the most common disorders of consciousness include vegetative state ( vs ) and minimally conscious state ( mcs ) .
patients in mcs show weak but definite self - awareness or environmental awareness , and some patients have spontaneous eye opening and sleep  wake cycles .
although the patient s cognitive behaviors are intermittent , they are reproducible or can last long enough to be distinguished from primitive reflexive activity 1,2 .
although mcs patients remain unable to communicate , the behavioral evidence of self - awareness and environmental awareness is clear .
a vs or an mcs may be prolonged and can continue until the patient s death 3 . currently , consciousness assessments mainly rely on clinical signs and various scales .
the coma recovery scale - revised ( crs - r ) is an internationally recognized scale for assessing vs 4 .
it evaluates auditory , visual , sensory , motor , and communicative responses and can sensitively reflect changes in patients conditions .
therefore , the crs - r has become the primary method to diagnose mcs in clinical trials and in follow - up and evaluation . however , clinical scales are very subjective and do not accurately identify small changes in consciousness .
electrophysiological examinations have certain advantages for the evaluation of patients with consciousness disorders because of their objectivity and high temporal resolution .
many studies have used event - related potential ( erp ) to assess prognoses of patients with consciousness disorders .
mismatch negativity ( mmn ) is a negative component appearing in the primary auditory and prefrontal cortices 5 around 100250  ms after any auditory change in a monotonous sequence of sounds ( i.e. an oddball paradigm aaab ) 6 .
the low amplitude of mmn implies that many repetitions are needed to observe a response .
the mmn is elicited by deviants generated by automatic change detection processes that occur when the current auditory input is different from the preceding one .
deviants can be detected if patients are not aware of the auditory changes , provided the changes exceed the patient s discrimination threshold 7 .
mmn is even evoked when the patients focus attention on aspects other than the auditory stimuli 8,9 .
the p300 is a positive component generated when patients detect a rare and unexpected stimulus in a regular train of standard stimuli ( i.e. oddball paradigm ) 10 .
mmn and p300 are two different brain responses elicited by similar stimuli ( deviant or novel ) , and their latencies after stimuli are different . for an auditory potential
, p300 appears around 300  ms after stimulus presentation , but for a visual potential , it may appear after 500 or 600  ms .
, a p300 wave might reflect either recognition of the target s intrinsic meaning or detection of its acoustic salience .
many authors have investigated mmn and p300 in comatose patients , but with inconclusive results 1217 .
one evidence - based medical analysis on the predictive values of n100 , mmn , and p300 ( auditory epr components ) found that mmn and p300 had greater predictive value in comatose and other low - response patients 18 .
however , it is unclear whether auditory erp can be measured during recovery from coma and whether it can be used to measure sensitive changes in consciousness .
moreover , most of these studies assessed patients in the acute stage ; patients in the recovery phase of coma were rarely studied .
few clinical studies have observed how these erps change or examined the long - term predictive value of mmn and p300 in prognosis .
, we performed a 15-week clinical follow - up on a 42-year - old man with intracerebral hemorrhage with persistent vs for 8 months . during admission
wake cycle and flexor responses in the limbs to supraorbital pressure , but did not respond to sound and light stimulation .
every 2 weeks , the patient was scored with the crs - r by two specialists .
erp examinations were performed at 2 days and 2 , 6 , and 15 weeks after admission .
the corresponding crs - r scores were 7/23 , 9/23 , 11/23 , and 11/23 , respectively .
before the experiment , brainstem auditory evoked potential testing was performed to exclude hearing impairment .
the experiment was approved by the ethics committee of the faculty of medicine of the hospital . written informed consent was obtained from a member of the patient s family and from control participants .
auditory stimuli were delivered binaurally through inserted earphones at an intensity of 90  db hl using the presentation software ( e - prime software , electrical geodesics inc . ,
eugene , orlando , usa ) . the oddball stimulation paradigm with pure tones lasted 75  ms and included frequent tones ( 1000  hz ) and salient tones ( 1500  hz ) .
the two tones selected for the acoustic test were determined as 20 and 80% of the 400  hz bandwidth range .
we elaborated four sequences of 80 stimulations comprising four first names , with one of them always being the subject s own name ( son ) .
the three other first names ( ofns ) were selected from chinese character tables as a series of first names with similar high frequencies . for each sequence ,
each name was presented 10 times randomly , thus making a complete series of 80 equiprobable first names ( 25% probability for each name ) , with an interstimulus interval between 1300 and 1400  ms .
after each recording session , the patient or their family was asked whether any of the other names had particular emotional importance ( e.g. they corresponded to names of close relatives or friends ) .
all first names were recorded by the same neutral female voice ( fp ) , and were digitized and replayed binaurally at a 90  db sound pressure level maximal intensity .
the e - prime software was used to present the stimuli , and electroencephalography ( eeg ) activity was continuously recorded and analyzed with netstation 4.3 .
the data obtained from 128 scalp electrodes mounted on an elastic cap ( electrical geodesics inc .
, riverfront research park , eugene , orlando , usa ) were bandpass filtered at 330  hz , notched at 50  hz , and digitized at a sampling rate of 1024  hz .
skin / electrode impedance was maintained below 5  k. all scalp signals were referenced online to both mastoids , but were later offline rereferenced to the average of all scalp electrodes .
trials were averaged to erps separately for each condition and each patient relative to a 100  ms prestimulus baseline .
single epochs with an amplitude of at least 60  v or those containing eye movements and epochs with an amplitude of at least 200  v because of eye blinking or electromyographic artifacts were excluded from averaging .
we used standardized low - resolution electromagnetic tomography ( sloreta ) 19 to provide estimates of the cortical sources of the evoked potentials .
the loreta solution was included in the egi analysis package ( geosource , electrical geodesics inc . , eugene , orlando , usa ) .
loreta was used to compute 3d linear solutions ( loreta solutions ) for the eeg inverse problem within a three - shell spherical head model , including the scalp , skull , and brain compartments .
a voxel was labeled as gray matter if its probability of being gray matter exceeded 33% , exceeded the probability of being white matter , and exceeded the probability of being cerebrospinal fluid . in the current implementation ,
auditory stimuli were delivered binaurally through inserted earphones at an intensity of 90  db hl using the presentation software ( e - prime software , electrical geodesics inc . , eugene , orlando , usa ) . the oddball stimulation paradigm with pure tones lasted 75  ms and included frequent tones ( 1000  hz ) and salient tones ( 1500  hz ) .
the two tones selected for the acoustic test were determined as 20 and 80% of the 400  hz bandwidth range .
we elaborated four sequences of 80 stimulations comprising four first names , with one of them always being the subject s own name ( son ) .
the three other first names ( ofns ) were selected from chinese character tables as a series of first names with similar high frequencies . for each sequence ,
each name was presented 10 times randomly , thus making a complete series of 80 equiprobable first names ( 25% probability for each name ) , with an interstimulus interval between 1300 and 1400  ms . after each recording session
, the patient or their family was asked whether any of the other names had particular emotional importance ( e.g. they corresponded to names of close relatives or friends ) .
all first names were recorded by the same neutral female voice ( fp ) , and were digitized and replayed binaurally at a 90  db sound pressure level maximal intensity .
the e - prime software was used to present the stimuli , and electroencephalography ( eeg ) activity was continuously recorded and analyzed with netstation 4.3 . the data obtained from 128 scalp electrodes mounted on an elastic cap ( electrical geodesics inc .
, riverfront research park , eugene , orlando , usa ) were bandpass filtered at 330  hz , notched at 50  hz , and digitized at a sampling rate of 1024  hz .
skin / electrode impedance was maintained below 5  k. all scalp signals were referenced online to both mastoids , but were later offline rereferenced to the average of all scalp electrodes .
trials were averaged to erps separately for each condition and each patient relative to a 100  ms prestimulus baseline .
single epochs with an amplitude of at least 60  v or those containing eye movements and epochs with an amplitude of at least 200  v because of eye blinking or electromyographic artifacts were excluded from averaging .
we used standardized low - resolution electromagnetic tomography ( sloreta ) 19 to provide estimates of the cortical sources of the evoked potentials .
the loreta solution was included in the egi analysis package ( geosource , electrical geodesics inc . , eugene , orlando , usa ) .
loreta was used to compute 3d linear solutions ( loreta solutions ) for the eeg inverse problem within a three - shell spherical head model , including the scalp , skull , and brain compartments .
a voxel was labeled as gray matter if its probability of being gray matter exceeded 33% , exceeded the probability of being white matter , and exceeded the probability of being cerebrospinal fluid . in the current implementation , a spatial resolution of 7  mm is used , producing 2394 voxels .
figures 1 and 2 show the mmn and p300 in the normal control participants . the salient tone - induced mmn ( red line , negative wave between 100 and 200  ms ) location was 3 , 52 , 6 ; intensity : 0.01099  na ; brodmann area : 10 ; gyri : medial frontal gyrus in the frontal lobe .
the frequent tone ( blue line ) was the same , except that the intensity was 0.011403  na .
the son - induced p300 ( red line , positive wave around 300  ms ) location was 3 , 45 , 13 ; intensity : 0.037858  na ; brodmann area : 11 ; gyrus : medial frontal gyrus in the frontal lobe .
the ofns ( blue line , positive wave around 300  ms ) elicited a response at 3 , 52 , 6 ; intensity : 0.019716  na ; brodmann area : 10 ; gyrus : medial frontal gyrus in the frontal lobe .
eeg , electroencephalography ; erp , event - related potential ; mmn , mismatch negativity .
erps to pure tone in the patient during each of the four assessments ( a  d ) .
erp was first performed 2 days after admission when the patient was in a vs ; the crs - r score was 7/23 .
( b ) erp was again performed 2 weeks after admission ; the patient was in an mcs with a crs - r score of 9/23 .
( c ) erp was again performed 6 weeks after admission ; the patient was in an mcs with a crs - r score of 11/23 .
( d ) erp was again performed 15 weeks after admission ; the patient was in an mcs with a crs - r score of 11/23 .
crs - r , coma recovery scale - revised ; erp , event - related potential ; mcs , minimally conscious state ; mmn , mismatch negativity ; vs , vegetative state .
the patient s erps to names during each of the four assessments ( a  d ) .
( a ) p300 in the first erp assessment 2 days after admission ; the patient was in a vs and had a crs - r score of 7/23 .
( b ) erp was performed 2 weeks after admission ; the patient was in an mcs and had a crs - r score of 9/23 .
( c ) erp was performed 6 weeks after admission ; the patient was in an mcs and had a crs - r score of 11/23 .
erp was performed 15 weeks after admission ; the patient was in an mcs and had a crs - r score of 11/23 .
crs - r , coma recovery scale - revised ; erp , event - related potential ; mcs , minimally conscious state ; vs , vegetative state .
latencies and amplitudes of individually detected waves the mmn amplitudes evoked by salient stimuli were higher than those evoked by frequent stimuli , whereas the latencies of the former were shorter than those of the latter .
when the crs - r score indicated vs , the latencies of p300 evoked by sons were longer than those evoked by ofns .
however , when the crs - r score indicated an mcs , the latencies of p300 evoked by sons were shorter than those evoked by ofns .
for the control participant , mmn amplitudes and latencies evoked by salient and frequent stimuli were roughly the same .
the son - evoked p300 amplitude was higher than that evoked by ofn , and the son - evoked p300 latency was shorter than that evoked by ofn .
in addition , while studying erp , we carried out topographic eeg and source analysis .
the results showed that mmn was generated in the frontal and temporal lobes and that p300 was generated in the frontal , temporal , and parietal lobes .
the occurrences of mmn and p300 are indicative of a good prognosis in patients with consciousness disorders 14,2123 .
along with increasing recovery of consciousness in these patients , there was a gradual increase in their ability to distinguish auditory stimuli .
a sudden increase in mmn amplitude suggested that the patients could interact with their environment .
14 found that mmn could still be recorded in some patients in permanent vs or mcs , indicating some level of awareness in these patients and the possibility of further recovery .
however , they did not carry out a follow - up study or describe the outcomes of these patients .
23 carried out an auditory erp study on 22 patients with disorders of consciousness caused by severe traumatic brain injury ( tbi ) and claimed that the occurrence of p300 in these patients indicated better patient outcome .
24 carried out an auditory erp study in 34 patients in a 23-month vs following tbi .
the auditory stimuli were 1000  hz pure tones and sons , and they found that the conscious states of the patients in whom p300 was recorded were improved at the 1-year follow - up .
25 carried out an auditory erp study in 50 comatose patients ( including patients with tbi , stroke , and hypoxic - ischemic encephalopathy ) and found that the emergence of mmn could not predict whether patients would regain consciousness .
conversely , their results indicated that p300 emergence played a predictive role in determining whether the patients would regain consciousness . taken together , the experimental results implied that the presence of p300 could predict whether patients would regain full consciousness . in the present study ,
an auditory erp study was carried out on one patient in a persistent vs ( crs - r7/23 ) using pure tone and name stimuli , while mmn and p300 were simultaneously recorded .
the patient was evaluated by crs - r at 2 and 6 weeks after his first erp examination .
interestingly , the patient s crs - r scores increased ( crs - r 9/23 and 11/23 ) , and intermittent verbal communication appeared .
after 15 weeks , the patient s crs - r scores stabilized , and another erp examination was performed .
according to the first assessment after he was admitted , the patient was in a vs because of an intracerebral hemorrhage .
the disease course was up to 8 months ; thus , the patient should have been diagnosed as being in a persistent vs ( > 6 months ) .
however , mmn and p300 were recorded simultaneously during erp examinations , suggesting that the patient might still recover . at 2 weeks after admission ,
the patient s consciousness state actually improved , indicating that mmn and p300 might occur earlier than improvements on clinical assessments of behavior ; however , this hypothesis needs to be tested in a large sample .
however , the mmn and p300 amplitudes did not increase with the improved state of consciousness ( table 1 ) .
in addition , the patient s consciousness state did not show significant recovery from 6 to 15 weeks after admission .
although the erp examination showed mmn and p300 at all erp examinations , the consciousness state of the patient has not yet significantly improved at 15 months , which may indicate that mmn and p300 can be recorded in patients in permanent vs or mcs , indicating some level of awareness and possibility of further recovery .
therefore , the predictive value of mmn and p300 for consciousness recovery needs to be explored in a large sample and with a long - term clinical follow - up . on the basis of our results
, we can conclude that mmn was generated in the frontal and temporal lobes , whereas p300 was generated in the frontal , temporal , and parietal lobes .
mmn and p300 might emerge earlier than previously believed and continue in persistent vs and mcs .
the predictive value of these erps for subsequent recovery of consciousness should be studied in a large sample with long - term clinical follow - up .
our group will continue this study and carry out a long - term clinical follow - up to find the predictive value of these erps .
 to observe changes in mismatch negativity ( mmn ) and p300 in a patient transitioning from a vegetative state ( vs ) to a minimally conscious state ( mcs ) . 
 one patient with intracerebral hemorrhage and an 8-month disease course was evaluated as being in the vs using the coma recovery scale - revised . 
 two weeks after the patient was admitted to the hospital , another evaluation was performed , and the patient was determined to be in an mcs . using the oddball paradigm , pure tone and name stimuli were presented to the patient to study event - related potentials ( erps ) . 
 a 15-week clinical follow - up was carried out , and four erp examinations were performed at 2 days and 2 , 6 , and 15 weeks after admission . 
 one healthy individual was assessed as a control participant . 
 mmn and p300 were elicited in all four erp examinations . 
 mmn and p300 may occur earlier than believed in patients in persistent vs and mcs ; their predictive values for prognosis need to be further confirmed by follow - up studies on a large clinical sample . 
Introduction
Methods
Auditory ERP recording (MMN)
P300
Electrophysiological data acquisition and analysis
Source localization results
Results and discussion
Conflicts of interest