Post-Stroke Apathy and Hypoperfusion in Basal Ganglia: SPECT StudyOnoda K.a · Kuroda Y.a · Yamamoto Y.c · Abe S.a · Oguro H.a · Nagai A.b · Bokura H.d · Yamaguchi S.a
Departments of aNeurology and bLaboratory Medicine, Faculty of Medicine, Shimane University, cDepartment of Radiology, Shimane University Hospital, and dDepartment of Neurology, Shimane Prefectural Central Hospital, Izumo, Japan Corresponding Author
Background: Although apathy has been reported as one of the neuropsychiatric symptoms following stroke, there are few studies on regional cerebral blood flow (rCBF) in stroke patients with apathy. The present study compared rCBF between apathetic and non-apathetic patients after stroke. Methods: We recruited 102 patients with cerebral infarction within 1 month after stroke and performed neuropsychiatric assessments that included the apathy scale. rCBF was quantitatively measured using N-isopropyl-p-123I-iodoamphetamine single-photon emission computed tomography. Results: Thirty-seven patients (36%) had apathy. The apathetic group showed lower cognitive function and a higher depressive state than the non-apathetic group. rCBF in the basal ganglia was reduced for the apathetic group compared with the non-apathetic group. Furthermore, lesions in the left basal ganglia were associated with hypoperfusion in bilateral basal ganglia and the presence of apathy. Conclusion: These findings demonstrate that apathy is a frequent symptom among stroke patients and that hypoperfusion caused by basal ganglia lesions may contribute to post-stroke apathy.
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Apathy is defined as the lack of motivation evidenced by the diminution of overt behavior, cognition, and emotional concomitants for goal-directed behaviors in cases when this diminution cannot be attributed to intellectual impairment, emotional distress, or a diminished level of consciousness [1,2]. It is reported that apathy is a prevalent symptom in various neurological and psychiatric diseases [3,4,5]. Since depression is also a common neuropsychiatric consequence of stroke, apathy and depression partially overlap in the clinical symptoms. However, apathy is an independent syndrome, distinct from depression [6,7,8].
Several studies have also identified apathy as a symptom frequently observed after stroke [9,10,11,12,13,14]. These reports indicated that the prevalence of post-stroke apathy ranged from 15 to 42% [10,14]. A number of neuroradiological studies have demonstrated structural correlates of post-stroke apathy. Starkstein et al.  showed that stroke patients with apathy had a higher frequency of lesions that involved the posterior limb of the internal capsule compared with normal or depressed groups; however, this finding was limited by a small sample size. Recently, Brodaty et al.  indicated an association of apathy with the extent of lesion in the right frontal-subcortical regions but not with total stroke volume or the number of lesions. Goldzik-Sobanska et al.  demonstrated using MRI spectroscopy that apathetic patients had a lower N-acetylaspartate/creatine ratio in the right frontal lobe compared with non-apathetic subjects. Furthermore, Hama et al.  showed that apathy scores were higher in patients with bilateral basal ganglia damage compared with those without it. Thus, the evidence suggests that apathy in stroke patients is associated with disruption of the frontal-subcortical circuit.
Information flow along the frontal-subcortical circuit originates in the prefrontal cortex and then proceeds to the ventral striatum, globus pallidus, and thalamus, returning through a final loop to the prefrontal cortex. It is thought to be involved in generating motivation, and any lesions in this circuit may result in a clinical presentation of apathy [15,16]. Neuroimaging studies using single-photon emission computed tomography (SPECT) or positron emission tomography in neurodegenerative disorders have provided evidence supporting the role of the prefrontal-striatum circuit in the development of apathy (see the review by Ishii et al. ). These studies reported hypoperfusion of the prefrontal cortex and basal ganglia [17,18,19,20,21,22,23]. As the target of these studies was Alzheimer’s disease, there is little evidence of the changes in regional cerebral blood flow (rCBF) related to post-stroke apathy. We previously reported a close relationship between post-stroke apathy and the hypoperfusion of prefrontal regions , but that study did not examine the subcortical blood flow owing to the 2-dimensional measurement of rCBF. It remains to be determined whether the appearance of post-stroke apathy depends on the hypoperfusion of subcortical areas. In the current study, we investigated the relationship between post-stroke apathy and rCBF using SPECT.
Patients included in this study were selected from consecutive admissions to the Shimane University Hospital for the treatment of acute brain infarction. We applied exclusion criteria for this study as follows: (1) patients presenting no lesion on MRI; (2) patients with brain hemorrhage; (3) patients with dementia that corresponded to the National Institute of Neurological Disorders and Stroke, the Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria for probable vascular dementia  and the National Institute of Neurological and Communication Disorders-Alzheimer Disease and Related Disorders Association criteria for probable or possible Alzheimer’s disease ; (4) patients with conscious disturbance or aphasia that prevented the estimation of cognitive and psychiatric functions, and (5) patients with previous psychiatric illness including depression and drug abuse. We identified 102 patients admitted to our hospital over the 49-month period between January 2005 and January 2009. Their demographic data including functional outcome after stroke (modified Rankin Scale: mRS ) are shown in the table 1. The approval of our institutional ethics committee was obtained for this study, and informed consent was obtained from all patients.
|Table 1. Clinical characteristics|
The evaluation of apathy was performed between 5 days and 1 month after stroke onset (median 9 days). We used the Japanese version of the apathy scale [28,29]. This scale was used in a self-assessment style, with assistance if necessary. We classified the patients into 2 groups according to their apathy scores: an apathetic group (≧16 points) and a non-apathetic group (<16 points). The cutoff point was determined on the basis of a previous report on Japanese stroke patients, and the scale displayed a high reliability (p = 0.96, p <0.0001, n = 20) and validity (sensitivity 81.3%, specificity 85.3%) with a cutoff point of 16 . Other cognitive functions were evaluated by the Mini-Mental State Examination (MMSE) , the Hasegawa dementia rating scale revised (HDS-R) , the frontal assessment battery (FAB) , and the self-rating depression scale (SDS) .
MRI scans were performed for all subjects using a 1.5-Tesla MR scanner (GE Signa) within a week from admission. T1-, T2-, and diffusion-weighted axial images were used to identify brain infarction. A spin-echo sequence (repetition time [TR] /effective echo time [TE] = 500/13 ms) was used for axial T1-weighted images. Axial multi-sliced T2 fast-spin echo images were obtained with the following sequences: TR/effective TE 4,000/100 ms, echo train length 12, matrix number 256 × 192, field of view 14 mm, slice thickness 3 mm, gap 1 mm, and 2 excitations. Non-cardiac-gated single-shot echo-planar diffusion-weighted images were obtained with the following sequences: TR/TE 10,000/100 ms, matrix number 128 × 128, and field of view 14 cm. We classified all patients into 8 groups according to the location of cerebral infarction: frontal cortex, parietal cortex, temporal cortex, occipital cortex, basal ganglia, corona radiata, thalamus, and other regions (cerebellum and brain stem). When the lesion size was large enough to extend over 2 or more regions, the patient was classified in more than 2 corresponding lesion groups. When more than 2 separate lesions were detected on MRI, the patient was also assigned to more than 2 corresponding lesion groups.
rCBF was measured using SPECT images. Patients received intravenous injections of 222 MBq N-isopropyl-p-123I-iodoamphetamine (Nihon Medi-Physics Co.) and were scanned approximately 30 min after the injection. A single-head gamma camera (Shimazu Prism Irix) was used to generate images with attenuation correction. A full 360° rotation was acquired (30 s/step, zoom 2.0, 5°/step). The matrix size was 128 × 128, and 1 pixel size was 2.0 mm with a zoom factor of 20. Continuous axial slices aligned parallel with the AC-PC line were reconstructed by filtered back-projection.
The rCBF value was measured non-invasively using the graph plot analysis method . The value of an individual voxel was divided by the mean of the whole brain. The region of interest (ROI) analysis was performed by statistical parametric mapping (SPM5, Wellcome Department of Cognitive Neurology, London, UK) and WFU_PickAtlas toolbox . The ROI targets were the same as those used for the MRI regional analysis, namely frontal cortex, parietal cortex, temporal cortex, occipital cortex, basal ganglia, thalamus and other regions (cerebellum and brain stem). The rCBF for each ROI was determined by averaging the values of all voxels included in the ROI.
Two-sample t tests, χ2 tests and correlation analysis were applied for clinical features. Analysis of covariance (ANCOVA) was performed for rCBF data from each region; the covariates were age, gender, MMSE, HDS-R, FAB, and SDS scores. The criteria were controlled by a false discovery ratio. Furthermore, to investigate the relationship between the location of stroke lesions and rCBF, we performed an ANCOVA with age, gender, and depression score (SDS) as the covariates. The level of significance was set at p < 0.05.
Thirty-seven patients (36%) met the criteria of apathy. Mean scores on the apathy scale were 21.7 ± 5.8 and 9.2 ± 3.9 for the apathetic and non-apathetic groups, respectively. There were no differences in age and sex between the groups with and without apathy (table 1). The apathetic group had significantly lower scores on the MMSE, HDS-R and FAB compared with the non-apathetic group (ts(100) > 2.21, ps< 0.029). The apathetic group was more depressed compared with the non-apathetic group according to the SDS (t(100) = –3.97, p < 0.001). Correlation analysis revealed that the apathy score was significantly correlated with the SDS (r = 0.36, p < 0.001; table 2), even after controlling the other 3 cognitive measurements as the covariates (r = 0.34, p < 0.001). The apathy score shows barely significant correlations with the cognitive measurements (rs > 0.21, ps < 0.05), whereas the SDS did not show such a relation. There was no difference in the modified Rankin Scale between the 2 groups.
|Table 2. Correlation analysis among psychiatric measurements|
We compared the location of stroke lesions between the 2 groups and confirmed that the left basal ganglia lesions were significantly associated with apathy (χ2 = 7.51, p = 0.006; fig. 1). There was no significant association of apathy with any other locations of stroke lesion.
|Fig. 1. Frequency of stroke lesions in each brain region for the apathetic and non-apathetic groups.|
Figure 2 shows the result of the ROI analysis for the rCBF. The rCBF was significantly reduced in bilateral basal ganglia in the apathetic group compared with the non-apathetic group, even after controlling for the covariates (left: F(1,94) = 11.42, p = 0.001; right: F(1,94) = 9.79, p = 0.002). However, no significant difference between the 2 groups was seen in other regions. Furthermore, correlation analysis revealed the negative correlations between the apathy score and the rCBF of the basal ganglia for both hemispheres (left: r = –0.25, p = 0.012; right: r = –0.24, p = 0.017; not significant after false discovery ratio correction).
|Fig. 2. %rCBF in each brain region for the apathetic and non-apathetic groups. The rCBF was presented as the mean relative value of each ROI to the whole brain value. The error bar shows the standard deviation.|
Furthermore, we studied whether the basal ganglia lesion was associated with reduced rCBF in bilateral basal ganglia. We selected left and right lesions of the basal ganglia as independent variables, and the mean rCBF of bilateral basal ganglia as the dependent variable for ANCOVA analysis (fig. 3). The main effect of left basal ganglia lesion was significant (F(1,95) = 6.33, p = 0.013), and the rCBF of the basal ganglia was lower in patients with left basal ganglia lesions compared with those without. In contrast, the right basal ganglia lesion did not affect the rCBF of the basal ganglia.
|Fig. 3. Relationship between the lesion side and the %rCBF in the basal ganglia. The error bar shows the standard deviation.|
Apathy is a frequent symptom in several neurodegenerative diseases and stroke. The prevalence of post-stroke apathy was 36% in the current study, and this frequency was similar to that reported in previous studies (15–42%) [9,10,11,12,13,14]. We confirmed that apathy was associated with decreased cognitive function. Brodaty et al.  reported that apathy was not correlated with stroke severity as measured by the European stroke scale and suggested that apathy may not be a direct effect of physical impairments resulting from stroke. Furthermore, the authors speculated that apathy might contribute directly to cognitive dysfunction in stroke patients. Our study showed that apathetic patients were more depressed; however, previous studies suggested that apathy and depression may be distinct but partially overlapping symptoms [6,9,14,36,37,38].
The present study found a higher rate of basal ganglia lesions in the apathetic patients. Starkstein et al.  suggested that apathy is associated with lesions that involve the posterior limb of the internal capsule, whereas Andersson et al.  reported that patients with subcortical lesions displayed more apathy compared with patients with cortical lesions. Recently, Hama et al.  suggested that bilateral damage to the basal ganglia was related to the appearance of apathy. Finally, our previous study also demonstrated a relatively high prevalence of apathy (55%) after subcortical ischemic stroke . These findings agree with the current data, which indicate that damage to the basal ganglia leads to a dysfunction of the frontal-subcortical system and results in apathy after stroke.
The functional significance of the basal ganglia was also confirmed by the current SPECT data. The hypoperfusion of the basal ganglia was associated with apathy. To our best knowledge, this is the first report demonstrating a direct relationship between subcortical rCBF change and post-stroke apathy. The left basal ganglia lesion had deteriorating effects on both ipsilateral and contralateral rCBF, although this asymmetrical influence of lesions on rCBF reduction should be examined in future studies with larger numbers of subjects. Functional imaging studies of Alzheimer’s disease have suggested an attribution of apathy to a dysfunction of the front-subcortical system . The fact that these areas are crucial components of the motivation and reward system suggests that the pathophysiology of apathy could be at least partially explained by a dysfunction of the dopaminergic system. Recently, it was reported that dopamine transporter uptake in the putamen in Alzheimer disease or Lewy body dementia was correlated with apathy . We have also reported a case with remarkable improvement of post-stroke apathy after the administration of a dopamine agonist . These data suggest that patients with apathy associated with stroke as well as neurodegenerative diseases could be characterized by dopaminergic dysfunction.
Several limitations of the present study must be noted. The number of patients was insufficient to analyze the effect of lesion location after the population was divided into small groups. Whereas lesion of the left basal ganglia showed a strong association with the appearance of apathy, the lack of effect of frontal lobe lesion may be due to the sample size. The sample size also did not allow us to group patients according to the etiology of the stroke as small vessel disease, large vessel disease or cardiogenic embolism. The underlying risk factors, such as hypertension or diabetes mellitus, may have affected the emotional and cognitive functions through subcortical white matter lesions or periventricular hyperintensity . In this study we assessed stroke patients exclusively in the subacute stage within 1 month after the onset. Thus, the conclusions of this study may be applied only to the early stage of stroke, and longitudinal studies would be necessary to generalize the current findings. However, because the evaluation of apathy during this period is useful for active participation in rehabilitation, under- standing of pathophysiology for post-stroke apathy in the subacute stage could be important for early medical intervention.
In conclusion, this study revealed a close relationship between apathy and hypoperfusion and ischemic lesions in the basal ganglia. Furthermore, as apathy had a negative impact on cognitive function and emotional state after stroke, active assessment of post-stroke apathy, including rCBF measurement, should be performed in stroke patients in the early phase to improve stroke recovery.
This work was supported by a grant-in-aid from the Japanese Ministry of Health, Labour and Welfare, and by the Mitsubishi Pharma Research Foundation.
Shuhei Yamaguchi, MD, PhD
Department of Neurology, Faculty of Medicine, Shimane University
Izumo, Shimane 693-8501 (Japan)
Tel. +81 853 20 2197, Fax +81 853 20 2194, E-Mail firstname.lastname@example.org
Received: March 17, 2010
Accepted: July 19, 2010
Published online: October 28, 2010
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 2, Number of References : 42
Vol. 31, No. 1, Year 2011 (Cover Date: December 2010)
Journal Editor: Hennerici M.G. (Mannheim)
ISSN: 1015-9770 (Print), eISSN: 1421-9786 (Online)
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