optic neuritis ( on ) refers to inflammation of the optic nerve and is caused by inflammatory demyelination of the optic nerve , by infection , or by non - specific inflammation .
the main clinical manifestations include pain during eye movement , sudden vision loss in one or both eyes , visual field defects , a relative afferent pupillary obstacle , and papilledema .
clinically , on leads to lesions of the optic nerve axons and apoptosis of retinal ganglion cells .
on can occur in patients with multiple sclerosis ( ms ) or neuromyelitis optica ( nmo ) .
studies have estimated a prevalence of 5 cases per 100 000 individuals per year in central europe .
although treatment of the inflammation results in good eyesight recovery in many patients with on , vision does not return to normal in others , and may be accompanied by abnormal color vision and visual field defects . on is commonly considered a retinal disease , but a previous study demonstrated that patients with on presented abnormalities in the visual cortex . currently , optical coherence tomography ( oct ) and visual evoked potential ( vep ) are the most important methods for diagnosis of on .
oct is a noninvasive , high - resolution method that measures the thickness of the retinal nerve fiber layer .
a previous study found that patients with ms had thinning of the retinal nerve fiber layer .
vep is an important clinical test and has been used in studying patients with on and demyelinating diseases .
the vep features of on are amplitude decrease and prolonged latency , which reflect nerve axon lesions and apoptosis of retinal ganglion cells .
the significant correlation of multifocal vep ( mfvep ) latency suggests a role for demyelination in promoting axonal loss .
a previous study showed that patients with on still had mfvep amplitude delays present in many locations , even if they recovered near - normal vision sensitivity .
diffusion tensor imaging can accurately measure fractional anisotropy ( fa ) and mean diffusivity of the visual pathway .
a previous study showed that axial diffusivity ( ad ) of affected nerves decreases during acute on and that this ad reduction correlates with the extent of axonal loss .
another study reported that patients with idiopathic demyelinating on showed decreased mean fa in the affected nerves .
in addition , a previous study using fmri found that patients with on had reduced functional connectivity within the visual system [ .
although these findings showed neuronal morphological changes in the on , there was far less evidence for changes in the neuromechanism of brain in patients with on .
vbm is a fully automated , whole - brain measurement technique that compares voxel - wise , between - group differences in local brain morphology .
the vbm method has been successfully used to investigate mechanisms of diseases such as alzheimer s disease , obsessive compulsive disorder , and glaucoma .
a previous study found that patients with neuromyelitis optica ( nmo ) showed white matter ( wm ) atrophy in areas such as the optic chiasm , pons , cerebellum , and frontal gyrus .
another study reported that patients with nmo showed wm atrophy in the corpus callosum and optic radiations , and gray matter ( gm ) atrophy in the thalamus and prefrontal cortex .
although these findings showed both wm and gm atrophy in patients with on , few studies have combined the vbm method with vep . to the best of our knowledge
the current study is the first to explore the changes in wm and gm in on and their relationship with vep .
twelve patients with on ( 4 males , 8 females ) were recruited from the ophthalmology department of the first affiliated hospital of nanchang university .
inclusion criteria were : 1 ) acute vision loss with or without eye pain ; 2 ) visual field abnormalities associated with damage to nerve fibers ; 3 ) patients with relative pupillary conduction block or abnormal vep ; 4 ) no clinical or laboratory evidence of compression , ischemic , toxic , genetic , metabolic , or invasive optic neuropathy ; 5 ) no acute vision loss due to retinal disease , alternative eye disease , or disease of the nervous system ; 6 ) no treatment with any drugs before resting - state fmri scanning ; 7 ) no obvious abnormality in the brain parenchyma on head mri scans ( including cerebral infarction , cerebral hemorrhage , cerebral hemangioma , and cerebral tumors ) ; 8) no history of congenital or acquired diseases such as psychiatric disorder , hypertension , diabetes mellitus , or coronary artery disease , and no addictions such as heroin , smoking , or alcohol ; 9 ) no receipt of organ transplantation ; and 10 ) moderate body shape and weight .
twelve healthy controls ( hcs ) ( 4 males , 8 females ) , who were age- , sex- , and education status - matched to the patients with on , were also recruited for this study .
all hcs met the following criteria : 1 ) no abnormalities in visual pathways or brain parenchyma on head mri scans ; 2 ) no ocular disease , naked eye , the corrected visual acuity > 1.0 ; 3 ) normal nervous system and mental status , with no headaches ; and 4 ) no contraindications for mri .
the study was authorized by the ethics committee of the first affiliated hospital of nanchang university .
for each subject , the study protocol and procedure were fully explained and consent was obtained .
all the methods of this research followed the declaration of helsinki and conformed to the principles of medical ethics .
participants were scanned on a 3-tesla mr scanner ( trio , siemens , germany ) with a 12-channel head coil .
high - resolution t1-weighted transversal images covering the whole brain were acquired with a magnetization - prepared rapid gradient echo ( mp - rage ) sequence : 176 slices with section thickness of 1.0 mm ; echo time=2.26 ms ; repetition time=1900 ms ; field of view=215230 mm . a neuroradiologist evaluated all scans for gross structural abnormalities .
functional data were classified by use of mricro software ( www.mricro.com ) to eliminate incomplete data .
structural images were processed with the voxel - based morphometry toolbox ( vbm8 ) ( http://dbm.neuro.uni-jena.de/vbm8/ ) implemented in statistical parametric mapping ( spm8 ) ( wellcome department of imaging neuroscience , london , uk ) running on matlab 7.9.0 ( r2009b ; the mathworks , inc , natick , ma , usa ) .
vbm is a whole - brain , unbiased , semi - automated technique for characterizing regional cerebral differences in structural magnetic resonance images .
segmentation of individual brains into gray matter , white matter , and cerebrospinal fluid was based on vbm8 using the default estimation options ( very light bias regularization , 60 mm cut - off for estimating the gaussian smoothness of bias in image intensity ; icbm [ international consortium for brain mapping ] european template for initial affine transformation ) .
spatial normalization into the montreal neurological institute ( mni ) standard space was done by the high - dimensional dartel ( diffeomorphic anatomical registration through exponentiated lie algebra ) approach implemented in vbm8 .
we used dartel to produce gray and white matter templates and used the generated template for all participants standardized gray matter and white matter .
finally , the modulated volumes were smoothed with a 6-mm full - width - at - half - maximum ( fwhm ) gaussian kernel .
normalized , modulated , smoothed images were submitted to group - level analyses . a general linear model ( glm ) analysis was performed with the spm8 ( http://www.fil.ion.ucl.ac.uk/spm ) toolkit to investigate the group differences in gm and wm between patients with on and healthy controls after controlling for the effects of age and sex .
the significance level was set at p<0.05 , gaussian random field ( grf ) theory corrected , minimum z>2.3 .
statistically significant voxels were superimposed on the standardization of 3dt1wi ( 3-dimensional magnetization prepared rapid acquisition gradient echo sequences ) to generate a color drawing .
voxel threshold was selected for 20 neighboring voxels to analyze the area of gm atrophy in patients with on . for vep stimulation analysis all subjects underwent pattern - reversal vep stimulation ( retlport electrophysiological instrument , roland , brandenburg , germany ) in a dark and quiet room .
three active skin electrodes were placed on the scalp along the midline ( over the inion ) and on lateral positions ( right and left ) .
all patients underwent monocular recording with the untested eye covered . using stimulus mode with pattern - reversal vep stimulation ,
the parameters were set as : stimulus frequency=1.0 hz and 100 hz ; interphase=500 ms ; number of stimulations=100 ; average screen brightness=5 cd / m ; spatial frequency=50 ms / s ; and contrast ratio=90% . amplitude and latency vep values
were studied at different angular dimensions of the stimulus ( 120 , 60 , and 15 degrees for stimuli with small , medium , and large spatial frequencies of stimulation , respectively ) .
veps were characterized by a series of n75 , p100 , and n135 peaks , each characterized by a specific amplitude and latency . the vep decreased amplitude and prolonged latency , which reflect nerve axon lesions and apoptosis of retinal ganglion cells . for visual tests analysis
first , the corneal curvature of all subjects was calculated , then we used the lens measurement instrument to detect the refractive diopter .
second , subjects were kept standing 5 meters from vision chart and the gaze was kept parallel with the vision chart 1.0 .
third , according to the diopter number , we chose the best lens to correct the vision .
twelve patients with on ( 4 males , 8 females ) were recruited from the ophthalmology department of the first affiliated hospital of nanchang university .
inclusion criteria were : 1 ) acute vision loss with or without eye pain ; 2 ) visual field abnormalities associated with damage to nerve fibers ; 3 ) patients with relative pupillary conduction block or abnormal vep ; 4 ) no clinical or laboratory evidence of compression , ischemic , toxic , genetic , metabolic , or invasive optic neuropathy ; 5 ) no acute vision loss due to retinal disease , alternative eye disease , or disease of the nervous system ; 6 ) no treatment with any drugs before resting - state fmri scanning ; 7 ) no obvious abnormality in the brain parenchyma on head mri scans ( including cerebral infarction , cerebral hemorrhage , cerebral hemangioma , and cerebral tumors ) ; 8) no history of congenital or acquired diseases such as psychiatric disorder , hypertension , diabetes mellitus , or coronary artery disease , and no addictions such as heroin , smoking , or alcohol ; 9 ) no receipt of organ transplantation ; and 10 ) moderate body shape and weight .
twelve healthy controls ( hcs ) ( 4 males , 8 females ) , who were age- , sex- , and education status - matched to the patients with on , were also recruited for this study .
all hcs met the following criteria : 1 ) no abnormalities in visual pathways or brain parenchyma on head mri scans ; 2 ) no ocular disease , naked eye , the corrected visual acuity > 1.0 ; 3 ) normal nervous system and mental status , with no headaches ; and 4 ) no contraindications for mri .
the study was authorized by the ethics committee of the first affiliated hospital of nanchang university .
for each subject , the study protocol and procedure were fully explained and consent was obtained .
all the methods of this research followed the declaration of helsinki and conformed to the principles of medical ethics .
participants were scanned on a 3-tesla mr scanner ( trio , siemens , germany ) with a 12-channel head coil .
high - resolution t1-weighted transversal images covering the whole brain were acquired with a magnetization - prepared rapid gradient echo ( mp - rage ) sequence : 176 slices with section thickness of 1.0 mm ; echo time=2.26 ms ; repetition time=1900 ms ; field of view=215230 mm . a neuroradiologist evaluated all scans for gross structural abnormalities .
functional data were classified by use of mricro software ( www.mricro.com ) to eliminate incomplete data .
structural images were processed with the voxel - based morphometry toolbox ( vbm8 ) ( http://dbm.neuro.uni-jena.de/vbm8/ ) implemented in statistical parametric mapping ( spm8 ) ( wellcome department of imaging neuroscience , london , uk ) running on matlab 7.9.0 ( r2009b ; the mathworks , inc , natick , ma , usa ) .
vbm is a whole - brain , unbiased , semi - automated technique for characterizing regional cerebral differences in structural magnetic resonance images .
segmentation of individual brains into gray matter , white matter , and cerebrospinal fluid was based on vbm8 using the default estimation options ( very light bias regularization , 60 mm cut - off for estimating the gaussian smoothness of bias in image intensity ; icbm [ international consortium for brain mapping ] european template for initial affine transformation ) .
spatial normalization into the montreal neurological institute ( mni ) standard space was done by the high - dimensional dartel ( diffeomorphic anatomical registration through exponentiated lie algebra ) approach implemented in vbm8 .
we used dartel to produce gray and white matter templates and used the generated template for all participants standardized gray matter and white matter .
finally , the modulated volumes were smoothed with a 6-mm full - width - at - half - maximum ( fwhm ) gaussian kernel .
a general linear model ( glm ) analysis was performed with the spm8 ( http://www.fil.ion.ucl.ac.uk/spm ) toolkit to investigate the group differences in gm and wm between patients with on and healthy controls after controlling for the effects of age and sex .
the significance level was set at p<0.05 , gaussian random field ( grf ) theory corrected , minimum z>2.3 .
statistically significant voxels were superimposed on the standardization of 3dt1wi ( 3-dimensional magnetization prepared rapid acquisition gradient echo sequences ) to generate a color drawing .
voxel threshold was selected for 20 neighboring voxels to analyze the area of gm atrophy in patients with on . for vep stimulation analysis all subjects underwent pattern - reversal vep stimulation ( retlport electrophysiological instrument , roland , brandenburg , germany ) in a dark and quiet room .
three active skin electrodes were placed on the scalp along the midline ( over the inion ) and on lateral positions ( right and left ) .
all patients underwent monocular recording with the untested eye covered . using stimulus mode with pattern - reversal vep stimulation ,
the parameters were set as : stimulus frequency=1.0 hz and 100 hz ; interphase=500 ms ; number of stimulations=100 ; average screen brightness=5 cd / m ; spatial frequency=50 ms / s ; and contrast ratio=90% . amplitude and latency vep values were studied at different angular dimensions of the stimulus ( 120 , 60 , and 15 degrees for stimuli with small , medium , and large spatial frequencies of stimulation , respectively ) .
veps were characterized by a series of n75 , p100 , and n135 peaks , each characterized by a specific amplitude and latency . the vep decreased amplitude and prolonged latency , which reflect nerve axon lesions and apoptosis of retinal ganglion cells . for visual tests analysis we combined the snellen vision chart with artificial optometry .
first , the corneal curvature of all subjects was calculated , then we used the lens measurement instrument to detect the refractive diopter .
second , subjects were kept standing 5 meters from vision chart and the gaze was kept parallel with the vision chart 1.0 .
third , according to the diopter number , we chose the best lens to correct the vision . if the subjects had no refractive errors , we recorded the unaided eye vision .
there were no obvious differences in weight ( p=0.749 ) , age ( p=0.827 ) , or height ( p=0.719 ) between the patients with on and the hcs .
there were significant differences between the patients with on and the hcs for best - corrected va - right ( p<0.001 ) and best - corrected va - left ( p=0.001 ) .
there were marked differences between the ons and the hcs in latency of the vep in the right eye ( p=0.001 ) , latency of the vep in the left eye ( p<0.001 ) , amplitudes of the vep in the right eye ( p<0.001 ) , and amplitudes of the vep in the left eye ( p=0.008 ) .
compared with the hcs , patients with on had significantly decreased gm volume ( gmv ) in the brain regions of the left postcentral gyrus , left inferior frontal gyrus , left anterior cingulate , right middle frontal gyrus , left middle frontal gyrus , and right inferior parietal lobule ( figure 1 [ blue ] , table 2 ) .
patients with on also had decreased wm volume ( wmv ) in the brain regions of the left middle frontal gyrus , right superior frontal gyrus , left precentral gyrus and right inferior parietal lobule , and increased wmv in the left fusiform gyrus and left inferior parietal lobule ( figure 2 , table 3 ) .
in addition , we showed the mean of altered gmv values and wmv values between the on group and hcs ( figure 3 ) . in the on group ,
the vep latency of the right eye showed a positive correlation with the wmv signal value of the left fusiform gyrus ( r=0.726 , p=0.008 ) and a negative correlation with the gmv signal value of the right inferior parietal lobule ( r=0.611 , p=0.035 ) .
duration of on showed a negative correlation with the wmv signal value of the right superior frontal gyrus ( r=0.662 , p=0.019 ) .
the best - corrected va of the right eye showed a negative correlation with the wmvs signal value of the left middle frontal gyrus ( r=0.704 , p=0.011 ) .
there were no obvious differences in weight ( p=0.749 ) , age ( p=0.827 ) , or height ( p=0.719 ) between the patients with on and the hcs .
there were significant differences between the patients with on and the hcs for best - corrected va - right ( p<0.001 ) and best - corrected va - left ( p=0.001 ) .
there were marked differences between the ons and the hcs in latency of the vep in the right eye ( p=0.001 ) , latency of the vep in the left eye ( p<0.001 ) , amplitudes of the vep in the right eye ( p<0.001 ) , and amplitudes of the vep in the left eye ( p=0.008 ) .
compared with the hcs , patients with on had significantly decreased gm volume ( gmv ) in the brain regions of the left postcentral gyrus , left inferior frontal gyrus , left anterior cingulate , right middle frontal gyrus , left middle frontal gyrus , and right inferior parietal lobule ( figure 1 [ blue ] , table 2 ) .
patients with on also had decreased wm volume ( wmv ) in the brain regions of the left middle frontal gyrus , right superior frontal gyrus , left precentral gyrus and right inferior parietal lobule , and increased wmv in the left fusiform gyrus and left inferior parietal lobule ( figure 2 , table 3 ) .
in addition , we showed the mean of altered gmv values and wmv values between the on group and hcs ( figure 3 ) .
in the on group , the vep latency of the right eye showed a positive correlation with the wmv signal value of the left fusiform gyrus ( r=0.726 , p=0.008 ) and a negative correlation with the gmv signal value of the right inferior parietal lobule ( r=0.611 , p=0.035 ) .
duration of on showed a negative correlation with the wmv signal value of the right superior frontal gyrus ( r=0.662 , p=0.019 ) .
the best - corrected va of the right eye showed a negative correlation with the wmvs signal value of the left middle frontal gyrus ( r=0.704 , p=0.011 ) .
to the best of our knowledge , our study is the first to investigate changes in wm and gm in patients with on using a vbm approach .
we found markedly decreased gmv in the brain regions of the left postcentral gyrus , left inferior frontal gyrus , left anterior cingulate , right middle frontal gyrus , left middle frontal gyrus , and right inferior parietal lobule in patients with on .
in addition , we observed that patients with on had significantly decreased wmv values in the brain regions of the left middle frontal gyrus , right superior frontal gyrus , left precentral gyrus , and right inferior parietal lobule , whereas they had significantly increased wmv values in the cluster of the left fusiform gyrus and left inferior parietal lobule .
furthermore , we observed that the vep latency of the right eye in patients with on had a positive correlation with the wmv signal value of the left fusiform gyrus ( r=0.726 , p=0.008 ) and a negative correlation with the gmv signal value of the right inferior parietal lobule ( r=0.611 , p=0.035 ) .
we also found that the duration of on had a negative correlation with the wmv signal value of the right superior frontal gyrus ( r=0.662 , p=0.019 ) .
the best - corrected va of the right eye had a negative correlation with the wmv signal value of the left middle frontal gyrus ( r=0.704 , p=0.011 ) . compared with the hcs
the postcentral gyrus is delimited by the central sulcus anteriorly and the postcentral sulcus posteriorly ; this area is the somatosensory cortex in the human brain .
previous studies have identified many diseases that lead to postcentral gyrus dysfunction , such as parkinson disease , alzheimer disease , and multiple sclerosis .
furthermore , duan et al . , using a voxel - based morphometry method , found that patients with nmo had decreased wmv in the right postcentral gyrus . in support of these findings
, we also found that patients with on had significantly decreased gmv in the left postcentral gyrus .
moreover , we found that patients with on had decreased gmv in the inferior frontal gyrus and bilateral middle frontal gyrus .
a previous study demonstrated that the frontal eye fields are causally involved in the attentional top - down control of anticipatory alpha power in the contralateral visual system .
in addition , the inferior frontal gyrus is related to emotional and cognitive empathy , while the middle frontal gyrus is associated with the processing of language .
many diseases lead to middle frontal gyrus dysfunction , including schizophrenia   and attention deficit hyperactivity disorder ( adhd ) .
liu et al .   found that patients with nmo had significantly increased amplitude of low - frequency fluctuations ( alff ) in the middle frontal gyrus .
however , liang et al .   showed that patients with nmo had decreased regional homogeneity ( reho ) in the left medial frontal gyrus . in support of these findings , we found significant regions of atrophy in the inferior frontal gyrus and bilateral middle frontal gyrus in patients with on .
we therefore speculate that on may lead to dysfunction of the frontal gyrus , while deficit in the frontal gyrus may reflect the damage to eye motion and cognition in patients with on .
we found that the vep latency of the right eye in patients with on correlated negatively with the gmv signal value of the right inferior parietal lobule ( r=0.611 , p=0.035 ) , which agrees with a previous study demonstrating that patients with on had prolonged latency .
the prolonged vep latency in on reflects the severity of on ; therefore , the decreased gmv signal values of the right inferior parietal lobule may be related to the severity of on .
compared with the hcs , patients with on had significantly decreased wmv values in the brain regions of the left middle frontal gyrus , right superior frontal gyrus , left precentral gyrus , and right inferior parietal lobule .
many brain function areas are involved in the default mode network ( dmn ) , including the posterior and anterior cingulate cortices , inferior parietal cortex , medial temporal lobes , and medial frontal cortex .
network , which shows higher activity at rest and tends to have a negative correlation with activity in task - positive networks .
liang et al .   found that patients with nmo had decreased reho in the left medial frontal gyrus .
demonstrated that patients with nmo had decreased wmv in the left middle and medial frontal gyrus , the right superior frontal gyrus , and the bilateral inferior and superior parietal lobules . in support of these findings , we found that patients with on had decreased wmv values in the left middle frontal gyrus and right inferior parietal lobule , which may reflect dysfunction of the dmn in the patients with on .
furthermore , the duration of on correlated negatively with the wmv signal value of the right superior frontal gyrus ( r=0.662 , p=0.019 ) , and we speculate that the longer the duration of on , the more serious the injury to the dmn .
we also found that the best - corrected va of the right eye correlated negatively with wmv signal value of the left middle frontal gyrus ( r=0.704 , p=0.011 ) .
we speculate that the decreased wmv signal value of the left middle frontal gyrus may reflect the damage to va in on .
interestingly , we found significantly increased wmv values regions in the left fusiform gyrus and left inferior parietal lobule in patients with on .
the fusiform gyrus is the  fusiform face area ,  which participates in face processing and social cognition .
a previous study showed that visual stimuli can cause increases in blood flow in the contralateral posterior fusiform gyrus .
the increased wmv areas in the left fusiform gyrus may be related to compensation for the damaged visual function in patients with on .
furthermore , we observed that the vep latency of the right eye in on correlated positively with the wmv signal value of the left fusiform gyrus ( r=0.726 , p=0.008 ) .
the increased vep latency in on reflects the severity of on , and thus the increased wmv values of the fusiform gyrus may relate to the severity of on .
, we found that patients with on had higher wmv values in the left inferior parietal lobule and reduced wmv values in the right inferior parietal lobule .
thus , the higher wmv values in the left inferior parietal lobule may reflect functional reorganization to compensate for the damaged areas in patients with on .
first , the sample size was too small , which may have affected the accuracy of the results .
second , there were some differences in the duration of on , and we were not able to entirely separate sex differences and age differences . in future studies
we found that patients with on had abnormal wm and gm involvement in regional brain changes , which correlated with the vep latency of the eye .
. however , there are some limitations to our study , such as the relatively small sample size , the use of a single center , and the lack of comparison between patients before and after treatment . in future studies we will use other methods to evaluate the changes in brain function in patients with on .
 backgroundthe aim of this study was to investigate potential morphological alterations of gray and white matter in patients with optic neuritis ( on ) and their relationship with behavioral performance , using voxel - based morphometry ( vbm).material / methodstwelve ( 4 males , 8 females ) patients with on and 12 ( 4 males , 8 females ) age- , sex- , and education - matched healthy controls ( hcs ) underwent magnetic resonance imaging ( mri ) . 
 imaging data were analyzed using two - sample t tests to identify group differences in gray and white matter volume ( gmv , wmv ) . 
 correlation analysis was used to explore relationships between observed gmv and wmv of different areas and visual evoked potential ( vep ) in on.resultscompared with hcs , on patients had : significantly decreased gmv in the left postcentral gyrus , left inferior frontal gyrus , left anterior cingulate , left and right middle frontal gyrus , and right inferior parietal lobule ; decreased wmv in the left middle frontal gyrus , right superior frontal gyrus , left precentral gyrus and right inferior parietal lobule ; and increased wmv in the left fusiform gyrus and left inferior parietal lobule . 
 vep latency of the right eye in on correlated positively with wmv signal value of the left fusiform gyrus ( r=0.726 , p=0.008 ) , and negatively with gmv signal value of the right inferior parietal lobule ( r=0.611 , p=0.035 ) . 
 duration of on correlated negatively with wmv signal value of the right superior frontal gyrus ( r=0.662 , p=0.019 ) , while best - corrected visual acuity ( va ) of the right eye correlated negatively with wmv signal value of the left middle frontal gyrus ( r=0.704 , p=0.011).conclusionsthese results suggest significant brain involvement in on , which may reflect the underlying pathologic mechanism . 
 correlational results demonstrate that vep in on is closely associated with wmv and gmv atrophy in many brain regions . 
Background
Material and Methods
Subjects
Structural MRI parameters
Image processing
Statistical analysis
Results
Behavioral results
Gray and white matter differences
Correlation analysis
Discussion
Conclusions