it is produced in the central auditory pathway.[15 ] this symptom is a common phenomenon disturbing millions of individuals worldwide .
study of tinnitus has resulted in a number of hypothetical mechanisms and suspected origins in the auditory pathways .
most hypotheses postulate that the generation of tinnitus is related to cochlear or acoustic nerve disorders , or central auditory cortices dysfunction and their interactions.[39 ] surgical destruction of the cochlea or the cochlear nerve has been ineffective ; therefore , tinnitus is described as an auditory phantom perception .
the perception of tinnitus sensation is thought to trace back to the central mechanism in most cases .
it has been speculated that the tinnitus may be a consequence of maladaptive cortical reorganization after an injury in the periphery , analogous to the pathophysiologic model of chronic pain .
numerous investigations showed that tinnitus is associated with an increased activity in central auditory system as demonstrated by electrophysiology and neuroimaging studies and with vascular pathogenic changes detected by ultrasonography .
single photon emission computed tomography ( spect ) scanning of the brain reflects regional cerebral blood perfusion .
brain blood perfusion scanning has a role in diagnosis , therapeutic management , and follow - up of patients and in researches .
spect scanning of the brain with the radioisotope technetium 99 m ( tc-99 m ) is a nuclear imaging technique providing an objective analytical detection of regional cerebral blood perfusion of the brain .
spect was introduced into the medical audiologic tinnitus patient diagnostic protocol ( matpp ) firstly , as an investigative tool to objectify tinnitus .
spect imaging of brain in patients with disabling tinnitus has revealed responsible loci by indicating perfusion asymmetries in cortical areas . in some studies ,
adjacent perfusion asymmetries involving the frontal , temporal and parietal lobes have suggested an inter - neural network resulting in the transition of the sense to the affected components of tinnitus .
there are few studies with low sample size , which have evaluated the brain blood perfusion findings using spect scanning of tinnitus patients and information about the blood flow in the brain , and diagnostic accuracy of this technique in tinnitus patients is extremely scarce .
brain perfusion scanning using spect was done to understand the pattern of brain blood perfusion of tinnitus subjects and find the areas which are mostly abnormal in these patients .
from january 2006 to may 2008 , 122 patients with subjective idiopathic tinnitus and 9 healthy controls were enrolled to this cross sectional study .
the subjects were selected from patients who were referred to ent and head and neck research center of rasoul - e - akram hospital ( tehran , iran ) to evaluate and treat their tinnitus .
the inclusion criteria were moderate to severe unilateral or bilateral tinnitus ( tinnitus questionnaire score of 44 or more ) which permanently lasted for more than 3 months .
all subjects had to be healthy , had no ear , mental , and brain disorders and history of invasive therapeutic brain procedures and brain trauma .
the pregnant and breastfeeding women and those who had decision to be pregnant , the subjects with history of tinnitus treatment in the last 3 months and alcohol / drug abuse in the last 6 months were not included into the study . all subjects gave written informed consent according to the declaration of helsinki , national committee of ethics in medical research ( technology and research deputy of health ministry ) and the committee on ethics at the ent and head and neck research center of tehran university of medical sciences , radiation safety and radioactive drug research committee prior to participating in the study .
pitch and loudness matching of tinnitus were identified for the affected ear to an external tone presented to the contralateral ear .
this task was accomplished using tinnitus evaluation device ( tined ) , which includes 6 channels to reconstruct the most troublesome tinnitus with a similar frequency and intensity .
an accuracy of the calibrating equipment shall be sufficient to determine that , the tined is within the tolerances permitted by american standard specification for audiometers , s3.6 - 2004 .
the subjects had to have loudness matching of tinnitus more than 6-decibel sensation level ( db sl ) to be included in this study .
using tinnitus questionnaire ( tq ) , the severity of tinnitus in subjects was rated to 6 scales .
subjects with tq score of 44 or more were considered to have moderate to severe tinnitus .
the patients were placed in a quiet , dimly lit room and instructed to keep the eyes open ( or use a mask ) and the ears unplugged .
they were also instructed not to speak , read , or move during 5 min prior to and 5 min post injection .
they were asked to think about their tinnitus during the test . a commercial ethyl cysteinate dimer ( ecd )
each subject received a 15 mci intravenous injection of tracer while they were still lying down .
one hour after intravenous injection of 15 mci 99mtc - ecd , spect scanning was acquired ( 120 projections ; 40 projections per head ; 25 sec / projection ) .
scanning was performed using a dual head smv gamma camera , equipped with a pair of low energy , high resolution collimators .
planar and processed spect images were visually assessed by a nuclear medicine physician twice , who was blinded to all other clinical and imaging information .
the images were visually graded as normal for no appreciable abnormal activity and abnormal for hyper activity .
semi - quantitative evaluation of planar images over the lesion and background areas on the anterior , was also performed by drawing regions of interest ( roi ) posterior or contralateral hemisphere images without any lesion .
geometric means of the contraleteral , posterior and anterior roi values were used for the calculation of lesion - to - background ratio .
transverse views with the best visualization of the lesions were selected for roi drawing on the spect images .
all activity ratios were classified to determine an intensity of activity as : 1 > normal , 1 < hyperactivity . if the ratio was < 1 , the visually suspected sites considered normal , and if > 1 , those were classified as abnormal sites or lesions .
the images were stored in dicom format , to be applied in brain anatomical functional images co - registration software ( brain afics ) .
spect is inherently a perfusion modality ; therefore , it is sometimes difficult to exactly define the anatomical area with disturbed function . therefore , it is helpful to correlate the relatively coarse spect images to high - resolution anatomic mr images .
brain anatomical functional images co - registration software ( brainafics ) , a software system designed in ent and head and neck research center of tums , is capable of registering and fusing unsynchronized positron emission tomography ( pet ) and spect images with mr images with different dimensions in a subject [ figure 1 ] .
activity ratio was calculated as follow ; for unilaterally involved subjects ; after localized abnormal area visually , rois were drawn and the count per voxel were compared with the rois in the other side or beside . in bilaterally involved subjects ; count per voxel of the abnormal areas were compared with similar rois on cerebellum ( as reference ) after fusion , cerebral zones were categorized in 8 regions ; middle temporal , inferotemporal , medial temporal , superior temporal , temporoparietal , frontal , frontoparietal and parietal .
after final fusion of images , each image was evaluated and reported by an expert twice .
almost all images were reported similarly in both times , but if the assessment was not similar , images were interpreted for third time and the repeated report was considered as main result .
the kendalls tau - b correlation confirmed validation of reports ( p value < 0.001 , r = 0.7 ) .
the nuclear medicine specialist was blinded to the patients and controls when she was interpreting the images .
for finding the association of sides and sites of spect abnormality with tinnitus and difference between groups , chi - square and fishers exact test were used .
comparison of quantitative variable was done by t - test between two independent groups and analysis of variance ( anova ) between more than two groups .
from january 2006 to may 2008 , 122 patients with subjective idiopathic tinnitus and 9 healthy controls were enrolled to this cross sectional study .
the subjects were selected from patients who were referred to ent and head and neck research center of rasoul - e - akram hospital ( tehran , iran ) to evaluate and treat their tinnitus .
the inclusion criteria were moderate to severe unilateral or bilateral tinnitus ( tinnitus questionnaire score of 44 or more ) which permanently lasted for more than 3 months .
all subjects had to be healthy , had no ear , mental , and brain disorders and history of invasive therapeutic brain procedures and brain trauma .
the pregnant and breastfeeding women and those who had decision to be pregnant , the subjects with history of tinnitus treatment in the last 3 months and alcohol / drug abuse in the last 6 months were not included into the study . all subjects gave written informed consent according to the declaration of helsinki , national committee of ethics in medical research ( technology and research deputy of health ministry ) and the committee on ethics at the ent and head and neck research center of tehran university of medical sciences , radiation safety and radioactive drug research committee prior to participating in the study .
pitch and loudness matching of tinnitus were identified for the affected ear to an external tone presented to the contralateral ear .
this task was accomplished using tinnitus evaluation device ( tined ) , which includes 6 channels to reconstruct the most troublesome tinnitus with a similar frequency and intensity .
an accuracy of the calibrating equipment shall be sufficient to determine that , the tined is within the tolerances permitted by american standard specification for audiometers , s3.6 - 2004 .
the subjects had to have loudness matching of tinnitus more than 6-decibel sensation level ( db sl ) to be included in this study .
using tinnitus questionnaire ( tq ) , the severity of tinnitus in subjects was rated to 6 scales .
subjects with tq score of 44 or more were considered to have moderate to severe tinnitus .
the patients were placed in a quiet , dimly lit room and instructed to keep the eyes open ( or use a mask ) and the ears unplugged .
they were also instructed not to speak , read , or move during 5 min prior to and 5 min post injection .
they were asked to think about their tinnitus during the test . a commercial ethyl cysteinate dimer ( ecd )
each subject received a 15 mci intravenous injection of tracer while they were still lying down .
one hour after intravenous injection of 15 mci 99mtc - ecd , spect scanning was acquired ( 120 projections ; 40 projections per head ; 25 sec / projection ) .
scanning was performed using a dual head smv gamma camera , equipped with a pair of low energy , high resolution collimators .
planar and processed spect images were visually assessed by a nuclear medicine physician twice , who was blinded to all other clinical and imaging information .
the images were visually graded as normal for no appreciable abnormal activity and abnormal for hyper activity .
semi - quantitative evaluation of planar images over the lesion and background areas on the anterior , was also performed by drawing regions of interest ( roi ) posterior or contralateral hemisphere images without any lesion .
geometric means of the contraleteral , posterior and anterior roi values were used for the calculation of lesion - to - background ratio .
transverse views with the best visualization of the lesions were selected for roi drawing on the spect images .
all activity ratios were classified to determine an intensity of activity as : 1 > normal , 1 < hyperactivity . if the ratio was < 1 , the visually suspected sites considered normal , and if > 1 , those were classified as abnormal sites or lesions .
the images were stored in dicom format , to be applied in brain anatomical functional images co - registration software ( brain afics ) .
spect is inherently a perfusion modality ; therefore , it is sometimes difficult to exactly define the anatomical area with disturbed function .
therefore , it is helpful to correlate the relatively coarse spect images to high - resolution anatomic mr images .
brain anatomical functional images co - registration software ( brainafics ) , a software system designed in ent and head and neck research center of tums , is capable of registering and fusing unsynchronized positron emission tomography ( pet ) and spect images with mr images with different dimensions in a subject [ figure 1 ] .
activity ratio was calculated as follow ; for unilaterally involved subjects ; after localized abnormal area visually , rois were drawn and the count per voxel were compared with the rois in the other side or beside . in bilaterally involved subjects ; count per voxel of the abnormal areas were compared with similar rois on cerebellum ( as reference ) after fusion , cerebral zones were categorized in 8 regions ; middle temporal , inferotemporal , medial temporal , superior temporal , temporoparietal , frontal , frontoparietal and parietal .
after final fusion of images , each image was evaluated and reported by an expert twice .
almost all images were reported similarly in both times , but if the assessment was not similar , images were interpreted for third time and the repeated report was considered as main result .
the kendalls tau - b correlation confirmed validation of reports ( p value < 0.001 , r = 0.7 ) .
the nuclear medicine specialist was blinded to the patients and controls when she was interpreting the images .
for finding the association of sides and sites of spect abnormality with tinnitus and difference between groups , chi - square and fishers exact test were used .
comparison of quantitative variable was done by t - test between two independent groups and analysis of variance ( anova ) between more than two groups .
subjects consisted of 89 ( 73% ) males and 33 ( 27% ) females undergone evaluation .
tinnitus was present in left ear of 35 ( 28.7% ) subjects , right ear of 23 ( 18.9% ) subjects , and both ears of 64 ( 52.5% ) subjects [ table 1 ] .
side of tinnitus in patients the time interval between the spect scanning and the tinnitus symptom was 77.17  78.7 months for the left ear ( from 3 to 300 months ) and 81.8  76.6 months for the right ear ( from 3 to 396 months ) .
mean recorded pitching of the tinnitus was 7.76  3.71 db , based on subjective assessment .
abnormalities ( defined as hyperperfusion areas detected by brain spect scanning ) were seen in 101 tinnitus patients ( 83% ) and 4 controls ( 44% ) .
most tinnitus subjects ( 74 [ 60% ] ) had multifocal abnormalities from which 27 subjects ( 36.5% ) had more than one abnormalities in each hemisphere .
there was no significant association between the side of the tinnitus and number of brain abnormal foci ( p value > 0.05 ) .
patients with unifocal and multifocal brain abnormalities did not show different tinnitus severity ( p value > 0.05 ) .
the subjects with multifocal brain involvement had the lowest mean age than the patients with unifocal or no abnormal area .
( 45.62  13.98 years vs. 52.75  12.83 years vs. 52.22  9.11 years for multifocal , unifocal and no lesion , respectively ; p value = 0.045 ) . in controls ,
3 persons ( 33.3% ) had multifocal abnormalities , and more than one abnormality was seen in 1 hemisphere of 2 ( 22% ) persons .
the most common abnormal areas were middle temporal gyrus ( 30.3% in the right and 37.7% in the left hemispheres ) and temporoparietal cortex ( 24.6% in the right and 13.1% in the left hemispheres ) [ table 2 ] . from all evaluated tinnitus subjects , 19 ( 15.6% )
had left sided brain perfusion abnormality , 17 ( 13.9% ) had right sided brain perfusion abnormality , and 65 ( 53.3% ) had brain perfusion abnormalities in both hemispheres . statistically significant relation was found between the side of the brain perfusion abnormalities and the side of the tinnitus ( p value = 0.027 ) [ table 3 ] .
the patients with right hemisphere lesion in spect scanning had the most severe sensation of tinnitus , while the least severity was seen in the patients with left hemisphere involvement ( right sided brain abnormality : 12.8  6.1 db sl vs. left sided brain abnormality : 5.8  2.2 db sl vs. bilateral brain abnormality : 7.3  2.7 db sl vs. no brain perfusion abnormality : 7.2  3.03 db sl , p value = 0.006 using anova ) .
site of abnormalities in brain spect scanning results of brain spect scanning in patients with different side of tinnitus .
generating peripherally or centrally , tinnitus is believed to be associated with activity in specific cortical regions as shown by pet and spect and functional mri and with vascularity changes . unilaterally increased metabolic activity in the secondary auditory cortex represents a robust finding in tinnitus patients .
there is controversy in different studies whether more abnormal side is the left or the right hemisphere .
some studies have reported the right hemisphere , but others found the left hemisphere more involved in imaging studies , no investigation has shown bilateral brain involvement in the tinnitus patients .
all studies declare that there is no association between the side of tinnitus and dominant side of brain perfusion / function abnormality . in the present study ,
bilateral brain abnormalities detected by spect scanning were seen in most tinnitus patients , and in contrast to the previous studies , it was associated to the side of tinnitus .
right hemisphere was more abnormal in patients with sensation of tinnitus in the right ear , and the patients with left ear tinnitus had more lesions in the left hemisphere , and in patients with bilateral tinnitus , bilateral brain involvement in spect scanning was the most finding .
superior and transverse temporal gyrus , middle frontal gyrus , middle temporal gyrus , lateral and medial posterior sites , temporofrontal , paralimbic , anterior middle temporal gyrus and hippocampus are represented as the most common involved areas in different studies .
but , based on the results of the present study , the most common involved area was middle temporal ( brodmann area 21 ) which is a secondary auditory cortex , and temporoparietal cortex ( brodmann area 22 ) was the second most common involved part in the brain that is an associative cortex .
patients with more severe tinnitus had right hemisphere perfusion abnormality more frequently than the left hemisphere . considering association between tinnitus severity with side of brain abnormalities
, it could be concluded that the tinnitus severity may be an important predictor of brain abnormality side with unknown mechanisms , or the pathologic brain perfusion in the right hemisphere cause more severe tinnitus , and vice versa .
patients age seems to play an important role in the brain perfusion abnormality , and older patients should be expected to have unifocal abnormality more while younger patients have multifocal brain perfusion abnormalities .
relationship between number of brain lesions with age may be due to the negative feedback at the result of more stress in young person about tinnitus as a life threatening condition that leads to more brain involvement and multifocal abnormality .
another hypothesis is more plasticity in cortical neurons of young patients that lead to involvement of more areas in younger patients . as other hypothesis
, this could be the atrophic effect of tinnitus that results in brain atrophy in older patients with longer duration of tinnitus and actually leads to less brain hyperperfused foci .
finally , auditory processing is shifted from the phylogenetically non - classical system , towards the phylogenetically classical auditory system that performs the finer analysis of sounds .
the efficiency of synapses that connect auditory input to the non - classical pathways decreases during ontogeny and these synapses become ineffective at the time of adulthood . in the study performed by farhadi m. et al .
, 5 mci f18-fdg ( fluorodeoxyglucose ) was used for metabolic function assessment of 55 tinnitus patients .
similar to the present study , the most involved brain regions were reported there to be secondary auditory cortex and associative cortex ; middle temporal gyrus ( brodmann area 21 ) and temporoparietal cortex ( brodmann area 22 ) , respectively . in that study
, the brain metabolic function was evaluated using radiotracer f18-fdg , while herein , we evaluated the brain perfusion of the subjects using technetium-99 m .
brain perfusion in each area may be compatible with function of that area , but these may be differently patterned in tinnitus patients and results in different findings as could be seen herein , in contrast to the findings of the present study , there was no significant association between the side of tinnitus and side of brain metabolic function abnormalities , and between age and metabolic lesions numbers , and also between the tinnitus severity and brain lesion side in the that study .
it has to be considered that , these differences may be due to smaller sample size in the mentioned study .
although it caused interpretation of tinnitus origin and mechanism unbiased , not considering hearing loss made us unable to categorize the findings on the basis of tinnitus type .
intermittent or constant , evoking and inhibiting with and without some sensory - motor pathways may have some association with brain findings but were not involved in the interpretation of the results .
although it caused interpretation of tinnitus origin and mechanism unbiased , not considering hearing loss made us unable to categorize the findings on the basis of tinnitus type .
intermittent or constant , evoking and inhibiting with and without some sensory - motor pathways may have some association with brain findings but were not involved in the interpretation of the results .
abnormalities of the cerebral blood flow are seen in the patients who complain of tinnitus .
the most common abnormal foci are middle temporal gyrus ( brodmann area 21 ) and temporoparietal cortex ( brodmann area 22 ) , that means the secondary auditory cortex and associative cortex are mostly associated with tinnitus , and the pathophysiology of tinnitus could be there .
higher number of abnormal foci in younger patients could be explained with more cognitive and emotional brain centers involvement due to tinnitus or stress , and anxiety of tinnitus in the young patients or atrophic effect of tinnitus or developing process by aging .
 background and purpose : tinnitus is associated with an increased activity in central auditory system as demonstrated by neuroimaging studies . 
 brain perfusion scanning using single photon emission computed tomography ( spect ) was done to understand the pattern of brain blood perfusion of tinnitus subjects and find the areas which are mostly abnormal in these patients.materials and methods : a number of 122 patients with tinnitus were enrolled to this cross - sectional study . 
 they underwent spect and magnetic resonance imaging ( mri ) of brain , and the images were fused to find the regions with abnormal perfusion.results:spect scan results were abnormal in 101 patients ( 83% ) . 
 most patients had bilateral abnormal perfusion ( n = 65 , 53.3% ) , and most subjects had abnormality in middle - temporal gyrus ( n = 83 , 68% ) and temporoparietal cortex ( n = 46 , 37.7% ) . patients with multifocal involvement had the least mean age than other 2 groups ( patients with no abnormality and unifocal abnormality ) ( p value = 0.045).conclusions : brain blood perfusion pattern differs in patient with tinnitus than others . 
 these patients have brain perfusion abnormality , mostly in auditory gyrus ( middle temporal ) and associative cortex ( temporoparietal cortex ) . 
 multifocal abnormalities might be due to more cognitive and emotional brain centers involvement due to tinnitus or more stress and anxiety of tinnitus in the young patients . 
INTRODUCTION
METHODS
Subjects
Tinnitus assessment
Single photon emission computerized tomography imaging (SPECT imaging)
Magnetic resonance imaging
Image fusion
Validation
Statistical analysis
RESULTS
DISCUSSION
Study limitations
CONCLUSION