Hippocampal Volume Reduction Correlates With Apathy in Traumatic

Hippocampal Volume Reduction Correlates With Apathy in Traumatic Brain Injury, But Not Schizophrenia Yoichiro Takayanagi, M.D., Ph.D. Gwendoly Gerner, Psy.D. Mizuho Takayanagi, M.D. Vani Rao, M.D. Tracy D. Vannorsdall, Ph.D. Akira Sawa, M.D., Ph.D. David J. Schretlen, Ph.D. Nicola G. Cascella, M.D. Apathy commonly accompanies both traumatic brain injury (TBI) and deficit syndrome schizophrenia (DSZ), despite unclear neurological bases. The authors examined differences in cortical thickness and subcortical/cerebellar regional volumes between adult TBI survivors, patients with DSZ, and healthy-control subjects by use of 3-D magnetic resonance imaging (MRI), and correlated imaging findings with clinical ratings of apathy and selected cognitive test scores. Imaging findings revealed specific areas of volume reduction in TBI survivors and areas of cortical thinning among patients with DSZ. The severity of apathy symptoms was similar across patient groups; however, severity of apathy was only correlated with imaging findings in TBI survivors. (The Journal of Neuropsychiatry and Clinical Neurosciences 2013; 25:292–301)

A

pathy refers to a loss of motivation, in combination with impairments of behavioral, cognitive, and emotional aspects of goal-directed behavior.1 Individuals with apathy can be misperceived as “lazy” because of difficulty marshaling the effort required to initiate and complete activities. Apathy is seen under various medical or psychiatric conditions, such as traumatic brain injury (TBI), 2 schizophrenia (SZ),3 Alzheimer’s disease (AD),4 and Parkinson’s disease (PD).5 TBI apathy among TBI survivors may be as high as 71%,2 and can emerge immediately after a TBI or up to several years later.6–8 The negative symptoms of schizophrenia include apathy. Those with severe and enduring negative symptoms might represent a homogeneous subgroup, termed the “deficit syndrome” of schizophrenia (DSZ), characterized by restricted affect, poverty of speech, anhedonia, diminished sense of purpose, and social withdrawal.3,9 Previously, we found similar levels of apathy among patients with DSZ and TBI survivors selected on the basis of prominent apathy symptoms. However, compared

Received April 14, 2012; revised September 1, December 5, 2012; accepted December 6, 2012. From the Dept. of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, and the Dept. of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. Send correspondence to Dr. Cascella; e-mail: [email protected] or Dr. Schretlen; e-mail: dschret@ jhmi.edu Copyright © 2013 American Psychiatric Association

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J Neuropsychiatry Clin Neurosci 25:4, Fall 2013

TAKAYANAGI et al. with those with TBI, the DSZ group showed higher rates of other negative symptoms, including anhedonia, blunted affect, and alogia.10 Those findings suggest that individuals with DSZ have a constellation of apathy symptoms that differs from that of TBI patients, and possibly associated with different neuroanatomic correlates. Numerous MRI studies have demonstrated broad regional brain volume reductions after TBI.11–21 These changes are thought to result from the acute injury, as well as delayed neuronal death attributable to more widespread processes that occur after TBI.18,21 Likewise, structural MRI studies have shown volumetric differences in the prefrontal and temporal regions among DSZ patients relative to healthy controls (HCs),22–24 and we previously found gray matter (GM) volume reductions among adults with DSZ in the insula and superior temporal, superior frontal, and fusiform gyri.25 Cognitive performance is also substantially affected in both TBI20 and DSZ.26 Specifically, DSZ patients show poorer performance on a variety of cognitive tests, including memory, as compared with HCs, and the severity of negative symptoms (psychomotor poverty, alogia) significantly relates to the amount of decrement in performance on cognitive tests.27,28 A relationship between cognitive deficits, including verbal memory, and apathy symptoms has also been shown among TBI survivors.29 We have been interested in delineating the clinical and biological correlates of apathy across specific neuropsychiatric diseases in order to assess the validity of its syndromal construct.10 This interest has been initially driven by our study of DSZ and the need to better define the biological characteristic of this syndrome, including brain structure abnormality. We thought that TBI apathy would constitute a “model” for DSZ because of the high prevalence of apathy among TBI survivors and because TBI apathy could be more easily related to localized brain abnormality with potential pathophysiological relevance to DSZ. Therefore, the goals of the present exploratory study were to 1) compare brain morphology among DSZ, TBI, and HC participants; and 2) assess whether specific differences in cortical thickness or regional brain volume correlate with the severity of apathy and performance on tests of cognitive functioning in TBI and DSZ.

METHODS Study Participants A group of 10 TBI patients were recruited from the Brain Injury Clinic at Johns Hopkins Hospital and from local


rehabilitation centers. Injury details were obtained from the patient, a collateral informant when available, and medical records. All TBI patients survived a closed head injury secondary to either a motor vehicle accident (N=8) or a fall (N=2) sustained at least 18 months (mean: 72 [standard deviation {SD}: 47] months; range: 18–157 months) before study participation. Based on available data, including Glasgow Coma Scale scores and the duration of loss of consciousness, 6 individuals were rated as having sustained a severe TBI; 2 had a moderate brain injury; and 2 had a mild TBI. These participants all met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for a “personality change secondary to TBI, apathetic subtype.” A group of 15 adults with schizophrenia, diagnosed according to DSM-IV criteria, were recruited from outpatient clinics, inpatient services, and psychiatric day hospitals affiliated with the Johns Hopkins University and Hospital. All participants in the TBI and DSZ groups met criteria for the “deficit syndrome” on the basis of the Schedule for Deficit Syndrome (SDS).30 None of the DSZ or TBI patients met criteria for either a mood disorder or substance abuse/dependence during the preceding 6 months. The HC group comprised 47 healthy adults recruited for a study of normal aging from the Baltimore metropolitan region via random-digit dialing or telephone calls to randomly selected telephone numbers in the residential telephone directory. Exclusion criteria included any reported history of neurological disorders, neurodegenerative disorders, psychiatric illness, and current alcohol/drug abuse or dependence. These studies were reviewed and approved by the Johns Hopkins Hospital Institutional Review Board, and all participants provided written informed consent before participation. Procedure The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) was used to diagnose both schizophrenia and personality change secondary to TBI. The presence and severity of apathy in TBI and DSZ participants were assessed based upon the Apathy Evaluation Scale, Clinician Version (AES–C).31 The SDS and the AES–C were administered by one of two boardcertified psychiatrists (NC and VR). Acceptable interrater reliability for the SDS (k=0.73) was established between raters. The AES–C has been shown to have good internal reliability, test–retest reliability, and interrater reliability (reviewed by Clarke et al.32). We used


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HIPPOCAMPAL VOLUME REDUCTION, APATHY, AND TBI the Scale for the Assessment of Positive and Negative Symptoms (SAPS and SANS) and the Hamilton Rating Scale for Depression (Ham–D) to assess severity of psychopathology and depressive symptoms. The National Adult Reading Test–Revised Version (NART–R) was used to estimate premorbid IQ.33 The HC group was administered diagnostic and clinical assessments, including the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) interview,34 review of medical history, and physical and neurological examinations. Whereas the majority of TBI survivors and HCs underwent physical and neurological examination, psychiatric interview, a brain MRI scan, and cognitive assessment on the same day, most of the DSZ patients needed several days (mean: 4.1 [7.5] days) to complete these procedures. Cognitive Measures Each participant was administered a brief neuropsychological test battery detailed in our previous study.20 This battery assessed functions including psychomotor speed and dexterity, psychomotor processing speed, auditory divided attention, letter–word fluency, visual construction, verbal learning and memory, visual learning and memory, and concept-formation. MRI Acquisition and Pre-Processing All participants underwent brain MRI on the same 1.5-tesla GE Signa scanner (Milwaukee, WI). We acquired 124 contiguous 1.5-mm, 3-D SPGR slices in the coronal plane. The parameters were the following: repetition time: 35 seconds, echo time: 5 seconds, flip angle: 45°, and image matrix: 2563256. Cortical reconstruction and volumetric segmentation were performed with the FreeSurfer Image Analysis Suite, Version 5.0 (http://surfer. nmr.mgh.harvard.edu/fswiki). Detailed methodology of the Freesurfer program is available elsewhere.35 Statistical Analysis One-way analysis of variance (ANOVA) was used to compare all three groups with regard to age, years of education, estimated full-scale IQ, and cognitive test results. The Scheffé test was used for post-hoc pairwise comparisons. Chi-square tested for differences in sex and handedness between the TBI and DSZ groups. Finally, independent-sample t-tests assessed for differences between the TBI and DSZ groups with respect to AES scores, SANS/SAPS total scores, SANS subscale scores, and Ham–D scores.

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Subcortical and cerebellar volumes were compared across the three diagnostic groups via analysis of covariance (ANCOVA), with diagnosis as a betweensubject factor, and age, gender, and intracranial volume (ICV) as covariates. Scheffé tests were used for post-hoc group comparisons. When significant volumetric changes were found between either patient group and the HC group, we calculated partial correlation coefficients between the region-of-interest (ROI) volumes of that patient group and AES scores and neurocognitive measures while controlling for age, sex, and ICV. We used FreeSurfer’s general linear model with a 10-mm, full-width, half-maximum Gaussian kernel to compare cortical thickness across groups (DSZ versus HC, TBI versus HC, and DSZ versus TBI) and to correlate AES ratings and neurocognitive scores, while treating age and sex as nuisance variables. When significant cortical thickness changes were observed between either (or both) clinical groups (i.e., DSZ or TBI) and the HC group, additional correlation analyses were conducted independently for each patient group. Monte Carlo simulation was used to correct multiple comparisons. Separate associations were explored between apathy symptoms and cognitive performance for each patient group by calculating partial correlation coefficients between AES scores and cognitive measures while covarying for age and sex. The statistical significance level was set at p ,0.01 for most statistical analyses, to control for type I error. Based on the anticipated loss of statistical power secondary to modest sample sizes of the patient groups, the statistical significance level was set at p ,0.05 for t-tests and posthoc comparisons (i.e., Scheffé’s test and Monte Carlo simulation). All statistical analyses were performed with SPSS Version 19, with the exception of the cortical thickness analyses, which were conducted in FreeSurfer.

RESULTS Neurocognitive Performance DSZ patients, as compared with HCs, demonstrated worse performance on all 12 cognitive measures. The TBI group performed worse than HCs on tests of motor speed and dexterity (Grooved Pegboard Test; GPT), divided attention (Brief Test of Attention; BTA), verbal memory (Hopkins Verbal Learning Test [HVLT–R] recall), and visual memory (Brief Visuospatial Memory Test–Revised [BVMT–R] learning and recall). Compared


TAKAYANAGI et al.

TABLE 1.

Demographic and Clinical Characteristics of the Subjects Control Subjects (N=47)

Demographic variables Men Handedness, right On typical antipsychotics On atypical antipsychotics On antidepressants Age, years Education, years NART IQ Duration of illness, years Clinical and neurocognitive variables AES score SAPS sum SANS sum SANS Affect SANS Alogia SANS Anhedonia SANS Apathy SANS Attention Hamilton Depression score Grooved Pegboard (DH) Grooved Pegboard (NDH) Trail-Making, Part A, sec. Trail-Making, Part B, sec. Brief Test of Attention Letter Fluency RCFT Copy HVLT–R Learning HVLT–R Recall BVMT–R Learning BVMT–R Recall m-WCST Categories

N 38 37

% 81 78

Mean 41.4 14.7 105.3

SD 12.2 2.3 8.7

Mean

68.3 74.5 29.1 75.1 16.4 28.6 32.4 25.6 9.3 25.4 9.6 5.4

DSZ Patients (N=15)

TBI Patients (N=10)

SD

N 12 14 4 13 1 Mean 33.5 11.7 92.5 12.1 Mean

% 80 93 27 87 7 SD 10.6 1.8 7.5 8.4 SD

N 8 9 0 1 0 Mean 43.7 14.8 104.1 6.0 Mean

% 80 90 0 10 0 SD 11.1 2.5 12.3 3.9 SD

11.9 14.5 14.6 36.0 2.6 8.7 3.4 3.6 2.1 6.1 2.1 1.3

49.7 2.9 17.1 3.8 3.5 4.0 4.0 1.7 6.0 88.2 103.1 49.7 162.0 10.3 17.6 26.4 18.2 4.6 13.2 5.5 3.2

8.5 2.8 2.3 0.6 0.8 0.4 0.0 1.3 2.3 24.0 29.1 25.3 115.1 3.8 7.5 7.7 4.5 2.7 9.1 3.7 2.2

55.7 1.4 12.7 2.3 1.7 3.6 3.6 1.5 5.1 87.8 98.2 45.3 108.5 10.4 20.9 30.6 22.0 6.6 18.2 6.7 5.1

8.6 2.5 5.3 1.6 1.8 0.7 0.5 1.4 2.1 24.2 31.4 16.8 58.9 5.9 11.0 5.5 8.2 4.1 8.5 4.2 1.7

Statistical Findings x2=0.08 x2=2.26

Post-hoc Pairwise Comparison

p NS NS

F=3.079 F=10.67 F=11.17

0.052 ,0.001 HC . DSZ; TBI . DSZ ,0.001 HC . DSZ; TBI . DSZ

t = –1.736 t=1.409 t=2.845 t=3.423 t=3.501 t=3.033 t=1.857 t=0.426 t=0.978 F=10.44 F=12.65 F=9.51 F=10.2 F=25.33 F=10.3 F=8.6 F=15.44 F=20.4 F=18.23 F=14.4 F=9.29

0.096 NS 0.009 0.002 0.002 0.006 0.076 NS NS ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001

HC , DSZ, TBI HC , DSZ, TBI HC , DSZ HC , DSZ HC . DSZ, TBI HC . DSZ HC . DSZ HC . DSZ HC . DSZ, TBI HC . DSZ, TBI HC . DSZ, TBI HC . DSZ; TBI . DSZ

SD: standard deviation; HC: healthy controls; DSZ: deficit schizophrenia; TBI: traumatic brain injury; NART: National Adult Reading Test; AES: Apathy Evaluation Scale; SAPS: Assessment of Positive Symptoms; SANS: Assessment of Negative Symptoms; DH: dominant hand; NDH: nondominant hand; RCTF: Rey-Osterrieth Complex Figure Test; HVLT–R: Hopkins Verbal Learning Test–Revised; BVMT–R, Brief Visuospatial Memory Test–Revised; mWCST: modified Wisconsin Card-Sorting Test.

with patients with DSZ, the TBI group showed better concept-formation (Modified Wisconsin Card-Sorting Test [M–WCST]). There were no cognitive tests on which patients with DSZ outperformed those in the TBI or HC groups (Table 1). Subcortical and Cerebellar Analyses Results of the ANCOVAs revealed significant main effects of diagnosis for volumes in the bilateral hippocampi, the right thalamus, and the brainstem. Post-hoc analyses demonstrated that, compared with HCs, TBI survivors showed reduced volumes (p ,0.001) of the hippocampi bilaterally, right thalamus, and brainstem. Compared with the DSZ group, TBI survivors also had smaller volumes of the left hippocampus (p=0.016), right thalamus (p=0.025), and brainstem (p=0.018).


There were no significant volume differences between HCs and DSZ in subcortical and cerebellar ROIs (Table 2). Correlational analyses controlling for age, sex, and ICV revealed a significant inverse correlation between left hippocampal volume and Apathy Evaluation Scale (AES) scores among TBI survivors (r = 20.93, p=0.002; Figure 1). Cortical Analysis Compared with the HC group, the DSZ group demonstrated widespread cortical thinning, predominantly in prefrontal and temporo-paralimbic regions, including the bilateral superior, middle, and inferior frontal gyri, as well as the left superior temporal gyrus, right fusiform gyrus, right anterior and posterior cingulate gyrus, bilateral insular cortices, and right supramarginal gyrus


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TABLE 2.

Comparison of Mean Volumes of the Subcortical/Cerebellar Regions of Interest (ROIs), Adjusted for Age, Gender, and Intracranial Volume (ml) Healthy Controls (N=47)

ROIs

Amygdala Thalamus Caudate Putamen Pallidum Cerebral white matter

Cerebellar white matter

ANCOVA

Volume

SD

Volume

SD

F

p

1,537.3

134.4

1,488.7

186.9

1,480.4

137.8

1.056

NS

Left

4.6

0.4

4.3

0.4

3.8

0.8 10.378 ,0.001

Right Left Right Left Right

4.3 1.6 1.6 7.3 7.1

0.4 0.2 0.2 0.8 0.8

4.1 1.6 1.6 7.2 6.8

0.4 0.2 0.3 0.9 0.8

3.7 1.4 1.5 6.6 6.1

0.7 0.2 0.3 0.8 0.9

7.122 3.189 0.510 3.189 7.645

Left Right Left Right Left Right Left Right

3.3 3.4 5.3 5.1 1.8 1.6 264.3 266.2 3.2 8.1 22.6

0.5 0.5 0.6 0.6 0.2 0.2 30.5 30.9 0.5 0.9 2.5

3.6 3.7 5.5 5.2 1.8 1.7 251.8 253.6 3.1 8.0 21.3

0.7 0.6 0.5 0.9 0.3 0.3 38.3 37.1 0.7 0.8 2.8

3.2 3.3 4.9 4.6 1.6 1.4 239.4 241.3 2.6 7.1 19.2

0.4 0.4 0.6 0.5 0.3 0.2 33.0 31.8 0.5 0.9 2.1

2.065 2.274 1.257 2.252 3.245 3.648 2.364 2.233 3.826 4.294 9.000

Left Right Left Right

56.8 57.9 14.6 14.2

5.5 5.3 2.1 1.8

54.1 55.2 14.1 13.8

5.7 6.4 2.9 2.2

52.9 53.6 13.9 12.9

7.5 7.0 2.3 1.7

1.959 2.349 0.161 1.215

Corpus callosum Ventral diencephalon Brainstem Cerebellar gray matter

TBI Survivors (N=10)

SD

Hemisphere Volume

Intracranial volume (ICV)a Hippocampus

DSZ Patients (N=15)

Post-hoc Pairwise Comparison

HC . TBI (p ,0.001), DSZ . TBI (p=0.016) 0.0016 HC . TBI (p ,0.001) 0.048 NS 0.048 0.001 HC . TBI (p ,0.001); DSZ . TBI (p=0.025) NS NS NS NS 0.045 0.031 NS NS 0.027 0.018 ,0.001 HC . TBI (p ,0.001); DSZ . TBI (p=0.018) NS NS NS NS

Values represent mean of measured volume (ml). ANCOVA: analysis of covariance; DSZ: deficit schizophrenia; ROI: region of interest; TBI, traumatic brain injury; SD: standard deviation. a Adjusted for age and gender.

(Figure 2). There was no significant difference in cortical thickness between TBI survivors and HCs. Comparisons of cortical thickness between the DSZ and TBI groups demonstrated that TBI survivors had thicker cortices in the pars orbitalis and in the lateral orbitofrontal regions bilaterally (Figure 3). In the DSZ group, additional correlation analyses did not reveal any significant associations between cortical thickness and either AES ratings or cognitive test performance. Correlation of Apathy Evaluation Scale (AES) Ratings With Cognitive Measures Patients with DSZ did not demonstrate any significant correlation between cognitive test performance and apathy severity. In contrast, in the TBI group, higher AES ratings were associated with worse performance on measures of verbal learning (HVLT2R learning r = 20.88; p=0.004), verbal memory (HVLT2R recall r = 20.84; p=0.0094), and phonemic fluency (Letter Fluency r = 20.85; p=0.0076) even after controlling for age and sex.

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DISCUSSION To our knowledge, this is the first study to demonstrate an association between brain structure and post-TBI apathy. We observed volume reductions of the hippocampus, the thalamus, and the brainstem among TBI survivors. Among these patients, greater reductions of left hippocampal volume correlated strongly with more severe apathy, and the severity of apathy was negatively associated with performance on measures of verbal learning and memory in TBI patients. In contrast, subcortical volume change was not seen in DSZ patients as compared with HCs. Taken together, these findings suggest that apathy resulting from TBI might have a different neural basis from apathy resulting from schizophrenia. The hippocampus plays a critical role in memory function, including verbal and narrative memory.7,36,37 Ariza and colleagues17 reported an association between verbal memory deficits and left hippocampal atrophy in TBI. Andersson and Bergedalen previously


TAKAYANAGI et al.

FIGURE 1.

Correlation Between Left Hippocampal Volume and AES Ratings in Patients With TBI (left) and DSZ (right)

TBI Survivors

Schizophrenia Patients 6.0

Left hippocampus (mm3)

Left hippocampus (mL)

6.0

5.0

4.0

3.0

2.0

5.0

4.0

3.0

2.0 40

45

50

55

60

65

70

AES

35

40

45

50

55

60

65

AES

There was an inverse correlation of AES ratings and volume of the left hippocampus in TBI patients (partial correlation coefficient = 20.93; p=0.002, adjusted for age, sex, and intracranial volume). AES: Apathy Evaluation Scale; DSZ: deficit schizophrenia; TBI: traumatic brain injury.

reported a relationship between cognitive deficits, including verbal memory, and apathy symptoms among TBI survivors.29 Although we acknowledge that apathy may affect patients’ cognitive performance, it could be possible that, taken together with our data, the lesions to the left hippocampus might be causally related to the development of apathy and verbal memory impairment in TBI. However, given that subcortical and cortical areas of the brain are interconnected both structurally and functionally, it is possible that, in TBI, the cortical areas associated with the development of apathy could be functionally impaired as a result of structural lesions of subcortical regions such as the thalamus, the brainstem, or the hippocampus. An apathy syndrome has been previously described both after thalamic stroke38 and brainstem lesions,39 indicating that such a mechanism is possible. In addition, or as an alternative to, the above explanations, our data showing a correlation of left amygdala volume with AES score (r = 20.81 [p=0.03], controlling for age, gender, and ICV) suggest, if confirmed in a larger sample, a role of the left amygdala2hippocampus complex in mediating apathy symptoms in TBI. Findings in this study also highlight differences in structural and functional brain changes between TBI


survivors and patients with DSZ. Whereas TBI survivors exhibited several regions of subcortical volume loss as compared with HCs, patients with DSZ demonstrated thinner cortices, particularly in fronto-temporo-paralimbic regions, as compared with HCs. Patients with DSZ also showed significantly reduced cortical thickness of the pars orbitalis bilaterally and lateral orbitofrontal cortices (LOFC) relative to the TBI group. Lesions to the LOFC, one of the frontal lobe areas that is connected with subcortical limbic regions, results in personality blunting and change, possibly due to the absence or impairment of limbic affective input.40 Furthermore, LOFC is particularly sensitive to the implementation of reversal learning,42 and schizophrenia patients with “residual” negative symptoms are more likely to fail the set-shifting stage of the reversal learning task.43 Our results revealed that, DSZ patients completed significantly fewer categories on the M-WCST, compared with TBI survivors with equally severe apathy. Although Roth and colleagues 44 reported smaller bilateral frontal lobe volumes among SZ patients with severe apathy, based on the SANS Apathy subscale, as compared with HCs, we failed to find any significant correlations between structural brain changes and apathy in DSZ patients. A larger sample size may be


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HIPPOCAMPAL VOLUME REDUCTION, APATHY, AND TBI

FIGURE 2.

Cortical Thickness Difference Maps Between DSZ and Healthy Control Subjectsa

DSZ vs HC

RH

LH

DSZ < HC

p HC

p