silent lacunar infarction ( sli ) has commonly been regarded as a benign subtype of stroke , associated with relatively mild disability .
most previous studies reported a close link between fresh infarcts and post - stroke depression ( psd ) .
psd is defined as  depression occurring in the context of a clinically apparent stroke , which is opposed to silent cerebral vascular disease which belongs to vascular depression .
compared to vascular depression , the course of psd seems even more complex and dependent on timing of onset .
the role of vascular risk factors in the etiology of psd and vascular depression is less obvious than it appears .
as we known , hypertension , atrial fibrillation , smoking , diabetes , and cardiovascular disease are premorbid vascular risk factors with clear longitudinal association with cerebrovascular disease , however , previous study found strong positive association between vascular burden and frequency of depression among patients without stroke , but not among patients with stroke .
these different findings in the etiologies of psd and vascular depression may suggest an independent etiologic process for each depressive syndrome .
the presence of lacunar infarction ( li ) in subcortical regions , namely in the thalamus , basal ganglia , and deep white matter has been shown to promote depression .
another study only found an association of li in deep white matter with depressive symptoms .
differences in inclusion criteria , diagnostic protocols of li , and assessment of depression may contribute to such different viewpoints in the above studies .
recent study has also suggested that chronic vascular burden may contribute significantly to the pathogenesis of depression .
the prevalence of vascular risk factors has been empirically linked with the onset and severity of depression in both cross - sectional and longitudinal studies .
conditions such as hypertension , diabetes , obesity [ 12 , 13 ] , inflammation , extent of physical activity , and serum lipid profile   had been associated with depression in the general population .
however , only few previous studies have examined the influence of these risk factors on depression in a population of patients diagnosed with sli . in the present study , we performed a cross - sectional study focusing on the location of sli and the related risk factors to explore the relationship between sli and depression .
a cross - sectional study was performed on the patients attending to the department of neurology in 10th people s hospital at shanghai from september 2012 to november 2013 , mainly with non - specific symptoms such as headache , dizziness , vertigo and limb numbness , simultaneously without any localized neurological signs .
the study has been approved by the institutional review boards and all participants have provided written consent for participation .
a total of 272 participants diagnosed with sli through magnetic resonance imaging ( mri ) were consecutively recruited in our study and attributed to depression and non - depression groups , respectively .
the number of focal lesions of sli should be between three and five in each location .
patients with histories of stroke , vascular dementia , heart failure with a new york heart association degree 3 or 4 , myocardial infarction , atrial fibrillation , rheumatic valvular heart disease , arteritis during this study were excluded .
patients with any grade of leukoaraiosis according to fazekas scale and fresh infarction identified through mri were also excluded .
sli was defined as focal lesions ranging from 3 to 15  mm in diameter , with hypointensity on t1-weighted images , hyperintensity on t2-weighted images . at the time , the location of the sli was recorded as thalamus , basal ganglia , deep white matter , or brain stem .
age , gender , education ( less than high school / high school or college / graduate degree ) , smoking habits ( smoking or non - smoking ) , alcohol intake ( yes or no ) , history of diabetes mellitus , and coronary heart disease were recorded for each subject during enrolment .
systolic and diastolic blood pressures ( mmhg ) were recorded according to the average levels in the last 3  months by questionnaire .
each participant s height and weight were measured without shoes and heavy clothing . the body mass index ( bmi )
was calculated as the ratio of weight in kilograms to the height in square meters ( kg / m ) .
the participants were grouped into three categories according to their bmi value . based on who recommended bmi cutoffs for asian populations , the participants were considered as underweight to normal for bmi values <
23  kg / m , overweight for bmi values 23.027.5  kg / m , and obese for bmi values 27.5 
waist and hip circumference was measured and waist  hip ratio ( whr ) was calculated .
physical activity was determined by the question :  how much exercise you did in the last 6  months , i.e. , have you exercised for 1520  min of brisk walking , swimming , general conditioning , or recreational sports ? 
possible answers included not at all active , a little active ( 12 times / month ) , fairly active ( 34 times / month ) , quite active ( 12 times / week ) , very active ( 34 times / week ) , or extremely active ( 5 times / week ) .
the participants were grouped into three categories according to the activity level : inactive , light or moderately active , and vigorously active .
the fasting blood samples from the participants were obtained at around 7:00 am and were analyzed at the clinical laboratory department of the shanghai 10th people s hospital of tongji university .
the blood samples were assessed for the following markers of inflammation : c - reactive protein ( crp ) , high - sensitivity c - reactive protein ( hs - crp ) , interleukin-6 ( il-6 ) , and tumor necrosis factor alpha ( tnf- ) . additionally , insulin , total cholesterol , triglycerides , high - density lipoprotein cholesterol ( hdl - c ) , and low - density lipoprotein cholesterol ( ldl - c ) were also measured . in the present study , diagnosis of depression in all patients
depression was assessed with the patient health questionnaire ( phq)-9 , a 9-item scale that assesses the presence of 9 dsm - iv symptoms for major depressive disorder .
responses were scored on a 4-point scale from 0 to 3 , indicating that the participant experienced the symptom  not at all   on several days   on more than half the days  or  nearly every day  with higher scores indicating more severe symptoms .
scores on this scale were categorized as none to minimal ( phq score 03 ) , mild to moderate ( phq score 49 ) , or severe ( phq score 10 ) .
participants with the phq scores 4 were attributed to depression group and the phq scores 03 were attributed to non - depression group .
continuous variables were assessed as mean    sd and categorical variables were assessed as counts in percentage . to compare the baseline characteristics ,
continuous variables were analyzed using t tests and categorical variables were analyzed using  test . only the variables with p  <  0.05 were included in the multivariate logistic regression model .
odds ratio ( or ) and 95  % confidence intervals ( cis ) were obtained in models that adjusted for potential confounders .
consistency tests about the radiological diagnosis between two radiologists were performed by calculating intra - class correlation coefficient ( icc ) .
p  <  0.05 was considered to be statistically significant difference.table  1baseline descriptive statistics for all subjects and by depression statusnon - depression ( n  =  183)depression ( n  =  60 ) 
 p valueage ( years)67.16 ( 9.09)66.45 ( 9.95)0.203gender 
 0.013 
 men81 ( 44.3  % ) 15 ( 25.0  % )  women102 ( 55.7  % ) 45 ( 75.0  % ) smoker42 ( 23.0  % ) 9 ( 15.0  % ) 0.259alcohol consumption21 ( 11.5  % ) 6 ( 10.0  % ) 0.752education 
 0.044 
 less than high school / high school152 ( 83.6  % ) 58 ( 95.0  % )  college and graduate degree30 ( 16.4  % ) 3 ( 5.0  % ) physical activity 
 < 0.001 
 none51 ( 27.9  % ) 33 ( 55.0  % )  mild to moderate60 ( 32.8  % ) 9 ( 15.0  % )  vigorous72 ( 39.3  % ) 18 ( 30.0  % ) bmi ( kg / m ) 
 < 0.001 
 < 2397 ( 53.0  % ) 15 ( 25.0  % )  2327.563 ( 34.4  % ) 27 ( 45.0  % )  > 27.524 ( 13.1  % ) 18 ( 30.0  % ) whr [ m(sd ) ] 
 0.98 ( 0.08)0.96 ( 0.08)0.089systolic bp ( mmhg ) [ m(sd)]137.05 ( 15.43)135.10 ( 15.90)0.400diastolic bp ( mmhg ) [ m(sd)]77.43 ( 9.91)75.25 ( 7.00)0.135coronary artery disease39 ( 21.3  % ) 15 ( 25.0  % ) 0.551diabetes50 ( 27.9  % ) 18 ( 30.0  % ) 0.751fasting insulin ( miu / l ) [ m(sd)]13.00 ( 20.93)11.34 ( 10.04)0.554blood lipid ( mg / dl ) [ m(sd ) ]  total cholesterol4.88 ( 1.13)5.14 ( 1.09)0.120  triglycerides1.43 ( 0.67)1.49 ( 0.79)0.549  hdl - c1.25 ( 0.42)1.35 ( 0.39)0.105  ldl - c2.97 ( 0.94)3.12 ( 0.96)0.287inflammation markers [ m(sd ) ]  crp ( mg / l)7.14 ( 2.34)8.80 ( 2.19 ) 
 < 0.001 
 hs - crp ( mg / l)2.14 ( 2.76)3.53 ( 3.41 ) 
 0.005 
 il-6 ( pg / ml)3.28 ( 1.80)4.22 ( 2.53 ) 
 0.002 
 tnf- ( pg / ml)11.54 ( 4.56)17.02 ( 5.37 ) 
 < 0.001 
 location of lacunar infarction  thalamus50 ( 27.9  % ) 19 ( 30.0  % ) 0.879  basal ganglia60 ( 32.8  % ) 39 ( 65.0  % ) 
 < 0.001 
 deep white matter68 ( 37.2  % ) 18 ( 30.0  % ) 0.395  brain stem53 ( 29.0  % ) 15 ( 25.0  % ) 0.612the p values
< 0.05 are in bold 
 m(sd ) , mean ( standard deviation ) baseline descriptive statistics for all subjects and by depression status the p values < 0.05 are in bold 
 m(sd ) , mean ( standard deviation )
a cross - sectional study was performed on the patients attending to the department of neurology in 10th people s hospital at shanghai from september 2012 to november 2013 , mainly with non - specific symptoms such as headache , dizziness , vertigo and limb numbness , simultaneously without any localized neurological signs .
the study has been approved by the institutional review boards and all participants have provided written consent for participation .
a total of 272 participants diagnosed with sli through magnetic resonance imaging ( mri ) were consecutively recruited in our study and attributed to depression and non - depression groups , respectively .
the number of focal lesions of sli should be between three and five in each location .
patients with histories of stroke , vascular dementia , heart failure with a new york heart association degree 3 or 4 , myocardial infarction , atrial fibrillation , rheumatic valvular heart disease , arteritis during this study were excluded .
patients with any grade of leukoaraiosis according to fazekas scale and fresh infarction identified through mri were also excluded .
sli was defined as focal lesions ranging from 3 to 15  mm in diameter , with hypointensity on t1-weighted images , hyperintensity on t2-weighted images . at the time , the location of the sli was recorded as thalamus , basal ganglia , deep white matter , or brain stem .
age , gender , education ( less than high school / high school or college / graduate degree ) , smoking habits ( smoking or non - smoking ) , alcohol intake ( yes or no ) , history of diabetes mellitus , and coronary heart disease were recorded for each subject during enrolment .
systolic and diastolic blood pressures ( mmhg ) were recorded according to the average levels in the last 3  months by questionnaire .
each participant s height and weight were measured without shoes and heavy clothing . the body mass index ( bmi )
was calculated as the ratio of weight in kilograms to the height in square meters ( kg / m ) .
the participants were grouped into three categories according to their bmi value . based on who recommended bmi cutoffs for asian populations , the participants were considered as underweight to normal for bmi values
< 23  kg / m , overweight for bmi values 23.027.5  kg / m , and obese for bmi values 27.5 
waist and hip circumference was measured and waist  hip ratio ( whr ) was calculated .
physical activity was determined by the question :  how much exercise you did in the last 6  months , i.e. , have you exercised for 1520  min of brisk walking , swimming , general conditioning , or recreational sports ? 
possible answers included not at all active , a little active ( 12 times / month ) , fairly active ( 34 times / month ) , quite active ( 12 times / week ) , very active ( 34 times / week ) , or extremely active ( 5 times / week ) .
the participants were grouped into three categories according to the activity level : inactive , light or moderately active , and vigorously active .
the fasting blood samples from the participants were obtained at around 7:00 am and were analyzed at the clinical laboratory department of the shanghai 10th people s hospital of tongji university .
the blood samples were assessed for the following markers of inflammation : c - reactive protein ( crp ) , high - sensitivity c - reactive protein ( hs - crp ) , interleukin-6 ( il-6 ) , and tumor necrosis factor alpha ( tnf- ) . additionally , insulin , total cholesterol , triglycerides , high - density lipoprotein cholesterol ( hdl - c ) , and low - density lipoprotein cholesterol ( ldl - c ) were also measured . in the present study , diagnosis of depression in all patients
depression was assessed with the patient health questionnaire ( phq)-9 , a 9-item scale that assesses the presence of 9 dsm - iv symptoms for major depressive disorder .
responses were scored on a 4-point scale from 0 to 3 , indicating that the participant experienced the symptom  not at all   on several days   on more than half the days  or  nearly every day  with higher scores indicating more severe symptoms . scores on this scale
were categorized as none to minimal ( phq score 03 ) , mild to moderate ( phq score 49 ) , or severe ( phq score 10 ) .
participants with the phq scores 4 were attributed to depression group and the phq scores 03 were attributed to non - depression group .
all the data were analyzed with spss ( version 18.0 , spss , inc . ,
continuous variables were assessed as mean    sd and categorical variables were assessed as counts in percentage . to compare the baseline characteristics ,
continuous variables were analyzed using t tests and categorical variables were analyzed using  test . only the variables with p  <  0.05 were included in the multivariate logistic regression model .
odds ratio ( or ) and 95  % confidence intervals ( cis ) were obtained in models that adjusted for potential confounders .
consistency tests about the radiological diagnosis between two radiologists were performed by calculating intra - class correlation coefficient ( icc ) .
p  <  0.05 was considered to be statistically significant difference.table  1baseline descriptive statistics for all subjects and by depression statusnon - depression ( n  =  183)depression ( n  =  60 ) 
 p valueage ( years)67.16 ( 9.09)66.45 ( 9.95)0.203gender 
 0.013 
 men81 ( 44.3  % ) 15 ( 25.0  % )  women102 ( 55.7  % ) 45 ( 75.0  % ) smoker42 ( 23.0  % ) 9 ( 15.0  % ) 0.259alcohol consumption21 ( 11.5  % ) 6 ( 10.0  % ) 0.752education 
 0.044 
 less than high school / high school152 ( 83.6  % ) 58 ( 95.0  % )  college and graduate degree30 ( 16.4  % ) 3 ( 5.0  % ) physical activity 
 < 0.001 
 none51 ( 27.9  % ) 33 ( 55.0  % )  mild to moderate60 ( 32.8  % ) 9 ( 15.0  % )  vigorous72 ( 39.3  % ) 18 ( 30.0  % ) bmi ( kg / m ) 
 < 0.001 
 < 2397 ( 53.0  % ) 15 ( 25.0  % )  2327.563 ( 34.4  % ) 27 ( 45.0  % )  > 27.524 ( 13.1  % ) 18 ( 30.0  % ) whr [ m(sd ) ] 
 0.98 ( 0.08)0.96 ( 0.08)0.089systolic bp ( mmhg ) [ m(sd)]137.05 ( 15.43)135.10 ( 15.90)0.400diastolic bp ( mmhg ) [ m(sd)]77.43 ( 9.91)75.25 ( 7.00)0.135coronary artery disease39 ( 21.3  % ) 15 ( 25.0  % ) 0.551diabetes50 ( 27.9  % ) 18 ( 30.0  % ) 0.751fasting insulin ( miu / l ) [ m(sd)]13.00 ( 20.93)11.34 ( 10.04)0.554blood lipid ( mg / dl ) [ m(sd ) ]  total cholesterol4.88 ( 1.13)5.14 ( 1.09)0.120  triglycerides1.43 ( 0.67)1.49 ( 0.79)0.549  hdl - c1.25 ( 0.42)1.35 ( 0.39)0.105  ldl - c2.97 ( 0.94)3.12 ( 0.96)0.287inflammation markers [ m(sd ) ]  crp ( mg / l)7.14 ( 2.34)8.80 ( 2.19 ) 
 < 0.001 
 hs - crp ( mg / l)2.14 ( 2.76)3.53 ( 3.41 ) 
 0.005 
 il-6
( pg / ml)3.28 ( 1.80)4.22 ( 2.53 ) 
 0.002 
 tnf- ( pg / ml)11.54 ( 4.56)17.02 ( 5.37 ) 
 < 0.001 
 location of lacunar infarction  thalamus50 ( 27.9  % ) 19 ( 30.0  % ) 0.879  basal ganglia60 ( 32.8  % ) 39 ( 65.0  % ) 
 < 0.001 
 deep white matter68 ( 37.2  % ) 18 ( 30.0  % ) 0.395  brain stem53 ( 29.0  % ) 15 ( 25.0  % ) 0.612the p values < 0.05 are in bold 
 m(sd ) , mean ( standard deviation ) baseline descriptive statistics for all subjects and by depression status the p values < 0.05 are in bold 
 m(sd ) , mean ( standard deviation )
the kappa value was 0.923 , indicating significant consistency between two physicians about the diagnosis of depression .
the icc value for different locations of sli namely thalamus , basal ganglia , deep white matter , brain stem was 0.972 , 0.946 , 0.962 and 0.953 , respectively , indicating significant consistency between two radiologists about the radiological diagnosis .
women and those with high school or less than high school education showed more symptoms of depression . both overweight and obese patients and physically inactive participants displayed more symptoms of depression .
those with high levels of inflammation markers including crp , hs - crp , il-6 , and tnf- also showed depressive symptoms .
the proportion of the patients with sli in basal ganglia was significantly higher in the depression group compared with the non - depression group .
no significant statistical differences were noticed within whr , blood pressure , blood lipid levels , coronary artery disease , diabetes , fasting insulin , or other locations of sli between the depression and non - depression groups .
the following variables were entered into the multivariate logistic model : gender , education , physical activity , bmi , inflammation markers , and sli in basal ganglia .
the results of multivariate logistic regression were shown in fig .  1 according to the adjusted or value of each variables which were statistically significant .
sli in basal ganglia was a significant independent imaging predictor of depression with an or of 3.12 ( 95  % ci : 1.2218.015 ) . compared with complete lack of physical activity , mild to moderate ( or : 0.21 ; 95  % ci : 0.050.82 ) , and vigorous physically active ( or : 0.28 ; 95  % ci :
0.100.80 ) group showed strong association with depression . compared with normal weight , overweight ( or : 3.56 ; 95  % ci : 1.279.94 ) , and obese ( or : 8.94 ; 95  % ci : 2.4133.17 ) population displayed more depression .
additionally , all inflammation markers were significantly associated with depression . those with high levels of crp ( or : 4.63 ; 95  % ci : 1.8511.61 ) , tnf- ( or : 4.59 ; 95  % ci : 1.9111.06 ) , il-6 ( or : 3.38 ; 95  % ci : 1.298.90 ) , and hs - crp ( or : 1.5 ; 95  % ci : 0.583.85 ) exhibited more depressive symptoms compared with those of normal levels . however , gender , and education were no longer associated with depression.fig . 
1adjusted or value by each variables which were statistically significant , namely sli in basal ganglia , mild to moderate / vigorous physical activity , bmi , tnf- , il-6 and crp adjusted or value by each variables which were statistically significant , namely sli in basal ganglia , mild to moderate / vigorous physical activity , bmi , tnf- , il-6 and crp
in our study of 243 patients , 24.7  % of the participants were classified as depressed . after considering a set of possible confounding factors , we found multiple prevalent factors that affected depression . in particular , sli in basal ganglia and vascular risk factors including higher bmi levels , and
inflammation markers , crp , tnf- , hs - crp , and il-6 can increase the risk for depression .
physical activity on the other hand can protect against depression . despite the fact that li is found in 1030  % of elderly individuals with 6  % of newly affected cases annually , they are thought to be clinically silent in the majority of elderly cases .
majority of the previous neuroimaging studies have reported a close link between small subcortical fresh infarcts and psd ; however , only limited studies have examined the effect of sli in depression - related disorders .
the main biological mechanism of psd is the ischemic lesion interrupted the neural fiber projections ascending from the midbrain to the brainstem , which leaded to a decreased bioavailability of biogenic amines , namely serotonin ( 5ht ) , dopamine ( da ) , norepinephrine ( ne ) and acetylcholine . in case of slis ,
the damage to small vessels supplying subcortical pathways disrupts the neurotransmitter circuitry that is involved in mood regulation in a chronic pattern .
when the accumulation of the infarcts exceeds a certain threshold , patient could become more vulnerable to developing depression .
some putative mechanisms suggest that lesions at various sites may result in depression through direct disruption of the cortico - striato - pallido - thalamo - cortical ( csptc ) circuits or their modulating systems .
our findings indicate that sli in basal ganglia can increase the risk of depression , which is partly consistent with the results of the previous study .
given that basal ganglia consist of many central gray matter nuclei , cortico - basal ganglia circuitry dysfunction may play a role in the neurobiology of depression .
cortico - basal ganglia circuitry consists of segregated functional subcircuits and their fibers project from specific functional regions of the cortex to specific nuclei in the basal ganglia .
these fibers include monoamine and glutamatergic fibers , which are involved in the mood disorder .
interruption of the monoamine neurotransmitter fibers results in the fluctuation of serotonin and norepinephrine levels in the orbitofrontal pathway and the prefrontal lobe .
in addition , damage in the glutamatergic routes disrupts glutamatergic transmission , which is also associated with depression . alexopoulos et al .
proposed the theory of  vascular depression  to suggest that pathologies to the vessels play a unique role in the onset of depression .
in this model , vascular risk factors may lead to depression only after crossing a certain threshold .
in addition , this model allows for each risk factor alone or in combination to cross the threshold to induce neural circuit changes , thereby mediating depression .
thus , the processes of these pathways could all contribute to depression both independently and collaboratively . by conducting univariate analysis
however , on multivariable analysis , we found that some of these effects were eliminated , and other effects remained associated with depression .
this finding indicates that risk factors are intertwined , thereby promoting the pathological basis of depression in sli . since , we found vascular risk factors included obesity , inflammation , and lack of physical activity
adrenalaxis ( hpa axis ) dysregulation , which is associated with depression [ 25 , 26 ] .
abnormalities to the inflammatory system of both depressed and obese people were observed , providing possible biological explanations for the association between depression and obesity . in our study , we found that both obesity and inflammation markers were risk factors for depression .
increase in physical activity is also linked to the reactivity of the hpa axis and is associated with lower levels of inflammatory markers .
our finding suggests that engaging in both mild to moderate and vigorous physical activity acts as protective factor in depression , which is in line with existing research .
our data on the effect of inflammation markers on depression are consistent with these findings [ 29 , 30 ] .
furthermore , pro - inflammatory cytokines may lead to a reduced hippocampal volume , which is also seen in depression .
this result may indicate that treatment with the anti - inflammatory agent may result in a significant decrease in depressive symptoms .
first , our data were gathered by self - reported questionnaires , which could have led to bias by patients over or underreporting physical activity , depression , past history , or educational attainment .
the fact that these individuals have agreed to participate in a clinical trial may suggest different emotional and behavioral characteristics , which may impact the generalizability of our results concerning depression . however , our prevalence estimates were similar to those previously reported studies on li .
second , our cross - sectional study was restricted to the participants with a baseline depression score .
finally , we can not draw firm conclusions regarding the direction of causality between the progression of structural changes and depressive symptoms , because depressive symptoms were only assessed at the follow - up study .
in conclusion , our findings suggest that sli in basal ganglia and vascular risk factors including bmi , inflammation markers , and physical activity is strongly associated with depression .
furthermore , these risk factors are clearly intertwined , proposing a pathological basis of depression following sli . by demonstrating
such mechanisms affect neural circuit function , this study opens a door for future research to further examine the mechanisms that can improve the outcome for depression .
it is critical that patients with sli are screened early for depression and are provided with appropriate treatment .
 most previous studies reported a close link between fresh infarcts and post - stroke depression . 
 however , studies on the relation of depression and silent lacunar infarction ( sli ) are limited . 
 this study aims to analyze the effects of sli and the vascular risk factors on depression . 
 a total of 243 patients with sli were divided into depression and non - depression groups . 
 the presence and location of sli were evaluated with magnetic resonance imaging . 
 depression was assessed with the patient health questionnaire-9 and vascular risks factors were collected . 
 we used t tests and 2 test to compare the baseline characteristics of the two groups and the multivariate logistic regression model to identify the risk factors for depression . 
 univariate analysis results showed that the proportion of patients with sli in basal ganglia was significantly higher in the depression group ( 65.0 versus 32.8  % ; p  <  
 0.001 ) than in the non - depression group , and multiple prevalent factors had significant differences between the two groups . 
 however , on multivariate logistic analysis , some of these factors were eliminated , and sli in basal ganglia remained an independent predictor of depression with an odds ratio of 3.128 ( p  =  0.018 ) . 
 in addition , vascular risk factors , including high body mass index level , presence of inflammation markers ( e.g. , crp , tnf- , hs - crp , and il-6 ) , and lack of physical activity , were associated with depression . 
 our findings suggest that sli in basal ganglia is associated with a higher risk of depression . 
 vascular risk factors , which are intertwined , may propose the pathological basis of depression in sli . 
Introduction
Materials and methods
Participants
Measurement
Data analysis
Results
Discussion
Conclusion