Tune deafness has been characterized in a number of ways. However, the pathophysiological mechanisms that underlie the defining feature of the disorder–subjects' inability to recognize distortions in melodic structure–have rarely been investigated in context. Here we have attempted to do so in a group of severely affected TD subjects. We used a modification of the Distorted Tunes Test, a clinically relevant, ecologically valid paradigm–that is, one that makes it possible to investigate, in context, the essential behavioral features of this disorder.
We used EEG/ERP to measure the brain's responses to correct and distorted melodies. (Text S1
). Two of these responses, the MMN and P300, are established indices of change detection and, since TD subjects are unaware of melodic distortions, we predicted that both of these responses would be absent in these individuals in response to distorted notes. This was not the case. The pattern of responses we detected was more complex, suggesting that this disorder may not only provide insights into music processing, but also into brain mechanisms that underlie both conscious and unconscious perception.
The long-latency components of the AEP reflect the earliest cortical responses to auditory stimuli. Of these, the P1 and N1 components were evoked by deviant as well as standard notes–that is, they were unmodulated by melodic abnormalities–in controls and TD subjects. Significant group differences were instead related to the later, P2 component, which was selectively attenuated in response to deviant tones in controls. This was not unexpected. Nittono and coworkers, using a similar paradigm, reported an attenuation of the P2 component in response melodic abnormalities in normal individuals 
. Such a response was absent in TD subjects. (, Movie S1,S2
Because the role of the P2 is less well understood than that of the other long-latency AEP components, it is not clear what its selective attenuation may denote in physiological terms. However, the P2 may be obscured when a MMN, typically generated within same time window, is present, and this is the difference between TD and controls that may be most critical.
The MMN, is a well-established marker of change detection, most commonly elicited by deviant auditory stimuli 
A so-called pattern MMN, generated in response to deviations in complex auditory patterns or learned sequences
, can be readily evoked by musical pattern deviations 
Such a MMN, with a characteristic latency and morphology, was elicited by melodic abnormalities in controls (), likely accounting for attenuation of the P2 component. No MMN was generated by deviant stimuli in TD subjects. Normal AEPs, unmodulated by a MMN, indicate that these subjects perceive each note, but are simply unable to detect melodic errors.
In stark contrast, a robust P300 was evoked by melodic abnormalities in both TD subjects and normal controls. The P300 is another well-established signature of change detection; it is frequently differentiated from MMN in that while it can be generated automatically 
, it is more readily modulated by attention (Text S1
Although the P300 response was originally described as single entity, it is now clear that it consists of two distinct components - P3a and b 
. Both of these, each characterized by typical latencies and waveform morphologies, were evoked in TD subjects as well as controls (, Movie S1,S2
Our results therefore represent an apparent paradox. The absence of the MMN provides the predicted marker for auditory unawareness that is the hallmark of tune deafness. But the unexpected presence of the P300 indicates that TD subjects are at the same time processing the very abnormalities that they cannot consciously perceive. A recent paper, demonstrating a dissociation between conscious perception and behavioral performance in this patient population 
provides support for this notion.
Such a phenomenon, sometimes referred to as knowledge without awareness, has been recognized for some time 
in conditions such as blindsight 
, prosopagnosia 
or deaf-hearing 
. However in these disorders the symptoms–paradoxical responses to sensory stimuli that are not consciously perceived–are associated with structural brain lesions (although subliminal awareness may also be demonstrated in normal subjects by manipulating stimuli under experimental conditions 
In TD, the symptoms may be related to anatomical distinctions between the MMN and P300. Although both the MMN and P300 are indices of change detection, they are structurally dissociable: the neural assemblies that generate these waveforms are situated in different regions of the brain. The sources of the MMN are located for the most part in unimodal auditory areas of the superior temporal gyrus 
while the sources of the P300 are located in heteromodal regions of the frontoparietal cortex. These heteromodal regions are downstream projection areas which normally receive information that has already been processed in unimodal sensory cortices
. (TEXT S1
These anatomical differences suggest a model that may account for knowledge without awareness in tune deafness. Since it is the MMN that distinguishes TD and controls, our results suggest that conscious perception in TD subjects is likely disrupted at the level of the unimodal auditory cortex. This supports a more general notion that neural computations in early auditory areas are necessary for determining whether deviant auditory information is consciously perceived. Previous studies have indeed suggested that feature-specific neurons within these auditory regions regulate the access to auditory awareness in a bottom up fashion, and that responses underlying the MMN itself may operate as a gateway to consciousness
At the same time, the robust generation of the P300 suggests that deviant stimuli are nonetheless being discriminated and selectively processed in higher order frontoparietal cortices, having bypassed earlier mechanisms that regulate conscious perception.
A plausible explanation for this might be that acoustic stimuli are reaching the cortical sources of the MMN and P300 via independent, parallel pathways. This in turn, suggests a pathophysiological mechanism for TD similar to the one that accounts for the symptoms of blindsight,. In blindsight, perceptual processes mediated by direct projections from thalamus to primary visual cortex are disturbed, while alternate pathways to association areas remain intact 
. Similar parallel projections have been demonstrated in the auditory system 
, where direct projections from the thalamus to primary areas in the auditory core and belt are complemented by parallel, independent pathways to association areas in the parabelt and adjacent heteromodal cortices. In TD, as in blindsight, it may be the direct route in which processing is abnormal, while transfer of afferent information through alternate pathways is preserved.
Independent activation of the different cortical areas is clearly not the rule in the normal brain. The natural activation pattern may be consistent with a model 
in which perceptual awareness is part of a serial process connecting two modules–with heteromodal systems in the frontoparietal cortices receiving input that has already been extensively processed in unimodal sensory areas upstream. In this model, the modules could become uncoupled in disorders such as tune deafness or blindsight, where they would operate independently. In such cases, information would reach the heteromodal cortices, but in a fashion that cannot support conscious awareness.
In light of this, TD may provide a novel opportunity to study conscious perception. Unlike lesion-based disorders such as blindsight it should be possible to study the process in a brain that is structurally intact, and in a patient population that is far larger. In addition, TD is a highly heritable condition, and investigations currently underway may identify the genetic variants that underlie this condition. The tune deaf population may thus constitute a group in which the problem of consciousness might be approached at the cellular and molecular level using the tools of genetic research.