88 Poststroke depression
not have a history of success in psychiatry. Based in part on our findings with patients with brain lesions and in part on hypometabolic or hypermetabolic activ-ity in specific brain regions associated with primary (i.e., no known brain lesion) mood disorder, however, neuropsychiatrists are beginning to formulate a neu-roanatomy which may mediate mood disorders (Mega and Cummings 1994;
George et al. 1994–1995; Drevets et al. 1997; Mayberg et al. 1997). These and other findings led Soares and Mann in 1997 to conclude “decreased prefrontal blood flow and metabolism in depressed unipolar and bipolar patients are the most consis-tently replicated findings and correlate with the severity of illness. Basal ganglia abnormalities have also been found in depressed unipolar and bipolar patients.”
These findings from primary depressive disorder as well as the findings that left frontal atrophy (Jorge et al. 2004) or left frontal or left basal ganglia lesions (Fedoroff et al. 1992) were associated with depression following traumatic brain injury and that left but not right nigrostriatal dysfunction was associated with major depres-sion in unilateral Parkinson’s disease (Starkstein et al. 1990) provide considerable evidence that there is a neuroanatomy which mediates depressive disorder across a variety of neuropsychiatric disorders involving dysfunction of the left hemisphere.
Given these findings, it would be expected that lesions which disrupt a neu-roanatomical circuitry associated with depression could lead to depressive disor-der in patients with stroke. This, however, is an empirical question and I will review the world’s literature to assess the evidence for and against this hypothesis.
Effects of interhemispheric and intrahemispheric lesion location
We first examined the effect of unilateral ischemic lesions on depression in a series of patients who had no known risk factors for depression and were admitted to hospital after an acute stroke lesion (Robinson et al. 1984a). All patients were right-handed and had a single stroke lesion of the right or left hemisphere which was vis-ible on computed tomography (CT) scan. Patients were included only if they had no previous personal or family history of psychiatric disorder.
Major or minor depression was found in 14 of 22 patients with left hemisphere lesions and 2 of 14 patients with right hemisphere lesions (p 0.01) (Robinson et al. 1984a). In addition to the increased frequency of depression in patients with left hemisphere lesions, the intrahemispheric lesion location was also an important determinant of the existence of depression. Among 10 patients who had left ante-rior lesions (i.e., the anteante-rior border of the lesion was rostral to 40% of the overall anterior–posterior length of the brain on CT scan), 6 had depression as compared to only one of eight patients with left posterior lesions (i.e., the anterior border of the lesion was caudal to 40% of the anterior–posterior distance) (p 0.05).
Thus, patients with left anterior hemisphere injuries were found to have a
89 Relationship to lesion location
significantly greater frequency of major depression than patients with any other lesion location.
We also looked at this issue in another study of 45 patients with single lesions restricted to either cortical or subcortical structures in the right or left hemisphere (Starkstein et al. 1987). The background characteristics of these patients who are grouped according to whether they had a cortical or subcortical lesion location are shown in Table 10.1. Patients with subcortical lesions had infarcts limited to the basal ganglia, thalamus, or white matter of the internal capsule without any involvement of cortical gray matter or subcortical white matter. Patients with cor-tical lesions had ischemic damage of the cerebral corcor-tical gray matter or underly-ing white matter.
We found that 44% of patients with left cortical lesions were depressed (i.e., 4 of 16 had major depression) and 39% of patients with left subcortical lesions were similarly depressed (i.e., 4 of 13 with major and 1 of 13 with minor depression). In contrast, only 11% of patients with right cortical lesions (none of nine with major and one of nine with minor depression) and 14% of patients with right subcorti-cal lesions were depressed (one of seven with major, zero of seven with minor
Table 10.1. Characteristics of patients: lesion location
Left Cortical Right Cortical Left Subcortical Right Subcortical
(n 16) (n 9) (n 13) (n 7)
Age (mean SD) 59 12 54 13 63 12 54 8
Sex (% male) 60 88 54 57
Race (% black) 50 33 80 100
Marital status (% married) 87 100 100 86
Mean # children 2 2 3 3
Origin (% rural) 27 11 31 14
Mean # siblings 3 3 4 3
Tobacco use (%pack/day) 44 22 23 29
Previous medical illness 25 22 28 29
(% life threatening)
Time since stroke 23 25 18 14 19 21 20 19
(mean days SD)
Education (mean years SD) 9 3 11 4 9 3 8 3
Family history of psychiatric 6 23 11 14
disorder (% positive) Personal history of psychiatric
disorder (% positive)
Alcoholism 19 15 11 28
Other 6 0 11 14
90 Poststroke depression
depression) (Fig. 10.1). Patients with lesions of the left hemisphere had signifi-cantly higher rates of depression than patients with right hemisphere lesions, regardless of the cortical or subcortical location of the lesion (p 0.01).
The patients were further grouped according to whether they had anterior and posterior lesions using the anatomical criteria that the anterior border of the lesion was located in the frontal lobe. All five patients with left cortical anterior lesions involving the frontal lobe had depression (three major and two minor depression) as compared to only 2 of 11 patients with left cortical posterior lesions whose ros-tral border involved the temporal, parietal, and/or occipital cortex (one major, one minor depression, p 0.01). Moreover, four of the six patients with left subcorti-cal anterior lesions had major depression (none had minor depression) as com-pared to one minor depression (none with major depression) among seven patients with left subcortical posterior lesions (p 0.01).
In a subsequent study (Starkstein et al. 1988) which included the 20 patients with subcortical lesions from the previous study as well as five new patients, we com-pared patients with lesions limited entirely to the basal ganglia/internal capsule with those having thalamic lesions of the right or left hemisphere with no evidence of other brain lesions. Basal ganglia (caudate and/or putamen) lesions produced major depression in seven of eight patients with left hemisphere lesions but in only one of seven patients with right hemisphere lesions. None of the patients with left (n 6) or right (n 4) thalamic lesions had major depression (p 0.001).
The largest study examining clinical–pathological correlations in patients with stroke was reported by Vataja et al. (2001). Twelve to twenty weeks following stroke, 275 patients were examined, using the Structured Interview for Clinical Assess-ment in Neuropsychiatry (SCAN) and diagnostic and statistical manual (DSM)-IV
0 10 20 30 40
LC (n 16) LS (n 13) RC (n 9) RS (n 7)
% of patients with major and minor depression
Major depression Minor depression p 0.05
Figure 10.1 The percent of patients with major or minor depression divided by stroke lesion location.
LC left cortical, LS left subcortical, RC right cortical, RS right subcortical. Patients with either left cortical or left subcortical lesions had a significantly higher frequency of major depression during the acute post-stroke period than patients with right hemisphere lesions (data from Starkstein, Brain 1987).
diagnostic criteria for depressive disorders. The authors did not evaluate the hypotheses that patients with left frontal or left basal ganglia lesions in the first 2 months following stroke would have a greater frequency of major depressive dis-order than patients with comparable right hemisphere lesions and that there would be a significant correlation between the proximity of the lesion to the frontal pole and severity of depression. Of the 275 patients, 83 (30%) had prior stroke and 54 (20%) had prior depression. A logistic regression analysis examining independent magnetic resonance imaging (MRI) correlates of the existence of depression was conducted. Depressed patients (n 71) with major depression and (n 38) with minor depression were found to have an increased mean fre-quency of infarcts in the genu of the internal capsule on the left side (OR: 3.2; 95%
CI: 1.0–10.1) and in the pallidum of either side (OR: 1.6; 95% CI and over 1.1–2.3). In addition, the mean volume of infarcts in right occipital lobe was smaller in depressed compared with non-depressed patients (OR: 0.98; CI:
0.96–0.99). These authors have recently published a secondary analysis of this data utilizing the 70 who had a single infarct on magnetic resonance (MR) scan. A logis-tic regression analysis found that infarct localization in the pallidum of either side was the only correlate of poststroke major or minor depression. When a separate analysis of each hemisphere was done, lesions of the caudate and pallidum on the left hemisphere were significantly associated with depression while lesions of these structures in the right hemisphere were not (Vataja et al. 2004).
Studies by other investigators have sometimes shown similar lateralized effects of stroke lesions but sometimes have not. The variable which seemed most likely to account for differences in findings between studies was “time since stroke”. For example, in contrast to our studies of acute stroke patients examined 1–2 weeks following stroke, a study of 88 Australian patients seen in a rehabilitation hospital 8.4 weeks (average) following stroke found that 43% of patients with left hemi-sphere lesions had major or minor depression and 38% of patients with right hemisphere lesions had depression (Morris et al. 1990). Similarly, Eastwood et al.
(1989) examined 87 patients admitted to rehabilitation hospital 12 weeks (average) after stroke. Of 28 patients with left hemisphere lesions, 50% had either major or minor depression while among 45 patients with right hemisphere stroke 62% had major or minor depression. Thus, both of these studies which examined patients in rehabilitation hospitals at approximately 2–3 months poststroke failed to show a lateralized effect of hemispheric brain injury on frequency of depression.
Changes over time in lesion locations associated with depression
We examined the effect of time since stroke on the relationship between lesion loca-tion and depression (Shimoda and Robinson 1999). Using the same populaloca-tion of 91 Relationship to lesion location
92 Poststroke depression
stroke patients with 2-year follow-up (i.e., 142 patients), we identified patients who had a single stroke lesion involving either the right or left middle cerebral artery (MCA) distribution that was visible on CT scan and who had a follow-up evaluation either at 3 or 6 months (short-term follow-up) or at 12 or 24 months (long-term follow-up). Of 60 patients who met these qualifications, 41 were seen at short-term follow-up and 46 were seen at long-term follow-up. There were no statistically sig-nificant differences between the short- and long-term follow-up groups in terms of age, gender, race, marital status, education, socioeconomic status, frequency of family or personal psychiatric history or prevalence of major or minor depression (39% of the short-term follow-up patients and 43% of the long-term follow-up patients had in-hospital major or minor depression). The frequency of depression in patients with right and left hemisphere lesions during the initial evaluation and at the short- and long-term follow-up is shown in Fig. 10.2. During the initial eval-uation, patients with left hemisphere stroke had a significantly higher prevalence of both major and minor depression (as defined by DSM-IV criteria) than patients with right hemisphere stroke (p 0.0006) (Fig.10.2).At short- and long-term follow-up, however, there were no significant differences between right and left hemi-sphere lesion groups in terms of the frequency of major or minor depression.
Thus, failure by other investigators to find a lateralized effect of hemispheric lesion location as summarized by Carson et al. (2000) was probably the result of includ-ing studies that were conducted after the first 2 months followinclud-ing stroke.
Depression and hemispheric lesion location
0 20 40 60 80
L L L
% of patients
Initial 3–6 months 12–24 months
R R R
Minor depression Major depression p 0.006
Figure 10.2 The frequency of major and minor depression defined by DSM-IV criteria associated with single lesions of the right or left hemisphere during the acute stroke period and at follow-up. The lateralized effect of left hemisphere lesions on both major and minor depression was found only during the acute stroke period. At 3–6- and 12–24-month follow-up, there were no hemispheric lesion effects on the frequency of depression.
93 Relationship to lesion location
To test the hypothesis that depressive disorders are more frequent in patients with left frontal or left basal ganglia lesions over the first 2 months following stroke, we conducted our own meta-analysis (Robinson 2003). The results of the meta-analysis are shown in Table 10.2. All studies which examined patients within 8 weeks following acute stroke and compared the relative risk of major depression following left anterior versus left posterior stroke or left anterior versus right ante-rior stroke were included. Meta-analyses utilizing 126 patients, based on the fixed model effect found a relative risk of 2.29 (95% confidence interval, 1.55–3.33) and using the random model, found a relative risk of 2.29 (95% confident interval, 1.55–3.37) (Table 10.2). The random model is a more conservative statistic which assumes that there are random variations in the inter study variance. The fixed model does not make this assumption. When the effect of left anterior versus right anterior lesion location on the risk of major depression was compared, the odds ratio was 2.18 using the fixed model (95% confidence interval 1.44–3.30) and using the random model was 2.16 (95% confidence interval 1.28–3.64). Thus, by defining the parameters of the analysis, the statement by Carson et al. at the begin-ning of this chapter appears to be at least overstated. On the other hand, the Carson et al. (2000) analysis helped to define the parameters of the lesion location hypothesis. I stated in the first edition of this text that lesion location and depres-sion were phenomenon of the first few months following stroke. Although we do not know why this phenomenon of asymmetry in association with depression is a temporally related phenomenon, it suggests that pathophysiological changes pro-voked by the acute stroke are occurring within a 2-month period which initially promotes depressive disorder associated with left anterior hemisphere lesions and then changes in some way to allow both right and left hemisphere lesions to lead to depression. In fact, our data as well as other investigators (Finset et al. 1989; Sharpe et al. 1994; Shimoda and Robinson 1999) suggest that by 2 or more years poststroke, depressive disorders may be more common following right posterior lesions than any other lesion location.
Correlation between the severity of depression and anterior–posterior lesion location
In addition to the association of depression during the first 2 months following acute stroke with left frontal and left basal ganglia lesion location. A clinical–
pathological correlation between the severity of depression, as measured by depression rating scales, and the distance of the lesion from the frontal pole on CT or MRI scan image, as measured by the distance in millimeters between the ante-rior border of the lesion and the frontal pole, was first reported in 1981 by Robinson and Szetela.
Table 10.2.Meta-analysis of the relationship of depression to lesion location Left Left Relative Left Right Relative Nanteriorposteriorrisk95% CIpNanterioranteriorrisk95% CIp Astrom (1993)2112/142/72.62*1.20–8.630.0172512/132/125.54*1.55–19.820.000 Morris (1996)209/103/103.00*1.14–7.910.006299/143/153.21*1.08–9.510.016 Robinson (1984)186/74/112.36*1.02–5.450.040166/64/102.27*1.09–4.750.028 Robinson (1986)156/72/82.35*1.16–9.540.019116/62/52.230.85–5.870.46 House et al.(1990)131/17/121.30.52–3.280.642151/17/141.500.58–3.870.506 Herrmann (1995)177/73/102.95*1.21–7.130.007NANANANANANA Gainotti et al.(1999)221/48/180.560.95–3.320.474161/48/120.380.07–2.150.146 Fixed combined12842/5029/762.29*1.6–3.40.00011235/4426/682.18*1.4–3.30.000 Random combined12642/5029/762.29*1.5–3.40.00011235/4426/682.16*1.3–3.60.004 *p0.05.Major depression was significantly more frequent following left anterior lesions than right anterior or left posterior lesions.(Reprinted from (Robinson 2003) with permission.)
95 Relationship to lesion location
In 1984, the study previously described involving a new group of 36 patients with single lesions of the right (n 14) or left (n 22) hemisphere also found a significant inverse correlation between the severity of depressive symp-toms as measured by combined score on the Zung depression scale, Hamilton depression scale and total score on the present state examination and the distance from the anterior border of the lesion to the left frontal pole (r 0.92, p 0.01).
In the right hemisphere, however, the correlation was in the opposite direction with more posterior lesions being associated with more severe depressive symp-toms (R 0.76, p 0.05). Although the correlation was strongest in patients with left anterior lesions, if patients with left posterior lesions (i.e., anterior border of the lesion was caudal to 40% of the overall anterior–posterior length of the brain) were included (total increased from 11 to 22 patients), the correlation decreased to r 0.54 but remained significant (p 0.01). A similar correlation between the severity of depression and distance of the lesion from the frontal pole was also found in our previously described study of patients with cortical lesions (i.e., lesions restricted to the cortex) of the left hemisphere (n 16) (r 0.52, p 0.05) (Fig. 10.3) or subcortical lesions (i.e., lesions only involving subcortical gray matter) of the left hemisphere (n 13) (r 0.68, p 0.01) (Fig. 10.4) (Starkstein et al. 1987). We have also found a similar correlation between proximity of the lesion to the frontal pole and severity of depression in left-handed patients
Left cortical lesions
Distance of lesion from frontal pole 20
35
10 30
25 20 15 10 5 0
30 40 50 60 70 80
PSE score
r 0.52, p 0.05
Figure 10.3 Scattergram showing the correlation between severity of depression (as measured by the Present state examination (PSE) scores) and proximity of the anterior border of the lesion from the frontal pole. Patients all had cortical lesions.
96 Poststroke depression
with single left hemisphere lesions (n 13) (r 0.78, p 0.01) (see Chapter 11) (Robinson et al. 1985b).
Similar correlations have now been reported by investigators in Canada, UK, Germany, and Australia. Some investigators found that the correlation between the severity of depression and the proximity of the lesion to the frontal pole applied to combined right and left hemisphere lesion groups (Sinyor et al. 1986; House et al.
1990) while others found this to be the case only among patients with left-sided lesions (Eastwood et al. 1989; Morris et al. 1992).
We recently examined changes in this correlation over time in 60 patients with single lesion CT scans and follow-up over 2 years (Shimoda and Robinson 1999).
Correlations between the severity of depression, as measured by total score on the present state examination, and the proximity of the lesion to the frontal pole are shown in Fig. 10.5. During the initial evaluation, there were significant correlations between severity of depression and both proximity of the lesion to the left frontal pole and lesion volume (n 34). At short-term (i.e., 3–6 months) follow-up, there were significant correlations between the severity of depression and the distance of the anterior border of the lesion from the frontal pole for both left (n 26) and right (n 15) hemisphere lesions. At long-term (i.e., 12–24 months) follow-up, there was no significant correlation between the severity of depression and prox-imity of the lesion to the frontal pole or lesion volume among patients with left hemisphere stroke (n 25). Among patients with right hemisphere stroke (n 21), however, both lesion volume and proximity of the lesion to the occipital pole correlated with the severity of depression (Fig. 10.5).
50
Left subcortical lesions
r 0.68, p 0.01 40
30
PSE score 20
10 0
5 10
Distance of lesion from frontal pole
15 20 25 30 35 40 45
Figure 10.4 Scattergram showing the correlation between severity of depression (as measured by the present state examination (PSE)) and proximity of the anterior border of the lesion from the frontal pole: Only patients who had lesions restricted to the basal ganglia, thalamus or internal capsule of the left hemisphere were included.
97 Relationship to lesion location
Based on the finding that there was a significant correlation between the sever-ity of depression and the proximsever-ity of the lesion to the left frontal pole during both the acute and 3–6-month follow-up, we recently conducted a meta-analysis of studies which examined patients during the first 6 months following stroke (Tables 10.3 and 10.4) (Narushima et al. 2003). A total of 163 patients with left hemisphere lesions had been examined in a total of eight independent studies.
Results found a fixed model Z statistic of7.04 (p 0.001) and a random model Z of4.68 (p 0.001).The pooled correlation coefficient was 0.53 in the left hemi-sphere using the fixed model and0.59 employing the random model (Table 10.3).
Correlation coefficients, however, in the right hemisphere between the severity of depression and the proximity of the lesion to the frontal pole during the first 6 months following stroke were non-significant (n 150 in 5 studies) with pooled correlation coefficient, fixed model, r 0.20; random model, r 0.23 (p NS, Table 10.4). Thus, the correlation between the proximity of the lesion to the frontal pole and severity of depression was significantly stronger for the left hemisphere than the right hemisphere.
Left hemispheric lesion Right hemispheric lesion 0.6
0.4 0.2 0
0.2
0.4
0.6
Acute
Correlation coefficient
3–6 months 12–24 months p 0.05
Figure 10.5 Spearman correlation coefficients between severity of depression as measured by Present State examination (PSE) total score and distance of the lesion from the frontal pole as measured on CT scan. A negative correlation indicates that depression increased with proximity of the lesion to the frontal pole and a positive correlation indicates depression increased with proximity of the lesion to the occipital pole. During the acute stroke period, depression severity correlated with proximity of the lesion to the frontal pole but only among patients with left hemisphere lesions. During short-term follow-up, proximity of the lesion to the frontal pole was correlated with more severe depression for both right and left hemisphere lesions. At long-term follow-up, severity of depression was significantly correlated with proximity of the lesion to the occipital pole (i.e., lesions further away from the frontal pole) but only for patients with right hemisphere lesions. These findings demonstrate the dynamic nature of clinical–pathological correlations in poststroke depression.
Table 10.3.Description of the studies examining the association between severity of depression and the distance of the anterior border of the lesion from the frontal pole in the left hemisphere Left hemisphere AuthorCCNPooled RPopulationScaleIntervalQualityRemarks Eastwood et al.(1989)R0.74110.74RehabilitationGDS2.5 months6*PH() n4 Herrmann et al.(1993)Rho0.445200.445Acute/rehabilitationCDS2 weeks7*All left lesion,aphasics, PH() House et al.(1990)Rho0.3833CommunityPSE6 months7*PH() Rho0.21280.341BDINS Lipsey et al.(1983)R0.65150.645Acute/rehabilitationODS1.5 months6*Bilateral lesions,PH() R0.6415HamD Morris et al.(1992)R0.872140.872RehabilitationMARDS2 weeks7*PH() removed Robinson et al.Rho0.87130.87Acute/rehabilitationODS2.5 months6*All left handed, (1985a)PH() removed Sinyor (1986)R0.28190.28RehabilitationCDI2 months5NSPH() Overlapped Baltimore studies Parikh et al.(1987)R0.4128AcuteMean6 months7* Robinson et al.(1984a)R0.5418AcuteODS2 weeks6* Robinson (1984b)R0.6517AcuteThe PS2 weeks6* R0.56HamD* R0.70Zung*
Shimoda (1999)R0.4234AcutePSE2 weeks7* R0.2834HamDNS Starkstein et al.(1987)R0.5216Acute/rehabilitationPSE3 weeks*Cortical R0.39HamDNS R0.50Zung* R0.6813Acute/rehabilitationPSE*Sub-cortical R0.64HamD* R0.33ZungNS R0.4629Acute/rehabilitationPSE3 weeks7*Cortical and sub-cortical Combined Baltimore group Rho0.46430.441Acute/rehabilitationPSE2 weeks8*PH() removed Rho0.3643HamD* Total N1630.53,p0.001 fixed model0.59,p0.001 random model The overlapped Baltimore studies are listed but only the combined data with unique patients was used in the analysis.The definition ofabbreviations is provided in Table 10.4.(Reprinted from (Narushima et al.2003) with permission.)
Table 10.4.Description of the studies examining the association between severity of depression and the distance of the anterior border of the lesion from the frontal pole in the right hemisphere Right hemisphere AuthorCCNPooled RPopulationScaleIntervalQualityRemarks Herrmann et al.R0.55150.55AcuteCDS1 month7*All PH () (1995) House et al.(1990)R0.34280.284CommunityBDI6 months7NSAll PH () R0.2330PSENS Morris et al.(1992)R0.05790.057RehabilitationNARDS2 weeks7NSPH () removed Sinyor et al.(1986)R0.10160.1RehabilitationCDI2 months5NSAll PH () Overlapped Baltimore studies Parikh et al.(1987)R0.5210AcutePSE3 or 6 months6NS R0.65HamD* R0.40ZungNS Robinson et al.R0.7612AcuteODS2 weeks6* (1984a) Robinson (1984b)R0.6310AcutePSE2 weeks6* R0.73HamD* R0.62Zung* Robinson (1985a)Not stated10AcuteMean3 or 6 months7NS Rho0.65HamDNS Shimoda (1999)R0.0226AcutePSE2 weeks7NS R0.17HamDNS Starkstein (1987)R0.659Acute/rehabilitationPSE3 weeks6*cortical lesion R0.22HamDNS R0.43ZungNS
R0.087Acute/rehabilitationPSE3 weeks6NSSub-cortical lesion R0.18HamDNS R0.41ZungNS Not stated16Acute/rehabilitation3 weeks7NSCortical and sub-cortical CombinedBaltimore group Rho0.17380.084Acute/rehabilitationPSE2 weeks8NSPH() removed Rho0.00338HamDNS Total N1060.20,p-NS fixed model0.23,p-NS random model The overlapped Baltimore studies are listed but only the combined data with unique patients was used in the analysis.CC:correlation coefficient; CDI:composite depression index;CDS:Cornell depression scale;GDS:geriatric depression scale;HamD:Hamilton depression scale;Mean:Mean (Zung,HamD,PSE);MARDS:Montgomery and Asberg depression rating scale;N:number ofpatients;NS:not significant;ODS:overall depression scale;PSE:present state examination;PHpatients with/without past psychiatric history;*p0.05. Scoring System 012 ScaleNoneNot standardizedStandardized ImagingNot statedCT/MRIImagery and psychiatric Results uncleardata done blind Comprehension deficitNot statedClinicalOperational Criteria NN2020N30N30 Reprinted from Narushima et al.(2003) with permission.
Relationship between depression and MCA versus posterior circulation
MCA versus posterior circulation infarcts
Although brainstem and cerebellar strokes are less common than cerebral hemi-sphere strokes, they, nevertheless, constitute an important group of brain infarcts.
In contrast to the motor and sensory symptoms that are common in patients with hemispheric infarcts involving the MCA, patients with infarcts of the vertebral-basilar artery have symptoms of cranial nerve dysfunction, such as dysphagia or diplopia or cerebellar dysfunction, such as ataxias or intention tremor (see Chapter 4 for a review of “Vascular anatomy and clinical symptoms”).
We compared depression associated with infarcts of the posterior circulation (PC) (i.e., vertebral-basilar arteries supplying the brainstem, cerebellum, thala-mus, and posterior hemispheres) and infarcts of the MCA circulation (MCA) (i.e., large areas of frontal, temporal, and parietal cortex and subcortical structures including the basal ganglia) (Starkstein et al. 1988). This study included 37 conse-cutive patients with clinical findings or CT scan evidence indicating a first episode stroke in the PC as well as a consecutive series of 42 patients with single stroke lesions involving the MCA territory. The background characteristics of these groups were not significantly different in age, gender, education or prior psychia-tric or medial history. All patients were evaluated during the first 30 days following stroke except for two patients with PC infarcts who were assessed during the second month poststroke.
Cranial nerve abnormalities were found in 41% of the PC group and none of the MCA, while cerebellar signs were found in 24% of the PCA group and none of the MCA group. Based on clinical signs or CT scan imaging, 39% of the patients with PC group lesions had cerebellar involvement, 30% had midbrain lesions, 26% had lesions of the pons, 22% had paramedian infarcts of the tegmentum, and 9% had lateral medullary infarcts. Among patients with MCA group infarcts, 55% had left hemisphere lesions and 45% had right hemisphere lesions.
Among the 37 patients in the PC group, 27% were found to be depressed imme-diately after the acute lesion (four had DSM-III major and six had DSM-III minor depression). Among the 42 patients with MCA lesions, 48% developed depression immediately after the acute infarct (11 had major depression and nine had minor depression). This higher frequency of depression among the MCA compared with the PC group just failed to reach statistical significance (p 0.054).
At 6-month follow-up, 82% of the patients with MCA lesions who were depressed (major or minor) in hospital remained depressed (Fig. 10.6). Among patients with PC lesions who were depressed (major or minor) at the in-hospital evaluation only 20% remained depressed at the 6-month follow-up (p 0.05). At 1- or 2-year follow-up, the percentage of patients with continued depression was 102 Poststroke depression
103 Relationship to lesion location
68% for the MCA group and zero for the PC group (p 0.05). Although the sig-nificantly shorter course of depression in the PC as compared to the MCA group might be hypothesized to result from the PC group having smaller lesion volumes than the MCA group, there was no significant correlation between lesion volume and the severity of depression for the combined group of MCA and PC lesion patients either in hospital or at 1- or 2-year follow-up.
The relationship between depression and impairment was examined by dividing MCA and PC lesion patients into those with major depression, minor depression or no depression. Among patients with PC lesions, neither intergroup compari-sons using ANOVA (e.g., mini-mental state examination scores across the three diagnostic groups) nor dimensional comparisons using correlational analysis (e.g., Hamilton depression score correlated with mini-mental state examination score) demonstrated a significant relationship between depression (diagnosis or severity) and cognitive impairment (measured by the mini-mental state examination), activities of daily living (measured by the Johns Hopkins functioning inventory (JHFI)), or social support (measured by the social functioning examination).
Among the patients with MCA lesions, however, patients with major depression had significantly higher (i.e., more impaired) JHFI scores (activities of daily living) than patients with minor depression or no mood disorder (p 0.05).
Right hemisphere lesions
Although the frequency of major depression in the acute poststroke period has been found in several studies to be greater following left frontal cortical or left basal ganglia lesions than for any other lesion location, depressions do occur in many patients with right hemisphere lesions during both the acute and chronic
0 20 40 60 80 100 120
Acute 6 months 12–24 months
Time since stroke
% of depressed patients
MCA group (n 42) CB/BST group (n 37) p 0.05
Figure 10.6 The percent of patients depression after an acute stroke who remained depressed at 6 months and 1- or 2-year follow-up. Patients with brainstem or cerebellar infarcts (CB/BST) recovered from depression (without treatment) significantly more quickly than patients with left or right MCA (i.e., hemispheric) infarcts (data from Starkstein et al.
1988).
104 Poststroke depression
poststroke periods. We, therefore, examined the clinical correlates of depression associated with right hemisphere lesions to compare them with the clinical corre-lates of left hemisphere lesion location. This work included a consecutive series of 93 patients who had acute stroke lesions of the right hemisphere. Lesion location was based on CT findings and/or clinical diagnosis and patients were included only if there was no previous history or CT scan evidence of prior brain injury.
The 93 acute stroke patients consisted of both males and females in their late 50s and early 60s, primarily from lower socioeconomic classes (i.e., Hollingshead class IV and class V) examined 2 to 3 weeks poststroke (Table 10.5). There were 46 patients with no mood disturbance, 17 patients with major depression, 11 patients with minor depression, and 19 patients with undue cheerfulness. There were no statistically significant differences in age, gender, education, race, or marital status or time since stroke. The classification of “undue cheerfulness” was based on either a self-report of elevated or expansive mood or clinical observation of inappropri-ately cheerful affect or disinhibited behavior during the mental status interview.
One of the major findings was that patients with major depression had a signi-ficantly higher frequency of psychiatric disorder among their first- or second-degree relatives (i.e., 29% with 55% of these being alcoholism and 45% depression)
Table 10.5. Characteristics of right hemisphere lesion patients
Left
Right hemisphere hemisphere
No Undue Major Minor Major
depression cheerfulness depression depression depression
Characteristic (n 46) (n 19) (n 17) (n 11) (n 27)
Age, years (mean SD) 64 10 60 14 60 11 62 8 56 13
Gender (% females) 35 42 47 36 52
Race (% blacks) 65 74 41 55 59
Socioeconomic status:
Hollingshead class IV or V 87 74 82 82 89
Marital status (% married) 54 37 42 36 44
Handedness (% right-handed) 87 90 100 100 89
Education (mean years SD) 6.5 3.7 8.2 4.3 8.4 3.4 8.8 3.5 9.3 2.8
Familial history of psychiatric 6 5 29 9 4
disorders (% positive*)
Personal history of psychiatric 15 5 29 36 6
disorders (% positive)
Time since stroke 13 12 11 6 16 9 20 18 14 11
(mean days SD)
*p 00.05.
105 Relationship to lesion location
compared with other diagnostic groups (i.e., 6% for no diagnosis, 5% undue cheer-fulness, 9% for minor depression, and 5% for major depression following left hemi-sphere stroke) (Fig. 10.7).
In addition, among patients with undue cheerfulness, there was a significantly higher frequency of lesions involving the right frontal operculum compared with depressed (major and minor) and non-depressed patients. Of 12 patients with undue cheerfulness, five had right frontal opercular lesions compared with four of 25 non-depressed and one of 17 depressed patients (p 0.05). On the other hand, patients with depression (both major and minor) showed a significantly higher frequency of lesions involving either the right parietal cortex (i.e., six of nine with major depression and five of eight with minor depression compared to 1 of 12 with undue cheerfulness and 9 of 25 with no depression; p 0.02) or the right lateral frontal cortex (i.e., two of nine with major depression and four of eight with minor depression compared to none of 12 with undue cheerfulness and one of 25 with no depression; p 0.01).
Morris et al. (1990) examined family history in a study of 88 Australian patients in a rehabilitation hospital 8.4 weeks poststroke and found a significantly higher frequency of family history of psychiatric disorder among patients with major depression (i.e., 11 of 16 or 73%) compared to patients with minor depression (i.e., 5 of 18 or 28%) or no depression (i.e., 20 of 54 or 37%) (p 0.03). Patients with major depression following right hemisphere lesions had a positive family
0 20 40 60 80 100
Right lesion major
depression (n 17) Right lesion/no depression (n 46)
% of patients
Left lesion/major depression (n 27) Positive family Hx Negative family Hx p 0.05
Figure 10.7 The percent of patients with and without a family history of psychiatric disorder (defined by having seen a professional for treatment of an emotional disorder) following an acute right hemisphere infarction. Patients with major depression following a right hemisphere lesion were significantly more likely to have a family history of psychiatric disorder than those without major depression or patients with major depression following a left hemisphere lesion. These data suggest that some poststroke depressions may be related to genetic vulnerability and the factors associated with major depression following right or left hemisphere lesions may be different.
history in 71% of the cases (i.e., five of seven) similar to patients with major depression following left hemisphere lesions (i.e., 67% or six of nine patients).
Patients with right hemisphere lesions have also been studied by Finset et al.
(1989) who found that among 42 patients with CT-verified single right hemi-sphere lesions, ischemic damage involving white matter underlying the parietal cortex was associated with a higher frequency of depression (5 of 13 patients) than lesions in any other location in the right hemisphere (7 of 29 patients) (p 0.02).
House et al. (1990) reported on a group of 21 patients with CT-verified right hemi-sphere lesions examined 1 month following their first stroke. Of the three patients with major depression following a right hemisphere lesion, all of them had a right posterior lesion (i.e., three major depressions of eight patients with right posterior injury) compared with none of the patients with right anterior (n 7) or right intermediate (n 6) lesion locations (p 0.03). Sinyor et al. (1986) examined 16 patients with single CT-verified right hemisphere lesions studied an average of 56 days poststroke. There was a significant quadratic relationship between depression scores and the distance between the anterior border of the lesion and the frontal pole in patients with right hemisphere lesions (i.e., patients with the most anterior and most posterior lesions of the right hemisphere had the highest depression scores, p 0.05). Another study by Stern and Bachman (1991) examined 19 patients with CT-verified single right hemisphere lesions an average of 16 months poststroke. Lesions were classified as dorsal or ventral, frontal or non-frontal.
Dysphoric mood was significantly more severe in patients with right ventral non-frontal as compared with right ventral non-frontal lesions. This suggests that right tem-poral lesions are associated with depressed mood. Finally, Astrom et al. (1993) and Eastwood et al. (1989) found no association between lesion location in the right hemisphere and the existence of poststroke depression.
Insular lesions
We have recently examined the relationship between psychopathology and lesions of the insular cortex. The insular cortex is the in-folded cortex surrounding the central fissure beneath the motor and sensory cortex. Seven patients with left insu-lar stroke and six patients with right insuinsu-lar stroke were compared with six patients having left hemisphere non-insular stroke and six patients with right hemisphere non-insular stroke. Patients were studied between 4 and 8 weeks following acute stroke and were examined using the present state examination and DSM-IV diag-noses. Increased frequency of feelings of anergia and under activity (Fisher’s exact p 0.002) as well as tiredness (Fisher’s exact p 0.002) were found among patients with right insular stroke compared to patients with non-insular lesions or left insular lesions. We hypothesized that feelings of decreased energy or motiva-tion after right insular damage may result from disconnecmotiva-tion between the insula 106 Poststroke depression
and the frontal cortex or anterior cingulate cortex, structures that have been asso-ciated with willed action and motor behavior (Manes et al. 1999).
Frontal lobe lesions
We have also recently examined the relationship between depression and frontal lobe lesions involving either the lateral frontal cortex (n 8) or the medial frontal cortex (n 8) (Paradiso et al. 1999). The groups were composed of three women and five men with traumatic head injuries, and five men with strokes studied within the first 2 months following brain injury. The mean ages of the medial lesion group was 39.5 17 years SD and the lateral lesion group was 44.1 17 years SD. There were no statistically significant differences in group background characteristics.
Six of the eight patients with lateral lesions had depressive disorder (three major and three minor depressions) while the medial lesion group had only two depres-sions (one major and one minor depression) (p 0.05). Similarly, five of the eight patients in the lateral lesion group had generalized anxiety disorder (GAD) while only one patient in the medial group had this disorder (p 0.04). At 3-month follow-up, there were no significant intergroup differences in the frequency of depressive disorder or GAD. Patients with lateral lesions, however, showed greater severity of depressive symptoms, impairment in activities of daily living, and social functioning compared to the medial lesion group (p 0.05). In addition during the initial evaluation, five patients in the lateral group and one in the medial lesion group showed decreased emotion and motivation (p 0.04) while, at 3 months, five patients in the lateral group and none in the medial lesion group showed these symptoms (p 0.003). There were no significant differences between the groups in the frequency of mania, hypomania, or symptoms of disinhibition.
This study found that patients with single lesions of the lateral prefrontal cortex had significantly greater frequency of depression and anxiety disorders and symp-toms of decreased emotion and motivation than patients with medial frontal lesions both during the acute injury and at 3-month follow-up. It was surprising that the medial lesion group did not show significantly higher frequency of symp-toms of euphoria, disinhibition, loss of emotion or apathy compared to the lateral lesion group. Although apathy has been associated with damage to the cingulate cortex and mesial frontal regions (Marin 1991; Cummings 1993). Okada et al. (1997) found decreased blood flow in the right dorsal lateral frontal and left frontal tem-poral cortex in 40 patients with apathy after stroke compared with non-apathetic stroke controls. Similarly, Cummings found personality but not mood changes after damage to the frontal cingulate circuit (Cummings 1993). Thus, medial frontal activity may be necessary to experience emotions including depressed mood while lateral prefrontal damage appears to disrupt mood and drive while leaving intact the ability to experience these emotions.
107 Relationship to lesion location