the functional asymmetry of the cerebral hemispheres has been reported in patients with many sorts of brain damage , who failed to orient , report , or respond to stimuli located in one hemispace 1 .
line bisection has been employed as a sensitive test for unilateral neglect 1,3 . in this task ,
lateral deviation from the true center indicate the relative inattention for the contralateral side of space , and a consistent leftward error has been reported in healthy subjects in the western world , indicating a relatively right cerebral dominance in them ( reviewed in ref 4 ) .
nonetheless , patients with right hemispheric lesions usually place the subjective midpoint to the right of the true center 4 . of interest to psychologists and psychiatrists
are the possible functional cerebral asymmetries represented in sorts of psychiatric patients and in different emotional states of healthy individuals , which might be due to the different strategies for processing specific stimuli . in healthy subjects ,
negative emotions are more likely to be associated with the activation of the right hemisphere 5,6 .
for instance , some studies have shown that the induced anxiety in normal subjects selectively impaired their spatial , but not verbal performance 7,8 , other studies in both infants and adults have found that negative affects , such as anxiousness and depression , are more relatively associated with the right hemisphere activation , particularly the frontal lobe 6,9 - 11 . moreover
, the greater right hemisphere activation in depression patients has been demonstrated in studies that used the consonant - vowel task12 , and the electroencephalogram measurements 13,14 .
individuals with generalized anxiety disorder ( gad ) are found to be intolerant of uncertainty and perceive more potentially negative situations than the healthy subjects 15 - 17 , and people with depression also employ a maladaptive problem - solving method , which contributes to the maintenance of negative emotions they perceived 18,19 .
one question therefore arises how patients with gad , or with the treatment - resistant depression ( trd ) , a severe form of depression , would perform in the line bisection task .
the possible answers might help us to understand better the hemispheric functions that contribute to these pathologies on the one hand , and probably help to further address the overlaps between anxiety and depression on the other . bearing that gad and trd patients often present negative emotions in mind , we have hypothesized that these subjects would bisect lines further leftward than the healthy volunteers would .
in addition , given the high prevalence of anxiety / depression in the general population , it might be interesting to compare the levels of anxiety / depression between our patients and healthy subjects .
thus , we used the zuckerman - kuhlman personality questionnaire 20 to measure the subject 's anxiety trait , and the plutchik - van praag depressive inventory 21 to measure their depressive mood .
moreover , since the sensation seeking trait is correlated with a hemispheric asymmetry 22,23 , the zuckerman sensation seeking scales 24 were also used in the present protocol .
considering that most chinese people are trained to use their right hands as artful ones in their early lives 25 , studies of such training in athletes showed consistently moderate rightward errors in the line bisection task 26,27 , we therefore selected 155 moderate to strong right - handed subjects for our study .
fifty - six healthy volunteers were recruited among college students , medical staff members or paid volunteers . after a semistructured interview , it was determined that they were not suffering from any kinds of anxiety or depressive disorder .
forty - seven outpatients were diagnosed with gad according to the criteria of the diagnostic and statistical manual of mental disorders - version iv - text revision 28 .
fifty - two outpatients were diagnosed with trd using following criteria ( all the four criteria were met ) : ( 1 ) symptoms met criteria for major depressive disorder 28 ; ( 2 ) remission failed after using at least two antidepressants ; ( 3 ) patients scored more than 25 on the plutchik - van praag depression inventory ; ( 4 ) patients were without comorbidities of psychotic diseases or drug abuse .
in addition , patients were ascertained not to have any organic brain lesions after going through computerized tomographic or magnetic resonance imaging scans . about 50% of patients had received anxiolytics or antidepressants before arriving at our clinic , but no participants had ingested alcohol , drugs or medication at least 72 hours prior to the test .
there were no significant group differences when referring to age ( one - way anova , main effect , f ( 2,152 ) = .94 , p >
.05 ) , or gender ( main effect , f = .06 , p > .05 ) .
this study protocol was approved by a local ethics committee and all subjects gave their written informed consent .
each of the 12 items of the inventory were scored 1 , 2 or 3 according to the left - hand , either left or right , or right preference .
all subjects scored between 29 and 36 , and were thus considered to be moderate or strong right - handers .
, subjects were asked to complete three questionnaires on - site in a quiet room .
a brief overview of each questionnaire is described below : the zuckerman - kuhlman personality questionnaire .
the test provides five measurements : ( a ) impulsive sensation seeking ( 19 items ) ; ( b ) neuroticism - anxiety ( 19 items ) ; ( c ) aggression - hostility ( 17 items ) ; ( d ) activity ( 17 items ) ; and ( e ) sociability ( 17 items ) .
the internal reliabilities of these scales range from .72 to .86 . in this questionnaire ,
10 items of another scale of dissimulation ( infrequency or lie ) were randomly inserted into the test body .
any score above 3 on the infrequency scale suggests either inattention to the content of the items and acquiescence or a very strong social desirability set ; therefore , the infrequency scale was used as a test validity indicator for individuals 20 .
the test has proven to be reliable in the chinese culture 32;the zuckerman sensation seeking scales ( form v , 40 items ) .
the test provides four subscales of 10 items each , ( i.e. , disinhibition , thrill and adventure seeking , experience seeking and boredom susceptibility ) .
the total score in each subject was also calculated as the sum of the four scale scores .
the test has proven to be reliable in the chinese culture 34;the plutchik - van praag depression inventory .
this inventory contains 34 items ; each item has three scale points ( 0 , 1 , 2 ) , corresponding to depressive tendencies .
subjects have  possible depression  if they score between 20 and 25 , or  depression  if they score higher than 25 .
the test provides five measurements : ( a ) impulsive sensation seeking ( 19 items ) ; ( b ) neuroticism - anxiety ( 19 items ) ; ( c ) aggression - hostility ( 17 items ) ; ( d ) activity ( 17 items ) ; and ( e ) sociability ( 17 items ) .
the internal reliabilities of these scales range from .72 to .86 . in this questionnaire ,
10 items of another scale of dissimulation ( infrequency or lie ) were randomly inserted into the test body .
any score above 3 on the infrequency scale suggests either inattention to the content of the items and acquiescence or a very strong social desirability set ; therefore , the infrequency scale was used as a test validity indicator for individuals 20 .
the test has proven to be reliable in the chinese culture 32 ; the zuckerman sensation seeking scales ( form v , 40 items ) .
the test provides four subscales of 10 items each , ( i.e. , disinhibition , thrill and adventure seeking , experience seeking and boredom susceptibility ) .
the total score in each subject was also calculated as the sum of the four scale scores .
the test has proven to be reliable in the chinese culture 34 ; the plutchik - van praag depression inventory .
this inventory contains 34 items ; each item has three scale points ( 0 , 1 , 2 ) , corresponding to depressive tendencies .
subjects have  possible depression  if they score between 20 and 25 , or  depression 
the lines , drawn in black and oriented horizontally , ranged from 102 - 144 mm in length , were arranged randomly on a sheet of a4 size paper ( in a portrait orientation ) one below the other , and differed in their distances from the sheet margins so that their centers were not in alignment .
no restrictions were placed on head or eye movements , and no time limits were imposed .
subjects were instructed to use their right hand to make a mark indicating the center of the line .
there are many classical methods to analyze line bisection performance , for instance the percentage expression of bias errors 35 . here
briefly , the distance of the line bisecting task mark was measured from the actual center to the nearest millimeter .
the frequency of the directional errors ( frequency ) , irrespective of the magnitude , was calculated as ( right - left)/ ( right + left ) ; negative values indicate errors to the left and positive ones indicate errors to the right . the magnitude of line bisection deviation ( magnitude )
was calculated as an algebraic sum of the distance of marks from the true center divided by the number ( e.g. , 8) of trials .
negative values indicate errors to the left and positive ones indicate errors to the right .
two - way anova followed by a post - hoc , duncan 's multiple new range test was applied to the five trait scores of the zuckerman - kuhlman personality questionnaire or four scale scores of sensation - seeking in the three groups .
the mean frequency , magnitude , or depression scores in the three groups were submitted to a one - way anova plus duncan 's test .
the relationship between the frequency , magnitude , five personality traits , four sensation seeking scales , and depression scores was assessed by the spearman rank order correlation test . with the present sample size , power to detect an effect ( e.g. , a scale score ) was larger than 80% at p < .05 in a sample of 47 subjects per group ( the smallest group in the present study ) .
considering that most chinese people are trained to use their right hands as artful ones in their early lives 25 , studies of such training in athletes showed consistently moderate rightward errors in the line bisection task 26,27 , we therefore selected 155 moderate to strong right - handed subjects for our study .
fifty - six healthy volunteers were recruited among college students , medical staff members or paid volunteers . after a semistructured interview , it was determined that they were not suffering from any kinds of anxiety or depressive disorder .
forty - seven outpatients were diagnosed with gad according to the criteria of the diagnostic and statistical manual of mental disorders - version iv - text revision 28 .
fifty - two outpatients were diagnosed with trd using following criteria ( all the four criteria were met ) : ( 1 ) symptoms met criteria for major depressive disorder 28 ; ( 2 ) remission failed after using at least two antidepressants ; ( 3 ) patients scored more than 25 on the plutchik - van praag depression inventory ; ( 4 ) patients were without comorbidities of psychotic diseases or drug abuse .
in addition , patients were ascertained not to have any organic brain lesions after going through computerized tomographic or magnetic resonance imaging scans . about 50% of patients had received anxiolytics or antidepressants before arriving at our clinic , but no participants had ingested alcohol , drugs or medication at least 72 hours prior to the test .
there were no significant group differences when referring to age ( one - way anova , main effect , f ( 2,152 ) = .94 , p >
.05 ) , or gender ( main effect , f = .06 , p > .05 ) .
this study protocol was approved by a local ethics committee and all subjects gave their written informed consent .
each of the 12 items of the inventory were scored 1 , 2 or 3 according to the left - hand , either left or right , or right preference .
all subjects scored between 29 and 36 , and were thus considered to be moderate or strong right - handers .
before the line bisection task , subjects were asked to complete three questionnaires on - site in a quiet room .
a brief overview of each questionnaire is described below : the zuckerman - kuhlman personality questionnaire .
the test provides five measurements : ( a ) impulsive sensation seeking ( 19 items ) ; ( b ) neuroticism - anxiety ( 19 items ) ; ( c ) aggression - hostility ( 17 items ) ; ( d ) activity ( 17 items ) ; and ( e ) sociability ( 17 items ) .
the internal reliabilities of these scales range from .72 to .86 . in this questionnaire ,
10 items of another scale of dissimulation ( infrequency or lie ) were randomly inserted into the test body .
any score above 3 on the infrequency scale suggests either inattention to the content of the items and acquiescence or a very strong social desirability set ; therefore , the infrequency scale was used as a test validity indicator for individuals 20 .
the test has proven to be reliable in the chinese culture 32;the zuckerman sensation seeking scales ( form v , 40 items ) .
the test provides four subscales of 10 items each , ( i.e. , disinhibition , thrill and adventure seeking , experience seeking and boredom susceptibility ) .
the total score in each subject was also calculated as the sum of the four scale scores .
the test has proven to be reliable in the chinese culture 34;the plutchik - van praag depression inventory .
this inventory contains 34 items ; each item has three scale points ( 0 , 1 , 2 ) , corresponding to depressive tendencies .
subjects have  possible depression  if they score between 20 and 25 , or  depression  if they score higher than 25 .
the test provides five measurements : ( a ) impulsive sensation seeking ( 19 items ) ; ( b ) neuroticism - anxiety ( 19 items ) ; ( c ) aggression - hostility ( 17 items ) ; ( d ) activity ( 17 items ) ; and ( e ) sociability ( 17 items ) .
the internal reliabilities of these scales range from .72 to .86 . in this questionnaire ,
10 items of another scale of dissimulation ( infrequency or lie ) were randomly inserted into the test body .
any score above 3 on the infrequency scale suggests either inattention to the content of the items and acquiescence or a very strong social desirability set ; therefore , the infrequency scale was used as a test validity indicator for individuals 20 .
the test has proven to be reliable in the chinese culture 32 ; the zuckerman sensation seeking scales ( form v , 40 items ) .
the test provides four subscales of 10 items each , ( i.e. , disinhibition , thrill and adventure seeking , experience seeking and boredom susceptibility ) .
the total score in each subject was also calculated as the sum of the four scale scores .
the test has proven to be reliable in the chinese culture 34 ; the plutchik - van praag depression inventory .
this inventory contains 34 items ; each item has three scale points ( 0 , 1 , 2 ) , corresponding to depressive tendencies .
subjects have  possible depression  if they score between 20 and 25 , or  depression  if they score higher than 25 .
the lines , drawn in black and oriented horizontally , ranged from 102 - 144 mm in length , were arranged randomly on a sheet of a4 size paper ( in a portrait orientation ) one below the other , and differed in their distances from the sheet margins so that their centers were not in alignment .
no restrictions were placed on head or eye movements , and no time limits were imposed .
subjects were instructed to use their right hand to make a mark indicating the center of the line .
there are many classical methods to analyze line bisection performance , for instance the percentage expression of bias errors 35 . here
briefly , the distance of the line bisecting task mark was measured from the actual center to the nearest millimeter .
the frequency of the directional errors ( frequency ) , irrespective of the magnitude , was calculated as ( right - left)/ ( right + left ) ; negative values indicate errors to the left and positive ones indicate errors to the right . the magnitude of line bisection deviation ( magnitude )
was calculated as an algebraic sum of the distance of marks from the true center divided by the number ( e.g. , 8) of trials .
negative values indicate errors to the left and positive ones indicate errors to the right .
two - way anova followed by a post - hoc , duncan 's multiple new range test was applied to the five trait scores of the zuckerman - kuhlman personality questionnaire or four scale scores of sensation - seeking in the three groups .
the mean frequency , magnitude , or depression scores in the three groups were submitted to a one - way anova plus duncan 's test .
the relationship between the frequency , magnitude , five personality traits , four sensation seeking scales , and depression scores was assessed by the spearman rank order correlation test . with the present sample size , power to detect an effect ( e.g. , a scale score ) was larger than 80% at p < .05 in a sample of 47 subjects per group ( the smallest group in the present study ) .
when the two - way anova was applied to the five personality trait scores in the three groups , main group ( f ( 2 , 152 ) = 5.16 , p < .05 , mse = 77.89 ) , scale ( f ( 4 , 608 ) = 58.33 , p < .001 , mse = 632.62 ) , and group - scale interaction ( f ( 8 , 608 ) = 10.14 , p < .001 , mse = 109.29 ) effects were detected .
the post - hoc duncan 's test also detected that the gad subjects scored significantly higher on neuroticism - anxiety than the healthy subjects and trd patients did ; patients also scored significantly lower on sociability than the healthy subjects did .
the four sensation - seeking scale scores , however , were not significantly different between groups ( main group effect , f ( 2 , 152 ) = .45 , p > .05 , mse = 9.746 ) ( table 2 ) .
the mean depression scores among the three groups also had statistically significant differences from each other ( main effect , f ( 2 , 152 ) = 60.64 , p < .001 , mse = 6205.02 ) , with that of the trd patients higher than those of both the healthy subjects and the gad patients ( also see table 2 ) . on average , trd patients bisected slightly more frequently to the left of the true center , whereas healthy subjects bisected slightly more frequently to the right .
in contrast , gad patients bisected significant more frequently to the left of the true center than the healthy subjects did .
when the mean frequency errors in the three groups were analyzed , one - way anova detected a significant difference ( f ( 2 , 152 ) = 3.50 , p < .05 , mse = 1.40 ) .
the post - hoc duncan 's test showed that the gad group ( -.32  .56 s. d. ) was significantly different from the healthy control group ( .01  .67 , p < .05 ) .
the mean magnitude errors were also significantly different among the three groups ( f ( 2 , 152 ) = 3.31 , p < .05 , mse = 5.90 ) , post - hoc duncan 's test detected that the mean magnitude in the gad group ( -.54 mm  1.15 s.d . )
was significantly different from that in the healthy controls ' ( .12  1.42 ) , but not from that in the trd ( -.33  1.40 ) ; there was no statistical difference between the mean magnitude errors of the healthy controls and those of the trd either .
frequency was negatively correlated with the disinhibition - seeking score ( n = 56 , r = -.28 , p < .05 ) in healthy subjects , and with total sensation - seeking ( n = 47 , r = -.30 , p < .05 ) and experience seeking scores ( n = 47 , r = -.34 , p < .05 ) in gad patients .
in addition , the depression score was negatively correlated with magnitude ( n = 52 , r = -.30 , p < .05 ) in trd patients .
no other correlations , such as between the handedness and frequency/ magnitude , or personality trait scores were found in our study .
in the present study , patients scored higher on neuroticism - anxiety ( with gad patients scoring highest ) and on depression ( with trd patients scoring highest ) than the healthy subjects did .
these results lead to the observation that there is a great overlap between anxiety and depression symptoms in clinics 37,38 , and that these two disorders might share similar genetic dimensions and disease continuums 39,40 .
in addition , our patients scored lower on sociability than the healthy subjects did , which was also in line with the previous report that major depression affected the sociability trait 41 , and this low extraversion ( introversion ) 42 tendency has also been suggested as personality endophenotypes in many anxiety disorders , e.g. , social phobia and agoraphobia 43 . in compliance with our hypothesis ,
gad patients erred significantly leftward in line bisection , which suggests a right hemispheric overactivation , left hypoactivation , or both for this disorder . as we have noted in our introduction , negative emotions like anxiousness
some neuroimaging and electrophysiological data have also shown that patients with anxiety disorders ( e.g. , panic disorder ) displayed lower activation of the left parietal or superior temporal cortex , but relatively greater activation of the right frontal or hippocampal regions than the healthy subjects did 44 - 46 .
contrary to our hypothesis , trd patients did not show significant leftward line bisection errors in our study .
such a result is in line with previous studies , showing that the unipolar depressive patients displayed a non - significant leftward bias in manual line bisection , while schizophrenia patients bisected significantly leftward 47 - 49 .
however , results in regard to the hemispheric activation in the depressive disorder remain inconclusive up to date 50 - 55 .
albeit , the slight rightward error found in our healthy subjects was different from those documented in western countries 4 , this result is similar to those in other studies conducted in japan 56 and china 30,31 .
this discrepancy might result from a cultural background where most chinese people are forced to use their right hands during their early lives 25 .
the negative correlation between frequency and disinhibition - seeking scores in our healthy subjects , and the negative correlation between frequency and the total sensation - seeking and experience - seeking scores in gad patients , contradict the recent neurophysiologic results in sensation seekers .
for instance , a greater left frontal eeg asymmetry at rest is related to a tendency to engage in sensation - seeking and risky behaviors in young adults 23 .
likewise , the association of left hemisphere predominance and risk - taking in healthy university students has also proven by studying the line bisecting performance and zuckerman 's sensation seeking scales in drake and ulrich 's study 36 .
a rightward bias has been reported in healthy subjects in some eastern countries like japan and china , contradictory to those found in western societies , such a tendency might contribute to our current findings . moreover , whether the reversed correlation in our gad patients was due to the severity of anxiety itself merits further investigation . in our trd patients ,
this finding is in accordance with the results in the tension - type headache study 31 , which might be because many tension - type headache sufferers also displayed signs of depression 57 .
on the other hand , we could not completely ruled out the medication effects on our findings , since previous studies have shown the effect of anxiolytics or antidepressants on cognition ( e.g. , attention , memory or learning ) 58,59 , behavioral aspects ( e.g. , executive function or motor reaction ) 60 , and hemispheric asymmetry 48 . however , prior to the study , our patients were all medication - free for at least 72 hours , which helped to remove some effects of the anxiolytics or antidepressants .
nevertheless , further studies about the medication effects on brain asymmetry in anxiety and depression disorders would be of interest . some limitations in our study should be underlined .
firstly , we did not consider the menstrual cycles of our female subjects , since the line bisection performance might be influenced by the menstrual state of women 35,61 ; however , three groups of our subjects were gender - balanced .
secondly , we did not measure the disordered personality traits in our subjects , since the dependent personality disorder patients have shown a pronounced leftward line bisection error 30 .
thirdly , for more extensive comparisons , we would need more data from left - handed subjects , and data obtained using the neuroimaging or other indirect neuropsychological techniques .
fourthly , we used lines between 102 - 144 mm which were shorter than what other investigators used , and the line length was demonstrated to have influenced line bisection performance ( e.g. , ref 62 ) .
fifthly , we did not analyze the medication effect on the line bisection task since the individual medication strategies varied among our patients .
finally , we did not employ other attention - control paradigms such as using a cue during the task . in conclusion ,
the leftward line bisection errors in gad might indicate a stronger right , a weaker left hemispheric activation , or both .
the task is a non - invasive examination and easy to manipulate in typical clinics .
whether it could be used as a diagnostic auxiliary test for anxiety versus depression remains to be determined .
 background and objectives the line bisection error to the left of the true center has been interpreted as a relative right hemisphere activation , which might relate to the subject 's emotional state . considering that patients with generalized anxiety disorder ( gad ) or treatment - resistant depression ( trd ) often have negative emotions 
 , we hypothesized that these patients would bisect lines significantly leftward . 
 methods we tried the line bisection task in the right - handed healthy volunteers ( n = 56 ) , gad ( n = 47 ) and trd outpatients ( n = 52 ) . 
 subjects also completed the zuckerman - kuhlman personality questionnaire , the zuckerman sensation seeking scales , and the plutchik - van praag depression inventory . 
 results gad patients scored highest on the neuroticism - anxiety trait , trd patients scored highest on depression , and both patients scored lower on the sociability trait . patients with 
 gad also bisected lines significantly leftward compared to the healthy subjects . 
 the frequency of the bisection error was negatively correlated with disinhibition - seeking in the healthy subjects , and with total sensation - seeking and experience - seeking in gad patients , while the magnitude of the line bisection error was negatively correlated with depression in trd patients . 
 conclusions the study suggests a stronger right hemispheric activation , a weaker left activation , or both in the gad , instead of trd patients . 
Introduction
Materials and Methods
Subjects
Inventories
Procedures
Data analyses and statistics
Results
Discussion