolaterally from L2 to L5 -LRB- Fig. 2 -RRB- . An epidural infusion was used postoperatively for pain relief . Initial post operative neurological assessment was normal . Fig. 2AP and lateral X-rays following first stage of the procedure The following day deterioration in her lower limb neurological status was noted with no active movement or sensation in her lower limbs . That this was not recognised immediately was in part attributed to her epidural and to some difficulty with neurological assessment in a young child with systemic analgesia after major surgery . She was returned to theatre where a large haematoma was found and drained . Although subsequent sensory recovery was good , her motor recovery was slow with grade 1 power in her lower limbs . Two weeks later , once progressive neurological recovery was established , she underwent second stage anterior vertebrectomy of L3 through a retroperitoneal approach . Unilateral L2 , L3 and L4 segmental vessels were ligated to expose L3 . A complete excision of the remaining L3 and posterior longitudinal ligament was performed in order to adequately decompress the dural sac anteriorly . Three fibular strut autografts from L2 to L4 were used to reconstruct the anterior column . Posterior iliac crest graft was used for further augmentation -LRB- Fig. 3 -RRB- . Fig. 3AP and lateral X-rays following second stage of the procedure showing the fibular strut grafts used Neurological recovery continued post-operatively and she had regained normal sensation and grade 5 motor power in both lower limbs by 6 months . Bladder sphincter dysfunction has persisted , requiring intermittent self catheterisation and anti-cholinergic medication . She was nocturnally continent . Bowel function remained normal throughout . Radiographic fusion was evident at 6 months . Metal work was removed at 12 months and intra-operative biopsy showed no tumour recurrence -LRB- Fig. 4 -RRB- . Fig. 4AP and lateral X-rays following removal of metal work showing consolidation of the strut grafts She remained under annual follow-up with MRI and plain radiographs . At 8 years she has no evidence of tumour recurrence . Her neurological status is unchanged . Imaging has shown excellent remodelling of the graft -LRB- Figs. 5 , 6 -RRB- . She is skeletally matured with no lower limb malalignment and experienced no fibular donor graft site morbidity . Fig. 5Chronological X-rays showing graft incorporationFig . 6Eight year follow-up MRI Scan Discussion Chordoma is a primary bone tumour arising from notochord remnants . It is a rare tumour accounting for only 1 -- 4 % of primary bone tumours -LSB- 1 -RSB- . Chordoma is usually a slow growing tumour , often with local recurrence and it may metastasise late in its course -LSB- 1 -RSB- . Typically it presents in late middle age and may occur anywhere along the spinal column . Chordoma is found most commonly in the clivus , sacrum and infrequently in the mobile vertebrae -LSB- 2 -RSB- . The optimum treatment for vertebral chordoma is wide surgical excision . Radiotherapy may provide short term benefit when adequate excision is not possible and in cases of local recurrence -LSB- 3 -RSB- . Surgical treatment has become more aggressive in recent years evolving from intralesional debulking to en bloc resection , as documented by Boriani et al. , over a 45-year period in their treatment of 21 cases of chordoma located in the spine above the sacrum -LSB- 4 -RSB- . Chordomas are considered to be low grade tumours and metastases are infrequent at presentation -LSB- 1 , 5 -RSB- . The prognostic value of staging is therefore diminished , compared to the value of staging in other bone tumours , because all these tumours are stage IA or IB according to the Musculoskeletal Tumor Society Staging System -LSB- 6 -RSB- . Mobile segment chordomas have a 50 % survival rate at 5 years and a 28 % survival rate at 10 years -LSB- 4 , 7 -RSB- . Sacral chordomas on the other hand are reported as having 86 % 5 year survival -LSB- 3 -RSB- . Treatment outcome is significantly influenced by the size and site of chordoma -LSB- 1 , 4 -RSB- . Chordomas found in the vertebral bodies appear to be more aggressive than those arising in the clivus or the sacrum -LSB- 3 -RSB- . Metastases have been reported in 80 % of the vertebral body chordomas , as compared to a rate of 43 % of all chordomas -LSB- 3 -RSB- . However , the survival rate appears to be affected more by local tumour progression than by metastases -LSB- 1 -RSB- . Conclusion This case is unusual given the young age at presentation . She is the youngest patient reported in world literature . Despite the poorer published results of mobile segment chordomas , radical surgical excision and reconstruction has resulted in an 8 year disease free survival . Fibular strut graft reconstruction proved an excellent reconstructive option in the growing skeleton with potential for remodelling . It is likely that the young age has contributed to the near complete neurological recovery .

O O O O O B O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O B I I O O O O O O O O O O O O B O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

chordoma
benign tumour
mobile spinal segment
vertebrectomy
fibular strut graft reconstruction


Prevalence of anatomical variants and coronary anomalies in 543 consecutive patients studied with 64-slice CT coronary angiography The aim of our study was to assess the prevalence of variants and anomalies of the coronary artery tree in patients who underwent 64-slice computed tomography coronary angiography -LRB- CT-CA -RRB- for suspected or known coronary artery disease . A total of 543 patients -LRB- 389 male , mean age 60.5 ± 10.9 -RRB- were reviewed for coronary artery variants and anomalies including post-processing tools . The majority of segments were identified according to the American Heart Association scheme . The coronary dominance pattern results were : right , 86.6 % ; left , 9.2 % ; balanced , 4.2 % . The left main coronary artery had a mean length of 112 ± 55 mm . The intermediate branch was present in the 21.9 % . A variable number of diagonals -LRB- one , 25 % ; two , 49.7 % ; more than two , 24 % ; none , 1.3 % -RRB- and marginals -LRB- one , 35.2 % ; two , 46.2 % ; more than two , 18 % ; none , 0.6 % -RRB- was visualized . Furthermore , CT-CA may visualize smaller branches such as the conus branch artery -LRB- 98 % -RRB- , the sinus node artery -LRB- 91.6 % -RRB- , and the septal branches -LRB- 93 % -RRB- . Single or associated coronary anomalies occurred in 18.4 % of the patients , with the following distribution : 43 anomalies of origin and course , 68 intrinsic anomalies -LRB- 59 myocardial bridging , nine aneurisms -RRB- , three fistulas . In conclusion , 64-slice CT-CA provides optimal visualization of the variable and complex anatomy of coronary arteries because of the improved isotropic spatial resolution and flexible post-processing tool . Introduction Since the beginning of the 1990s , a variety of non-invasive techniques have been introduced in coronary artery imaging in an attempt to replace invasive conventional coronary angiography -LRB- CCA -RRB- . These techniques have shown promising results , although they were considered inadequate for large-scale clinical implementation . Furthermore , advanced modalities such as magnetic resonance -LRB- MR -RRB- and electron-beam computed tomography -LRB- EBCT -RRB- are still not widely available on the territory -LSB- 1 -- 6 -RSB- . The introduction of multislice computed tomography coronary angiography -LRB- MSCT-CA -RRB- allowed the detection of significant coronary artery stenosis . Improved performance of 64-slice CT equipment , characterized by isotropic spatial resolution and faster temporal resolution , provided a valid alternative to CCA in selected patient populations -LSB- 7 -- 11 -RSB- . MSCT-CA is currently considered the ideal tool to three-dimensionally visualize the complex and tortuous anatomy of coronary arteries -LSB- 12 , 13 -RSB- . Previous studies with four - and 16-slice CT-CA demonstrated that anomalous coronary arteries may be defined -LSB- 14 -- 16 -RSB- . However , to the best of our knowledge , 64-slice studies with large patient series have not yet been published . In the present study , a large patient population who underwent 64-slice CT-CA was reviewed to assess the prevalence of coronary artery variants and anomalies . Materials and methods Population A total of 543 consecutive patients -LRB- 389 male , 154 female , mean age 60.5 ± 10.9 , range 21 -- 87 years -RRB- , who underwent 64-slice CT-CA from 27/07/2004 to 28/02/2006 in our department , were reviewed for coronary artery variants and anomalies . The majority of patients -LRB- n = 476 -RRB- were scheduled for CCA because of suspected or known coronary artery disease -LRB- CAD -RRB- . The other 67 patients were addressed to 64-slice MSCT-CA after CCA to determine the three-dimensional image of a suspected origin or course anomaly . The indication for MSCT-CA were : atypical angina -LRB- n = 111 -RRB- , typical angina with inconclusive stress test -LRB- n = 162 -RRB- , presence of risk factors and high risk of major coronary events -LRB- n = 46 -RRB- , proximal stent patency follow-up -LRB- n = 112 -RRB- and by-pass patency follow-up -LRB- n = 45 -RRB- . The Institutional Review Board approved the study protocol . CT scan and reconstruction parameters All examinations were performed with a 64-slice CT scanner -LRB- Sensation 64 , Siemens , Forcheim , Germany -RRB- with the following parameters : slices/collimation 32/0 .6 mm , rotation time 330 ms , effective temporal resolution -LRB- with 180 ° algorithm -RRB- 165 ms , 120 kv , 900 mAs , table feed/s 11.63 mm , effective slice thickness 0.6 mm , reconstruction increment 0.3 mm , field of view -LRB- FOV -RRB- 140 -- 180 mm , isotropic voxel resolution of 0.4 × 0.4 × 0.4 mm . Patients with heart rate > 70 bpm received 100 mg of metoprolol per os 1 h prior the examination . A bolus of 100 ml of high iodinated contrast material -LRB- 400 mg/ml iomeprol , Iomeron 400 , Bracco , Milan , Italy -RRB- was injected into an antecubital vein of the right arm with a flow rate of 5 ml/s , followed by a 40-ml saline chaser . A bolus-tracking technique was used for the synchronization between arterial passage of contrast material and MSCT-CA . Data were reconstructed by retrospective gating in end-diastolic phase -LRB- from -300 to -450 ms before the peak of the subsequent R wave -RRB- or end-sistolic phase to better image the right coronary artery -LRB- RCA -RRB- . Image and data analysis All CT examinations were reviewed by three radiologists -LRB- L.L.G. , R.M. and F.A. -RRB- with a level 3 expertise in cardiac CT -LSB- 17 -RSB- , who loaded the datasets off-line into a dedicated workstation -LRB- Leonardo , Siemens , Germany -RRB- . A total number of 559 examinations were performed and only 13 scans were considered not assessable by the readers in consensus due to poor image quality -LRB- severe breathing , triggering or motion artefacts -RRB- . All data were analysed with post-processing tools such as multiplanar reconstructions -LRB- MPR -RRB- , curved MPR -LRB- cMPR -RRB- , maximum intensity projections -LRB- MIP -RRB- , and volume rendering -LRB- VR -RRB- to three-dimensionally image the complex anatomy of the coronary artery tree . Disagreement was solved by a consensus reading . Segments were classified according to the American Heart Association -LRB- AHA -RRB- scheme . Variants considered were : the coronary dominance -LRB- right , left , balanced -RRB- , the variable origin of the conus branch and sinus node artery , the left main -LRB- LM -RRB- length , the presence of the intermediate branch , the number of diagonal and marginal branches . Anomalies of origin and course , intrinsic coronary anomalies -LRB- myocardial bridging , aneurisms > 1.5 mm -RRB- and termination anomalies -LRB- fistulas -RRB- were checked . Prevalence data of single coronary artery variants and anomalies were collected . Results Our cohort results were heterogeneous because of the multi-ethnic Dutch population -LRB- immigrants 11 % , Table 1 -RRB- . Table 1Our population resulted heterogeneous because of the multiethnic Dutch populationEthnic group % -LRB- n -RRB- The Netherlands88 .95 -LRB- 483 -RRB- Middle East Asia3 .31 -LRB- 18 -RRB- South-East Asia2 .94 -LRB- 16 -RRB- East Europe1 .84 -LRB- 10 -RRB- South Europe1 .10 -LRB- 6 -RRB- South America0 .92 -LRB- 5 -RRB- Africa0 .92 -LRB- 5 -RRB- Most of coronary segments were identified , although with a variable rate due to different diameters -LRB- Table 2 -RRB- . The anatomical variants of the coronary artery tree are extremely frequent -LRB- Table 3 -RRB- . According to the literature , the dominance was right in 86.6 % -LRB- n = 470 -RRB- , left in 9.2 % -LRB- n = 50 -RRB- , balanced in 4.2 % -LRB- n = 23 -RRB- -LSB- 18 -RSB- . The LM trunk -LRB- segment 5 -RRB- presented a variable length -LRB- mean 112 ± 55 mm , range 17 -- 601 mm , median 106 mm -RRB- : < 1 cm -LRB- n = 226 , 41.6 % -RRB- , 1 -- 2 cm -LRB- n = 257 , 47.3 % -RRB- , and > 2 cm -LRB- n = 38 , 7 % -RRB- -LRB- Fig. 1 -RRB- . The LM trunk was absent in 22 cases -LRB- 4.1 % -RRB- due to split origin of the left coronary artery -LRB- LCA -RRB- -LRB- n = 18 , 3.3 % -RRB- or other origin anomalies -LRB- n = 4 , 0.7 % -RRB- . A variable number of diagonal branches was observed : one diagonal branch in 136 cases -LRB- 25 % -RRB- , two diagonal branches in 270 cases -LRB- 49.7 % -RRB- , and more than two in 130 cases -LRB- 24 % -RRB- -LRB- Fig. 2 -RRB- . No diagonal branches were visualized in just seven cases -LRB- 1.3 % -RRB- . Marginal branches of the left circumflex -LRB- LCX -RRB- artery were observed in the 99.4 % -LRB- n = 540 -RRB- : one in 191 cases -LRB- 35.2 % -RRB- , two in 251 cases -LRB- 46.2 % -RRB- , and more than two in 98 cases -LRB- 18 % -RRB- -LRB- Fig. 2 -RRB- . Table 2Segments visualized according to the American Heart Association classificationSegments % -LRB- n -RRB- 199.8 -LRB- 542 -RRB- 299.3 -LRB- 539 -RRB- 397.8 -LRB- 531 -RRB- 492.4 -LRB- 502 -RRB- 595.9 -LRB- 521 -RRB- 6100 -LRB- 543 -RRB- 7100 -LRB- 543 -RRB- 897.8 -LRB- 531 -RRB- 998.7 -LRB- 536 -RRB- 1073.7 -LRB- 400 -RRB- 11100 -LRB- 543 -RRB- 1299.4 -LRB- 540 -RRB- 1397.2 -LRB- 528 -RRB- 1464.3 -LRB- 349 -RRB- 1572.4 -LRB- 393 -RRB- 16a21 .9 -LRB- 119 -RRB- aSegment 16 refers to the intermediate branchTable 3Prevalence of coronary artery variants -LRB- RCA right coronary artery , LAD left anterior descending artery , LCX left circumflex , LM left main , ND not detected -RRB- Variants Patients % -LRB- n -RRB- Conus branchFrom proximal RCA64 .1 -LRB- 348 -RRB- From ostial RCA22 .3 -LRB- 121 -RRB- From aorta11 .6 -LRB- 63 -RRB- ND2 -LRB- 11 -RRB- Sinus node arteryFrom RCA65 .4 -LRB- 355 -RRB- From LCX16 .6 -LRB- 90 -RRB- From RCA and LCX9 .2 -LRB- 50 -RRB- From LCX and pulmonary artery0 .2 -LRB- 1 -RRB- From aorta0 .2 -LRB- 1 -RRB- ND8 .4 -LRB- 46 -RRB- LM length < 1 cm41 .6 -LRB- 226 -RRB- 1 -- 2 cm47 .3 -LRB- 257 -RRB- > 2 cm7 -LRB- 38 -RRB- Intermediate branch21 .9 -LRB- 119 -RRB- Diagonal branches from LADND1 .3 -LRB- 7 -RRB- 125 -LRB- 136 -RRB- 249.7 -LRB- 270 -RRB- > 224 -LRB- 130 -RRB- Septal branches from LAD93 -LRB- 505 -RRB- Marginal branches from LCXND0 .6 -LRB- 3 -RRB- 135.2 -LRB- 191 -RRB- 246.2 -LRB- 251 -RRB- > 218 -LRB- 98 -RRB- Fig. 1a LM length . b The separate origin of the LAD and LCX might cause technical difficulties during coronary angioplasty due to poor visualization . c -- e The LM may present variable lengthFig . 2Variable number and course of diagonal -LRB- a -- c -RRB- and marginal branches -LRB- d -- f -RRB- . The intermediate branch courses along the anterior wall of the left ventricle with a variable pattern -LRB- g -- i -RRB- When the intermediate branch supplies the vascularization of the antero-lateral wall of the left ventricle , a decreased number of diagonal branches -LRB- segments 9 and 10 -RRB- was observed : one , 38.6 % ; two , 43.7 % ; more than two , 14.3 % ; none , 3.4 % -LRB- Fig. 2 -RRB- . Furthermore , CT-CA may visualize smaller branches , such as the conus branch artery -LRB- 532/543 , 98 % -RRB- , the sinus node artery -LRB- 497/543 , 91.6 % -RRB- , and the septal branches -LRB- 505/543 , 93 % -RRB- . The conus branch artery may arise from the right coronary artery -LRB- RCA -RRB- -LRB- 64.1 % -RRB- , in proximity with the RCA ostium -LRB- 22.3 % -RRB- or from the aorta -LRB- 11.6 % -RRB- . The sinus node artery may originate from the RCA -LRB- 355/543 , 65.4 % -RRB- , from LCX -LRB- 90/543 , 16.6 % -RRB- , from RCA and LCX -LRB- 50/543 , 9.2 % -RRB- , from LCX and pulmonary artery -LRB- 0.2 % -RRB- , or from aorta -LRB- 0.2 % -RRB- -LRB- Fig. 3 -RRB- . Fig. 3The variable origin of the conus branch artery -LRB- arrow -RRB- : from RCA -LRB- a -RRB- , in proximity with the ostium -LRB- b -RRB- , and from aorta -LRB- c -RRB- . The variable origin of the sinus node artery -LRB- arrowhead -RRB- : from RCA -LRB- d -RRB- , from LCX -LRB- e -RRB- , or both pathways may be present -LRB- f -RRB- Coronary anomalies were observed in the 18.4 % of our population -LRB- n = 100 -RRB- . Patients presented single or associated coronary anomalies -LRB- Table 4 -RRB- . Table 4Prevalence of coronary artery anomalies -LRB- LM left main artery , PDA posterior descending artery -RRB- Coronary anomaliesPatients % -LRB- n -RRB- Myocardial bridging10 .9 -LRB- 59 -RRB- Absent LM3 .3 -LRB- 18 -RRB- Rotation of the aortic root with normal coronary origin from the sinuses of Valsalva2 .6 -LRB- 14 -RRB- Coronary aneurysms1 .6 -LRB- 9 -RRB- Anomalies of origin and course1 .5 -LRB- 8 -RRB- Fistulas0 .5 -LRB- 3 -RRB- Early take-off of PDA0 .5 -LRB- 3 -RRB- Single or multiple myocardial bridging was visualized in 59 patients -LRB- 10.9 % -RRB- -LRB- Fig. 4 -RRB- . Forty-three anomalies of origin and course were found with the following distribution : absence of left main artery occurred in 18 patients -LRB- 3.3 % -RRB- , origin anomalies of the RCA and the LCA caused by rotation of the aortic root between 45 ° and 90 ° -LRB- with normal coronary origin from the sinuses of Valsalva -RRB- in 14 patients -LRB- 2.6 % -RRB- , anomalies of origin and course -LRB- with anomalous origin from the sinuses of Valsalva -RRB- in eight patients -LRB- 1.5 % -RRB- , early take-off of the posterior descending artery in three patients -LRB- 0.5 % -RRB- . The anomalies of origin and course encountered were : three retroaortic LCX -LRB- two arising from RCA , one from the right sinus of Valsalva -RRB- , two inter-arterial LCAs from RCA , two inter-arterial RCAs from the left sinus of Valsalva , one septal RCA from left sinus of Valsalva -LRB- Fig. 5 -RRB- . Fig. 4Examples of myocardial bridging -LRB- arrowhead -RRB- . Myocardial bridging of mid-LAD displayed by MPR -LRB- a -RRB- and VR -LRB- b -RRB- images . Another case of myocardial bridging depicted by conventional angiogram in systole -LRB- c -RRB- , not visualized in diastolic image -LRB- d -RRB- , and clearly displayed by VR image -LRB- e -RRB- Fig. 5Anomalies of origin and course -LRB- arrowhead -RRB- . VR -LRB- a -RRB- and MIP -LRB- b -RRB- images of a LCA arising from the RCA with a septal course as confirmed by conventional angiogram -LRB- c -RRB- . VR -LRB- d -RRB- and MIP -LRB- e -RRB- images of a RCA arising from the left sinus of Valsalva with an interarterial course , and corresponding conventional angiogram -LRB- f -RRB- . VR -LRB- g -RRB- and cMPR -LRB- h -RRB- images of a stented retroaortic LCX arising from the right sinus of Valsalva and corresponding conventional angiogram -LRB- i -RRB- Coronary aneurisms -LRB- > 1.5 mm , if compared with the normal vessel diameter -RRB- were identified in nine patients -LRB- 1.6 % -RRB- -LRB- Fig. 6 -RRB- . Coronary fistulas were observed in three patients -LRB- 0.5 % -RRB- -LRB- Fig. 7 -RRB- . Fig. 6Examples of coronary aneurisms . Aneurisms of LCX and LAD displayed by VR -LRB- a -RRB- and MIP -LRB- b -RRB- images , and corresponding conventional angiogram -LRB- c -RRB- . Aneurisms of the RCA depicted by VR image -LRB- d -RRB- and vessel tree isolation -LRB- e -RRB- , confirmed by the conventional angiogram -LRB- f -RRB- Fig. 7Abnormal termination of coronary arteries . Fistula between the RCA and the coronary sinus depicted by VR -LRB- a -RRB- , coronary tree isolation -LRB- b -RRB- , and MPR images -LRB- c -RRB- . Fistula between the LAD and the right ventricle displayed by VR -LRB- d -RRB- and coronary tree isolation images -LRB- e -RRB- , and corresponding conventional angiogram -LRB- f -RRB- Discussion The wrong interpretation of a coronary variant or anomaly might cause technical difficulties during interventional procedures or lead to clinical misdiagnosis or major complications might occur during graft surgery . The need for an accurate anatomical evaluation of the coronary artery tree is relevant during angioplasty , due to revascularization purposes -LSB- 19 -RSB- . Coronary anomalies are often asymptomatic and may be accidentally discovered . Given the increase of interventional procedures , the detection of coronary anomalies is becoming of major clinical importance -LSB- 20 -RSB- . The coronary anomalies can not be considered just rare aspects because they may often lead to relevant clinical consequences -LSB- 21 -RSB- . In an attempt to clarify the variability of the coronary artery tree , Angelini et al. -LSB- 18 -RSB- proposed these definitions : normal , any morphological feature observed in > 1 % of an unselected population ; normal variant , an alternative , relatively unusual , morphological feature seen in > 1 % of the population ; and anomaly , a morphological feature -LRB- number of ostia , proximal course , termination -RRB- rarely encountered -LRB- < 1 % -RRB- in the general population . However , the incidence of coronary anomalies is relevant not only for conceptual and educational purposes but , more importantly , for public health issues , given that 5.6 % of the total American population could have some kind of coronary anomaly -LSB- 18 -RSB- . Moreover , the 19 % of sudden deaths in young athletes are related to these anomalies -LSB- 22 -RSB- . That is a reason why the diagnosis of coronary anomalies should be a healthcare priority . To date , despite some limitations , CCA has been the `` gold standard '' for the diagnosis of coronary anomalies . Selective catheterization and subsequent interpretation of vessel anatomy may be difficult in CCA because the operator is not aware of an atypical location of the vessel orifice . Therefore , the diagnosis of a coronary anomaly is often established on the impossibility of finding the coronary arteries in their normal anatomical position . Finally , interpretation of the courses of anomalous coronary arteries may be erroneous because CCA is two-dimensional and can not provide enough information about the complex three-dimensional vessel anatomy -LSB- 18 , 23 , 24 -RSB- . The study with the largest number of cases , performed in North America at the Cleveland Clinic on 126,595 patients who underwent coronary angiography , reported a 1.3 % incidence -LSB- 25 -RSB- . In recent years , other techniques in cardiologic diagnostic imaging have been developed , such as trans-thoracic echocardiography -LRB- TTE -RRB- , trans-oesophageal echocardiography -LRB- TEE -RRB- , magnetic resonance angiography -LRB- MRA -RRB- , EBCT and MSCT -LSB- 1 -- 4 -RSB- . TTE , which is used mainly in paediatric radiology , does not always provide reliable diagnostic results . When performed on adult patients , it proves difficult to obtain diagnostic images owing to the interposition of the bones of the ribcage -LRB- ribs and sternum -RRB- , pulmonary parenchyma and subcutaneous adipose tissue -LSB- 5 , 26 -RSB- . Data reported in the literature suggest that TEE is more sensitive than TTE in identifying coronary anomalies and assessing their course , although it remains an invasive technique -LRB- i.e. insertion of a probe down the oesophagus and a varying degree of sedation according to patient tolerance required to perform the examination -RRB- characterised by a significant level of operator dependence and therefore impossible to perform as a screening test -LSB- 6 -RSB- . In addition , both echocardiography techniques are able to assess only the proximal tract of the coronary arteries , and therefore , their diagnostic capabilities are limited to only a part of coronary arteries -LSB- 6 -RSB- . MRA is a highly promising technique since no ionising radiation is used . In the study of the origin of the coronary arteries , MRA can provide more complete information than CCA , particularly in patients with other concomitant congenital cardiac anomalies -LSB- 1 , 27 -RSB- . The main limitation of MRA is incomplete visualisation of the coronary vessels , particularly their distal tracts . This limits the diagnostic capabilities for the assessment of fistulas , the origin of coronary arteries other than the aortic sinuses -LRB- i.e. from the pulmonary artery -RRB- and collateral vessels . However , MRA provides optimal functional assessment of complex congenital heart disease including anomalies of great vessels , and cardiac chambers and valves -LRB- the procedures may include evaluation of ventricular mass and volumes , quantification of valvular disease , and contrast enhancement -RRB- -LSB- 12 -RSB- . Ropers et al. -LSB- 2 -RSB- firstly studied the ability of contrast-enhanced EBCT to identify anomalous coronary arteries and their course with good accuracy . Recent advances in MSCT-CA equipments have continuously improved the quality of non-invasive coronary artery imaging . Various studies have demonstrated a high accuracy of coronary angiography with MSCT-CA for the diagnosis of CAD . In particular , the high negative predictive value of 64-slice CT allows to reliably exclude significant coronary artery stenoses -LSB- 7 -- 11 -RSB- . Given the high sensitivity and negative predictive value of the technique , MSCT could represent a non-invasive alternative to CCA in patients prior to cardiac valve surgery . By selecting only those patients with coronary significant lesions to undergo CCA , MSCT-CA could avoid cardiac catheterization in a large number of patients without CAD -LSB- 28 -RSB- . The latest advance of CT technology is represented by the dual-source CT coronary angiography -LRB- DSCT-CA -RRB- , with improved temporal resolution of 83 ms. Scheffel et al. -LSB- 29 -RSB- firstly demonstrated that DSCT-CA provides high diagnostic accuracy for assessment of CAD in a high pre-test probability population with extensive coronary calcifications and without heart rate control . The advantages of MSCT lie primarily in its high level of diagnostic and anatomical accuracy . The technique offers excellent spatial resolution with the possibility of performing a flexible post-processing -LRB- i.e. MPR , MIP , and VR -RRB- . Previous studies with four - and 16-slice CT-CA confirmed that the complex and tortuous coronary anatomy can be readily visualized and anomalous coronary arteries may be defined -LSB- 14 -- 16 -RSB- . To the best of our knowledge , that is the first 64-slice CT-CA with large patient population , which evaluates the prevalence of coronary arteries variants and anomalies . The AHA classification is the currently used scheme to identify the coronary artery segments and refers to 16 segments , in the attempt to standardize the remarks -LSB- 30 -RSB- . Another classification was reported by the BARI group , with emphasis to the coronary dominance pattern -LSB- 31 -- 33 -RSB- . According to literature data , the dominance was right in 86.6 % -LRB- n = 470 -RRB- , left in 9.2 % -LRB- n = 50 -RRB- and balanced in 4.2 % -LRB- n = 23 -RRB- -LSB- 18 -RSB- . The majority of coronary segments was identified according to the American Heart Association scheme . The intermediate branch was present in 119 patients -LRB- 21.9 % -RRB- , slightly less than reported in the literature -LSB- 34 -RSB- . However , the need for reporting the intermediate branch is stressed by the correlation between its presence and the decreased number of diagonal branches observed . Furthermore , the septal branches of the left anterior descending artery -LRB- LAD -RRB- were detected in the 93 % -LRB- 505/543 -RRB- . The opportunity of reporting septal branches of LAD must be taken into account because of the hemodinamic relevance of these vessels . The prevalence of coronary anomalies was estimated at the 18 % -LRB- 100/543 -RRB- in our population . This prevalence rate is higher than reported in the literature . However , our department is a major centre for cardiovascular pathologies and many patients were enrolled in non-invasive cardiovascular research projects . Myocardial bridging occurred in the 10.9 % , a prevalence more comparable with autopsy rates , than with angiographic series -LSB- 35 -RSB- . The split of LCA also had a prevalence higher than reported in the literature -LSB- 18 -RSB- . Eighty-five patients with not significant CAD presented 14 coronary anomalies -LRB- 16.5 % -RRB- . Four hundred and fifty-eight patients with significant CAD -LRB- with > 50 % stenosis , during stent or by-pass follow-up -RRB- presented 86 coronary anomalies -LRB- 18.8 % -RRB- . Therefore , the prevalence was similar in the two groups . However , a bias is given by the fact that 67 patients were addressed to 64-slice CT-CA after CCA to determine the three-dimensional imaging of a suspected anomaly . After excluding these 67 patients , the prevalence of coronary anomalies was higher in the CAD patients -LRB- 11.4 % vs 4.2 % -RRB- . The prevalence of myocardial bridging resulted higher in the CAD group -LRB- 7.4 % vs 2.8 % -RRB- . There are several limitations in our study . The first one is inherent to the heterogeneous population consisting of various ethnic groups -LRB- immigrants 11 % -RRB- with a substantial age range -LRB- 21 -- 87 years -RRB- . The age may affect the development of the collateral vascularization and influence the percentage of segments visualized . A second limitation is related to the high prevalence of origin anomalies , due to the fact that 67 patients were addressed to 64-slice CT-CA after CCA to determine the three-dimensional imaging of a suspected anomaly . As opposed to MRA , which also permits the non-invasive evaluation of coronary anomalies -LRB- proximal tracts -RRB- , MSCT-CA requires radiation and a contrast agent . However , the high spatial and temporal resolution make it reasonable to use MSCT-CA as one of the first-choice imaging modalities in the work-up of known and suspected coronary anomalies -LSB- 12 , 13 -RSB- . The high radiation exposure should be a matter of concern and debate in young patients . In these patients , the first-choice imaging modality could be MRA . In the case of suspected complex congenital heart disease -LRB- including anomalies of great vessels , and cardiac chambers and valves -RRB- , the use of MRA would be highly advisable , since the optimal evaluation of ventricular and valvular function is provided -LSB- 12 , 13 -RSB- . Compared with 16-slice CT-CA , 64-slice CT-CA provides improved temporal resolution and isotropic spatial resolution which allow optimal three-dimensional visualization of the variable and complex anatomy of coronary arteries . Sixty-four-slice CT-CA may non-invasively define normal anatomical variants from potentially dangerous anomalies and support the clinical management of referring cardiologists and cardiac surgeons .

O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O

multislice computed tomography
anatomical variants
anomalies