Individuals with WS are known to be mesmerized by music and to show heightened emotional reactions to sounds of all kinds 
. Their musical engagement and receptivity almost uniformly surpasses that of typically developing age peers. WS subjects also possess a remarkable ability to recognize and imitate environmental sounds, such as cars, vacuum cleaners or lawnmowers 
. Given that the auditory phenotype is strikingly homogenous across the group and the genetic defect is well characterized, WS offers a rare opportunity to study the relationship between genes, behavior, brain morphology and function. In the present study, we employed a multimodal psychoacoustic and neuroimaging approach and found extreme holistic sound perception in WS, coupled with functional and structural leftward asymmetry of AC.
Extreme and almost uniform holistic sound perception in WS represents a significant deviation from the distribution of sound perception in the general population. Strong holistic sound perception is in agreement with the fact that the WS individuals express high rhythmic creativity 
and are particularly fond of rhythmic and percussive instruments such as drums, keyboard and piano 
A number of groups have previously analyzed brain morphology in WS and consistently found total brain volume reduction, mainly attributable to reduced parietal and occipital lobe volumes 
. On the other hand increased gyrification and cortical complexity were repeatedly observed 
. Additionally, several brain areas have been reported as relatively preserved, such as superior temporal gyrus (STG), amygdala, orbitofrontal cortex and posterior vermis of the cerebellum; often accompanied by a left-hemispheric dominance 
. The relatively preserved volumes and greater cortical complexity of structures along the Sylvian Fissure were proposed to underlie the distinctive linguistic and auditory strengths in WS 
; however, this hypothesis has not been sufficiently corroborated so far.
The auditory phenotype and musical abilities in WS have been characterized by a number of investigators 
and some groups have attempted to correlate the unusual auditory phenotype with a neural substrate 
. Post mortem
studies on a small collection of WS brains have found preserved size of auditory cortex 
. But MRI-based neuroimaging studies that employed group analysis methods such as voxel based morphometry (VBM) could not corroborate such findings. It is a known caveat of the VBM technique that the considerable inter-individual variability of cortical and sulcal structures might be obscured 
. Very recently Martens et al. employed an individual analysis method and found significant volume increase of the left PT in a subgroup of WS subjects who demonstrated specific musical strengths 
; but this finding remained unexplained so far.
In the present study we applied an individual analysis method of high resolution MRI images to account for the differences of peripheral cortical structures such as the HG. In agreement with previous individual HG morphometry in musicians, HG was larger in the right hemisphere in CSP
listeners of the control group and more pronounced in the left hemisphere in CH
listeners. In WS subjects we found strong leftward HG asymmetry correlating with their extreme holistic sound perception. Furthermore, HG volumes exceeded by far those of normal controls, identifying a very probable neural basis of the distinctive auditory skills of WS individuals. This finding bore up against brain normalization, that is left HG volumes in WS subjects were also increased before taking total brain volume reduction into account. Such over-proportional HG volumes can be typically encountered in professional musicians and talented music students 
So far it remained a matter of unresolved controversy in the neuroscience community, whether such cortical volume differences in the AC reflect neuroplastic effects due to intense training 
or represent an innate predisposition to a particular talent, i.e.
musicality. Schneider et al.’s previous work suggests that AC volume correlates with musical aptitude independent of the degree of musical training 
. The present results corroborate this idea, since musical training was negligible in WS participants and the control subjects have been specifically matched for this parameter.
At the functional level auditory evoked fields measured by MEG showed the expected rightward asymmetry in CSP
listeners and leftward asymmetry in CH
listeners of the control groups. Such relative auditory lateralization based on individual sound perception has been previously reported 
and originates from dominant processing of temporal resolution and holistic sound perception in left AC 
and spectral as well as fine pitch resolution in right AC, respectively 
. In agreement with the psychoacoustic test results, we found a strong functional leftward asymmetry in the WS group as an electrophysiological correlate of their extreme holistic sound perception. In addition to this relative
asymmetry, amplitudes of left AEF in WS subjects were increased in absolute
terms to almost twice the size as compared to normal controls. Since equivalent P50 amplitudes have been reported for professional musicians 
, increased left auditory responses in WS individuals might be pointing to a putative electrophysiological substrate of their particular musicality.
In the general population the PT 
, which is the plane cortical structure posterior to the HG, is typically more extended in the left hemisphere compared to the right due to a generally smaller left HG 
. It has been independently reported by several authors that this PT asymmetry is often reduced in WS 
. But so far, there was no satisfactory explanation for this phenomenon. The present study is the first to identify that the reduced PT asymmetry is in fact consequential to increased left HG volume. Unfortunately, calculated HG volumes cannot necessarily be compared to all previous studies on HG volumes due to the inconsistent definition of anatomical AC landmarks. Martens et al. did not find any differences of the “primary AC” volumes but revealed increased volumes of the PT in WS in comparison to controls (as opposed to increased HG in our study). However, the authors employed different definitions of AC structures and discuss restricted comparability as a critical point. We believe that their data are well in line with ours since structures they categorized as PT (i.e.
partial HG duplications) would have been ascribed to HG or HG duplications according to our definition. Interestingly in this respect is that Martens et al. also found leftward asymmetry (of the planum temporale) in a subgroup of particularly musical WS subjects, which is in accordance with our results 
We based our definitions of AC landmarks on results of cytoarchitectonic studies that demonstrated high inter-individual variability of the anatomical borders between the primary and the secondary auditory cortex 
, which cannot be distinguished by morphological criteria alone. In order to estimate the borders of the primary and secondary AC we employed functional localizers and probability maps according to well-established landmarks 
. Roughly, the primary AC is located within the medial two thirds of HG 
and the secondary AC includes surrounding belt areas, particularly lateral areas of HG and posterior HG duplications. Evidently, consistent application of AC structures would facilitate the comparability of data across studies and would be desirable in the future.
A further remarkable finding in the present study was increased gyrification of the HG, i.e.
higher occurrence of complete posterior HG duplications. If these were included into morphometric analysis, volume changes of HG were even more pronounced. The role of posterior HG duplications has not been sufficiently addressed in the literature as yet. An increased incidence of HG duplications has been reported in subjects with dyslexia 
but remained unexplained so far. Whether to attribute such duplications to the HG or to be part of the planum temporale is discussed controversially in the field 
. In our study, the dorsal shift of averaged MEG dipoles and the localization of BOLD-activations indicated that HG duplications were implicated in early auditory processing. Further investigations on a larger sample set are certainly warranted in order to fully understand the structure-function relationship of HG and its duplications and are currently underway in our laboratory.
A limitation of our study is the relatively small sample size for neuroimaging tests, which is mainly attributable to low incidence of WS, reduced attention span of subjects and frequent MRI contraindication (because of e.g. aortic valve prostheses or pacemakers). In addition we applied an early age cut-off in order not to interfere with age related brain volume reduction. WS subjects were recruited over a period of more than two years. However, our data showed very low variance and the group was extremely homogenous. Due to the hypothesis-driven approach, individual analysis method (not group averages) and homogenous data we are confident that the number is sufficient to validate our results.
In brief, we propose WS as a unique genetic model to investigate training-independent auditory properties. Additional studies which take candidate genes from the WS critical region into consideration will lead the way to extend our understanding of the genetic influence on musicality.