11
111
Background
In Chapter 10, I discussed studies demonstrating an association during the acute stroke period between major depressive disorder and lesions of the left dorsolateral frontal cortex or left basal ganglia. Although there is a statistically significant increase in the frequency of major depression among patients with lesions of the left ante-rior brain region, not all patients with left frontal or left basal ganglia lesions develop depression. We therefore questioned whether patients who had a left ante-rior brain lesion without depression might have structural differences in their brains compared with those patients who developed depression after left frontal lesions.
We have addressed this question in two different studies examining the effect of handedness and structural hemispheric asymmetry on the frequency and clinical correlates of depressive disorder.
Patients with left sided motor dominance
In the first study, a consecutive series of 30 patients who were left handed, without evidence of mixed motor cerebral dominance, was evaluated for depressive disor-ders (Robinson et al. 1985). Patients were included if they reported the predomi-nant use of their left eye for vision, left hand for writing and eating, and left foot for kicking. Patients also had to have a single stroke lesion without a clinical history or computed tomography (CT) scan evidence of prior brain injury. The study included 18 patients with left hemisphere lesions and 12 patients with right hemi-sphere lesions (Table 11.1). The right and left hemihemi-sphere lesion groups were not significantly different in any background characteristics except that the right lesion patients were significantly older than patients with left hemisphere lesions (p 0.05). Of the overall group of 30 patients, eight patients had major depres-sion, three patients had minor depresdepres-sion, and 19 patients were not depressed.
Among the 18 patients with left hemisphere lesions, seven had major, and three
112 Poststroke depression
had minor depression while eight were not depressed. Among the 12 patients with right hemisphere lesions, one had a major depression while 11 were not depressed (p 0.025 comparing the frequency of depression in patients with right versus left hemisphere lesions). When patients were divided into those with anterior and pos-terior lesions, patients with left anpos-terior lesions had a significantly higher fre-quency of depressive disorder than patients with left posterior lesions or patients with right hemisphere anterior or posterior lesions (Fig. 11.1) (p 0.001). In
Left-handed patients with stroke
0 20 40 60 80
LA (n 8) LP (n 7) RA RP (n 8) Lesion location
% with major depression
Figure 11.1 The percent of left-handed patients with major depression who had left anterior (LA), left posterior (LP) or right anterior or posterior lesions (RA RP). There was a significantly greater frequency of major depression among the patients with left anterior lesions than any other location.
Table 11.1. Demographic data on 30 left-handed stroke patients according to hemisphere of lesion
Left hemisphere Right hemisphere
Characteristics lesion (n 18) lesion (n 12)
Age (mean SD) 53 14 63 12
Male (%) 55 75
Married (%) 50 25
Widowed (%) 11 50
Hollingshead socioeconomic class IV or V (%) 83 83
History of alcohol abuse (% positive) 17 8
Personal history of psychiatric disorder (% positive) 11 8
Previous history of stroke (% positive) 28 25
JHFI (mean SD) 9.0 7.0 7.1 6.0
Mini-mental (mean SD) 20.8 6.9 21.8 4.5
Days since stroke (mean SD) 49 64 24 35
JHFI: Johns Hopkins functioning inventory.
113 Relationship of depression to cerebral dominance and structural asymmetries
addition, among 13 patients whose left hemisphere lesion border was anterior to 45% of the anterior–posterior distance, there was a significant correlation between proximity of the lesion to the frontal pole and the severity of depression (Fig. 11.2).
This is the same kind of correlation between depression and proximity of the lesion to the frontal pole that was previously found in patients who were right handed (see Fig. 10.5).
The major question that we could not satisfactorily answer in this study is how many of these left-handed patients had right hemisphere dominance for language.
It would be expected that approximately 60–70% of left-handed patients (i.e., patients with right hemisphere motor dominance) would show the same left hemi-sphere dominance for language as patients who were right handed (Rasmussen and Milner 1977). Since we found that left hemisphere (especially left anterior) lesions were associated with major depression, one might hypothesize that damage to the language dominant hemisphere and, therefore, language impairment were the factors that led to depression. Depression, however, was not significantly asso-ciated with aphasia (of 11 patients with depression, five had aphasia; of 19 non-depressed patients, four had aphasia, p NS). Furthermore, we assumed that 60%
of left-handers would show left hemisphere dominance for language and, there-fore, in these patients left hemisphere lesions would be associated with depression and only 40% would show the reversed pattern of right hemisphere lesions associ-ated with depression. Using this assumption for distribution of language domi-nance, 5 of the 12 patients with right hemisphere lesions (i.e., 40%) should have the reversed pattern (i.e., right lesions associated with depression). Of these five patients, three would be expected to be depressed (i.e., 60% of left hemisphere lesion patients were depressed) but only one was found. Similarly, in the left lesion group,
0 2 4 6 8 10 12 14
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 Distance between anterior border of lesion and frontal pole
(% of A–P distance)
Overall depression score
r 0.78, p 0.01
Figure 11.2 Correlation between severity of depression and proximity of the anterior border of the lesion to the frontal pole among 13 patients who were left handed and had a single lesion of the anterior left hemisphere. This is the same kind of correlation in the left anterior hemisphere found in right-handed patients (see Chapter 10).
A–P: anterior–posterior.
114 Poststroke depression
seven (i.e., 40%) would be expected to have the reversed pattern and no depression while 60% of the remaining 11 patients should be depressed. In fact, 10% or 92%
of the left lesion patients who were expected to have left hemisphere language dominance were depressed. This distribution of depressions and hemispheric injury was significantly different than the expected distribution (i.e., distribution based on the assumed pattern of language dominance).
This study indicated that the association of left anterior lesions with depression in left-handers was just like the association previously reported in right-handers.
Even when language dominance was taken into account, the number of depressed patients with left hemisphere lesions was higher than expected and the number of depressed patients with right hemisphere lesions was lower than expected if depression vulnerability was linked with language dominance. Thus, the associa-tion of left anterior lesions with major depression does not appear to be associated with motor dominance (i.e., handedness) or perhaps language dominance. It should be emphasized, however, that we did not test for language dominance and our conclusions about the lack of association with language are therefore tentative.
Patients with typical and reversed brain asymmetries
The second study was undertaken to assess depression in patients with evidence on CT scan of reversed anatomical organization of the brain (Starkstein et al.
1991). LeMay and Kido (1978) first reported normal brain asymmetries on CT scans. They found that 78% of right-handed males had a greater occipital length in the left hemisphere compared with the right hemisphere and 67% had a greater left than right occipital width. On the other hand, the right frontal length was greater than the left in 70% of subjects and the right frontal width was greater than the left in 53% of individuals studied. Although these findings have been exten-sively replicated (Chui and Damasio 1980; Weinberger et al. 1982), the functional significance of these structural brain asymmetries remains uncertain. Some inves-tigators (Bear et al. 1986) reported an increased frequency of asymmetries (espe-cially occipital asymmetries) in left-handed patients while other investigators have reported a similar frequency of asymmetries in both right- and left-handers (Chui and Damasio 1980). Chui and Damasio (1980) suggested that the asymmetries were probably related to language dominance rather than handedness. Studies of aphasic patients, however, have shown no association between language domi-nance and brain asymmetries (Naeser and Borod 1986). Thus, although the fun-ctional significance of brain asymmetries remains uncertain, frontal and/or occipital asymmetries are seen in approximately one-third of patients and, they are presumably associated with some hemispheric asymmetry in brain activity or function.
115 Relationship of depression to cerebral dominance and structural asymmetries
We examined patients with reversed brain asymmetries and compared the fre-quency of depressive disorders with that in patients with normal brain asymme-tries. All patients had a single stroke lesion which involved either the right or left hemisphere and a CT scan which demonstrated a single lesion but no mass effects of the lesion or lateral head tilt, so asymmetries on CT scan could be adequately assessed.
Asymmetries were assessed in the lowest CT cut showing both the frontal horns of the lateral ventricles and the trigone (i.e., the lateral ventricular region where the body, occipital horn and temporal horn join together). An asymmetry index was calculated by subtracting the area in the left occipital pole from the comparable area in the right hemisphere and dividing by the sum of the two areas. Interrater reliability for these measurements was high (r 0.99, n 20). Patients were con-sidered to have reversed asymmetry when the asymmetry index was more than two standard errors above the mean.
The numbers of patients and their background characteristics, based on the type of brain asymmetry (typical or reversed) and side of lesion (left or right hemi-sphere) are shown in Table 11.2. Patients were mainly in their 50s and early 60s with a slight predominance of black males and lower socioeconomic classes. No significant differences were observed between groups with the exception of educa-tion which was lowest in the right lesion group with typical asymmetry. Findings from the neurological examination revealed no significant intergroup differences except for aphasia which was observed only in patients with left hemisphere lesions.
The frequencies of major and minor depression in each of the groups is shown in Fig. 11.3. In patients with typical (i.e., normal) brain asymmetries in the occip-ital pole, the frequency of depression was significantly higher among patients with left (i.e., 10 of 23 patients had major depression) as compared with right (i.e., 2 of 16 patients had major depression) hemisphere lesions (p 0.05). The association of left hemisphere lesions with major depression in patients with the normal pat-tern of brain asymmetry was reversed in patients with the opposite patpat-tern of occipital asymmetries. Among patients with reversed occipital asymmetry, major depression was associated with right hemisphere lesions in three out of eight patients compared to none of nine patients with left hemisphere lesions (p 0.1, trend).
When patients with typical asymmetries were grouped according to whether they had an anterior or posterior lesion location, the highest frequency of depres-sion was found among patients with left anterior ledepres-sions (seven out of eight patients, 88%) compared with 3 of 15 patients with left posterior lesions (20%, p 0.05, Fig. 11.4). Among the patients with reversed asymmetries, two of five patients with right anterior lesions and one of three patients with right posterior lesions had major depression. Finally, the frequency of major depression in patients with typical asymmetries and left anterior lesions was significantly greater
116 Poststroke depression
than among patients with left anterior lesions and reversed occipital asymmetries (Fisher exact test p 0.025).
In contrast to these strong associations of depression with occipital asymmetry patterns, we did not find the reversal of the association between major depression and left anterior lesion location among patients with frontal brain asymmetries.
There were 19 patients with reversed frontal asymmetry; in the group with typical frontal asymmetry, five of seven patients (71%) with left anterior lesions had major depression compared with three of five patients (60%) with reversed frontal asym-metry and a left anterior lesion (p NS). Thus, reversal of frontal asymmetry did not produce a significantly different frequency of depression following left anterior
Table 11.2. Demographic data for patient with typical and reversed occipital asymmetries
Left lesion groups Right lesion groups
Characteristics Anterior Posterior Anterior Posterior
(A) Patients with typical occipital asymmetries
Number of patients 8 15 9 7
Age, mean years SD 53.8 17 60.4 15 62.4 9.9 57.1 11
Gender (% female) 63 33 44 29
Race (% blacks) 75 53 33 57
Socioeconomic status (% Hollingshead class IV–V) 100 73 78 71
Marital status (% married) 25 53 55 57
Education, mean years SD 9.2 2 10.7 3 8.5 3 11.2 5
Alcoholism (% hospitalized because of alcoholism) 12 13 0 29
Familial history of psychiatric disorder (%) 0 13 11 0
Personal history of psychiatric disorders (%) 12 0 0 0
Handedness (% right handed) 88 80 100 100
Time since stroke, mean days SD 15.7 11 13.4 10 16.7 10 14.2 7 (B) Patients with reversed occipital asymmetries
Number of patients 4 5 5 3
Age, mean years SD 57.7 18 58.2 10 59.0 7 62.3 11
Gender (% female) 75 20 20 66
Race (% blacks) 50 60 40 100
Socioeconomic status (% Hollingshead class IV–V) 75 40 80 66
Marital status (% married) 25 60 40 33
Education, mean years SD 10.5 1 13.4 4 11.8 2 13.3 4
Alcoholism (% hospitalized because of alcoholism) 500 20 60 33
Familial history of psychiatric disorder (%) 0 0 0 0
Personal history of psychiatric disorders (%) 0 0 0 0
Handedness (% right handed) 75 80 80 100
Time since stroke, mean days SD 14.2 11 14.2 12 20.4 11 19.3 15
117 Relationship of depression to cerebral dominance and structural asymmetries
brain injury. This suggests that posterior asymmetries may be more important than anterior asymmetries in producing the lateralized response to unilateral brain injury.
Findings from this study demonstrated that the association between poststroke major depression and left anterior lesions (i.e., left frontal and left basal ganglia
0 20 40 60
Typical Reversed
Asymmetry
% with major depression
Left lesion Right lesion p 0.05p 0.1
Figure 11.3 The percent of patients who had poststroke depression associated with typical (i.e., normal) occipital brain asymmetry as assessed on axial CT scan. Patients with typical occipital asymmetries had a significantly higher frequency of major depression following left as compared with right hemisphere stroke. Among patients with reversed occipital brain asymmetry, however, there was no association of major depression with left hemisphere lesions. There was a trend for right hemisphere lesions to be associated with depression among patients with reversed brain asymmetry. The frequencies of depression in patients with right or left hemisphere stroke were significantly different in patients with typical as compared to reversed brain asymmetries ( p 0.025).
0 20 40 60 80 100
Typical Reversed
Asymmetry
% with major depression
Left anterior Left posterior Right anterior Right posterior p 0.05
Figure 11.4 The percent of patients with major depression divided into anterior, posterior, right and left lesion location who had typical (i.e., normal) and reversed occipital brain asymmetry.
The expected pattern of major depression associated with acute left anterior brain injury was found only in patients with typical occipital asymmetry. There was a trend for patients with reversed occipital asymmetry to an increased frequency of depression associated with right hemisphere rather than left hemisphere stroke.
118 Poststroke depression
lesions) applied to patients with typical occipital asymmetries and was significantly less frequent among patients with reversed occipital asymmetries. Patients with reversed occipital brain asymmetries appeared to have major depression associated with right hemisphere lesions. The reason that depression and left anterior lesion location were not associated with one another among patients with reversed brain asymmetries may be related to reversal of neurochemical or neuroanatomical path-ways which have been hypothesized to mediate depression (see Chapter 21).
Although the functional and anatomical basis of reversed brain asymmetries remains to be established, several studies have found that the presence of either a typical or reversed pattern of brain asymmetry may play a role in the extent of a patient’s recovery from stroke related deficits. For example, Schenkman et al.
(1983) reported that patients with reversed cerebral asymmetries showed greater recovery from functional impairments than patients with typical brain asymme-tries. They suggested that the inherent flexibility of the cerebral organization of humans (as evidenced by reversed brain asymmetries) may significantly determine outcome following stroke. Pieniadz et al. (1986) also reported that recovery may be improved in patients with reversed asymmetries. Patients with global aphasia and reversed occipital asymmetries showed a better recovery in specific language deficits than patients with global aphasia and typical asymmetries.
In summary, although it remains unclear whether a reversed pattern of occipital brain asymmetries seen on CT scan is associated with cerebral dominance for lan-guage (the data from the present study showed no cases of aphasia in patients with reversed asymmetries and right hemisphere lesions), the reversed pattern of occip-ital asymmetry seems to play a role in the association of depression with lesion location following stroke. Patients with typical occipital asymmetries showed the expected increased frequency of major depression associated with left anterior lesions. In patients with reversed occipital asymmetries, however, there was no longer an association between left anterior lesions and major depression (see Fig.
11.4). Further research may elucidate the functional significance or anatomical basis of reversed asymmetries as well as the presumed asymmetry in neural path-ways which mediate reversal in hemispheric lesions associated with depression.
R E F E R E N C ES
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Chui, H. C., and Damasio, A. R. Human cerebral asymmetries evaluated by computed tomogra-phy. J Neurol Neurosurg Psychiatr (1980) 43:873–878.
LeMay, M., and Kido, D. K. Asymmetries of the cerebral hemispheres on computed tomograms.
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Naeser, M. A., and Borod, J. Aphasia in left handers: lesion site, lesion side, and hemispheric asymmetries on CT. Neurology (1986) 36:471–488.
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Rasmussen, T., and Milner, B. The role of early left-brain injury in determining lateralization of cerebral speech functions. N Y Acad Sci (1977) 299:355–369.
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Schenkman, M., Butler, R. B., Naeser, M. A., et al. Cerebral hemisphere asymmetry in CT and functional recovery from hemiplegia. Neurology (1983) 33(4):473–477.
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119 Relationship of depression to cerebral dominance and structural asymmetries