|Year : 2021 | Volume
| Issue : 1 | Page : 21-27
Neural substrates of psychiatric symptoms in patients with Huntington’s Disease
Nitish Kamble1, Jitender Saini2, Lija George1, Nikhil Ratna3, Amitabh Bhattacharya1, Ravi Yadav1, Sanjeev Jain3, Pramod Kumar Pal1
1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
2 Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
3 Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
|Date of Submission||27-Aug-2020|
|Date of Decision||30-Sep-2020|
|Date of Acceptance||17-Mar-2021|
|Date of Web Publication||17-Apr-2021|
Dr. Pramod Kumar Pal
Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bengaluru 560029, Karnataka.
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Numerous studies in Huntington’s disease (HD) have shown striatum as the major site of neuronal loss, but recently the presence of neurodegeneration in other regions of the brain is gaining attention. In our study, we used voxel-based morphometry and diffusion tensor imaging to identify other areas in the brain that are involved in the disease. METHODS: The present study is a prospective study conducted in the Departments of Neurology, Psychiatry, and Neuroimaging and Interventional Radiology (NIIR), NIMHANS, Bengaluru. The study included 20 genetically confirmed HD patients and 20 healthy controls. Magnetic resonance imaging was performed on a 3-Tesla Philips Achieva scanner with a 32-channel head coil with the acquisition of whole-brain T1-weighted and DTI. RESULTS: The patients (41.25 ± 10.04 years) and controls (38.27 ± 11.29 years) were age-matched (P = 0.38), and the mean age at the onset of the symptoms of the disease was 37.53 ± 10.11 years, and the expanded CAG repeat allele was 45.95 ± 7.27 (range 40–73) repeats. All patients had psychiatric symptoms at presentation such as anger outbursts, irritability, abusive behavior, apathy, low mood, crying spells, delusions, lack of initiation, and obsessive–compulsive disorder. Compared with controls, HD patients had significant atrophy of bilateral caudate nuclei, right globus pallidus, left culmen, right precuneus, hypothalamus, and right superior temporal gyrus. Fractional anisotropy was increased in bilateral cerebral white matter and thalamus with the reduction in mean diffusivity. CONCLUSIONS: In addition to atrophy of caudate, atrophy was also observed in globus pallidus, thalamus, hypothalamus and right superior temporal gyrus. This may explain the neuropsychiatric and cognitive symptoms observed in these patients.
Keywords: Chorea, diffusion tensor imaging, Huntington’s disease, magnetic resonance imaging, voxel-based morphometry
|How to cite this article:|
Kamble N, Saini J, George L, Ratna N, Bhattacharya A, Yadav R, Jain S, Pal PK. Neural substrates of psychiatric symptoms in patients with Huntington’s Disease. Ann Mov Disord 2021;4:21-7
|How to cite this URL:|
Kamble N, Saini J, George L, Ratna N, Bhattacharya A, Yadav R, Jain S, Pal PK. Neural substrates of psychiatric symptoms in patients with Huntington’s Disease. Ann Mov Disord [serial online] 2021 [cited 2022 Dec 1];4:21-7. Available from: https://www.aomd.in/text.asp?2021/4/1/21/313938
| Introduction|| |
Huntington’s disease (HD) is a progressive neurodegenerative disorder inherited in an autosomal-dominant fashion and is caused by an expanded trinucleotide (CAG) repeat on the short arm of chromosome 4. HD is characterized by abnormalities in motor, cognitive, and behavioral domains. The motor symptoms include chorea, dystonia, rigidity, bradykinesia, hypotonia, etc. There is a progressive loss of medium spiny neurons within the cortico-striatal circuits that is visible on the structural imaging of the brain.,, The cortico-striatal pathways are disrupted secondary to degeneration of cells in the striatum. Degeneration of these pathways leads to the motor, cognitive, and behavioral disturbances observed in the disease. There is a topographic organization of these circuits in the striatum., Numerous neuropathological and neuroimaging studies have shown striatum as the major site of neuronal loss, but recently the presence of neurodegeneration in other regions of the brain is gaining attention.,,, Widespread increased intracortical diffusivity and cortical thinning have been observed in HD.
Structural magnetic resonance imaging (MRI) is a noninvasive imaging technique for examining the macro- and micro-structural brain anatomy and pathology in patients with premanifest and manifest HD. Structural MRI includes sequences such as T1- and T2-weighted imaging, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), and quantitative susceptibility mapping (QSM). These techniques are employed to understand the progression of the disease and can be used as biomarkers in HD. These widespread changes in addition to the atrophy of the striatum may underlie the psychiatric and cognitive impairments observed in these patients. Hence, in this study, we used advanced neuroimaging techniques to identify anatomical areas and cortico-striatal circuits that are involved in the pathophysiology of psychiatric symptoms in patients with HD.
| Methods|| |
The present study was a prospective study conducted in the Departments of Neurology, Psychiatry, and Neuroimaging and Interventional Radiology (NIIR), NIMHANS, Bengaluru. The study period was from April 2013 to October 2014 with a total duration of 18 months. Patients were recruited from the neurology and psychiatry OPD’s and Parkinson’s disease and Movement disorders clinic at NIMHANS. The study included 20 genetically confirmed HD patients with psychiatric symptoms (age 18 years and above) and 20 age-matched controls. The presence of the HD mutation expanded trinucleotide CAG repeat sequence was confirmed by DNA analysis.
The controls were healthy volunteers, friends of the patients, and with no family history of chorea. Patients’ relatives were not taken as controls. Subjects with other neurological illness, severe medical comorbidities, prior head injury, or prior substance abuse were excluded.
The study was approved by the institute ethics committee and written informed consent was obtained from all the participants and the information kept confidential.
All the patients enrolled in the study were evaluated by a detailed history and complete neurological examination. Detailed neurological examination was performed by the movement disorders specialists (PKP, RY) and the psychiatric evaluation was done by the experienced psychiatrist (SJ). The severity of motor symptoms was assessed using the Unified Huntington Disease Rating Scale (UHDRS). All the recruited HD patients had psychiatric symptoms on presentation. The details about the psychiatric symptoms were collected from the patient and their family members in addition to the available medical records. These symptoms were significant enough to cause distress to the patient and/or caregivers. All the demographic and clinical details were recorded in a predesigned clinical proforma. All the participants underwent brain imaging using MRI.
MRI data acquisition technique
MRI was performed on a 3-Tesla Philips Achieva scanner with a 32-channel head coil. Whole-brain T1-weighted 3DTSE data sets were acquired in the coronal plane [TR (repetition time) = 12.4ms, TE (echo time) = 4.2ms, TI (inversion time) = 650ms, 256 × 256 matrix, 1.6mm slice thickness, flip angle = 15°, FOV (field of view) = 20cm, in plane resolution 0.78 × 0.78 mm] yielding 124 contiguous slices through the head. The DTI data were acquired using spin-echo echo-planar imaging (EPI) pulse sequences with the following imaging parameters: TR/TE = 8090/55ms; flip angle = 90°; FOV = 224 × 224 × 150, acquisition matrix, 112 × 109; reconstruction matrix, 128 × 128; voxel size, 2 × 2.04 × 2.5, and reconstruction voxel size of 1.75. Parallel imaging technique (SENSE) with a sense factor of 2 was used. Data acquisition was done with no interslice gap 16 noncollinear diffusion-sensitizing gradients with a b-value of 1000s/mm2. Standard head positioning was used throughout.
Images were transferred to a 3-T workstation computer and analyzed using SPM8 (Statistical Parametric Mapping, Wellcome Department of Cognitive Neurology, London, UK; http//www.®l.ion.ucl.ac.uk/ spm) and MATLAB 2013 (The MathWorks, MA, USA). The optimized VBM8 protocol was applied to the images. Before VBM analysis, all images were checked for movement artifacts and manually re-orientated using the reorient function of SPM8 so that they were centered on the anterior commissure. Those images degraded by the movement were excluded from further analyses. The standard procedure of voxel-wise cross-subject analysis of DTI data was performed using tract-based spatial statistics (TBSS). Pre-processing of DTI data including eddy current correction, motion correction (by linear registering to the nondiffusion weighted image using FLIRT) was performed. Voxel-wise statistical analysis of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (DA) maps were performed using TBSS.
Statistical analysis was done using R software. Data were expressed using descriptive statistics such as mean and standard deviation for continuous variables and frequency, the percentage for categorical variables. Tests of statistical significance used were independent Student ‘t’ test. Correlation between continuous variables was done using Pearson’s correlation co-efficient. P-value of <0.05 considered statistically significant.
| Results|| |
Twenty HD patients (9 F; age 41.25 ± 10.04) and 20 (8 F; 38.27±11.29 years) healthy individuals participated in our study, and the groups were comparable in age (P = 0.38) and gender. The mean age at onset of the disease was 37.53 ± 10.11 years with a range of 21–58 years. In males, the mean age at onset was 38.0 ± 10.77 years (range 25–58 years) and in women, it was 36.9 ± 9.84 years (range 20–47 years). The mean CAG repeat length of the upper allele was 45.95 ± 7.27 (range 40–73). Chorea was present in all the patients with the mean UHDRS motor score being 33.7 ± 14.2. All the patients had neuropsychiatric symptoms at presentation. Frequent anger outbursts, irritability, and abusive behavior were found in 9 (45%) patients, apathy, low mood, crying spells, delusions and lack of initiation was found in 7 (35%), overlapping symptoms and obsessive-compulsive disorder (OCD) in 2 (10%) patients each. Anger outbursts and irritability were seen in both genders (women = 2, men = 7) whereas apathy and depression were observed only in women (N = 7) and OCD in 2 men. The details are summarized in [Table 1].
MRI with VBM and DTI
Compared to controls, HD patients had significant atrophy of bilateral caudate nucleus (cluster size (k) 2448 and 2373). Also, atrophy was noted in right globus pallidus (k = 101), left culmen (k = 132), right precuneus (k = 74), hypothalamus (k = 24), right superior temporal gyrus [Figure 1]. FA was increased with a reduction in MD in bilateral cerebral white matter (WM) and thalamus [Figure 2]. AD was reduced in the superior and middle cerebellar peduncle, corpus callosum (CC), fornix and bilateral cerebral WM. The details are given in [Table 2]. There was no correlation of the imaging findings with the disease duration and UHDRS scores.
|Figure 1: Voxel-based morphometric analysis showing the atrophic regions in patients with HD|
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|Figure 2: Bilateral WM and thalamic abnormalities on DTI in patients with HD|
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|Table 2: Significant clusters of gray matter atrophy in patients with HD|
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| Discussion|| |
HD is a neuropsychiatric disorder which encompasses psychiatric symptoms in addition to the motor manifestations. Various psychiatric symptoms have been described in these patients that include depression, apathy, anxiety, irritability, aggression, verbal or behavioral outbursts, obsessive-compulsive disorder, psychosis etc. Previous findings indeed suggest that both neuropathology and environmental stress contribute to the occurrence of neuropsychiatric phenomena in HD. Routine MRI shows a loss of striatal volume and increased size of frontal horns of the lateral ventricles in patients of moderate-to-severe HD. PET and functional MRI studies have shown changes in the affected brains many years before the symptom onset., Studies have shown that caudate atrophy can occur as early as 11 years and putaminal atrophy 9 years before the disease onset. In addition to the striatum, the cerebral cortex is also involved and it is important to note that huntingtin protein is more concentrated in cortical neurons., Striatal degeneration may be secondary to cortical alterations.
DTI is a unique MRI method that is used to measure alterations in tissue composition in a variety of neurological diseases. It provides information about WM integrity, and tissue fiber architecture within gray matter (GM) by measuring FA and MD.,
In our study, there was significant atrophy of bilateral caudate nuclei, hypothalamus, right precuneus, superior temporal gyrus, globus pallidus, and left culmen. The thalamus and cerebral WM were also involved in our patients. Soneson et al. performed VBM and logistic regression analyses of cross-sectional MR images from 220 HD gene carriers and 75 controls in the PREDICT-HD study. They showed that changes in the hypothalamic region are detectable before clinical diagnosis and that its GM contents alone are sufficient to distinguish HD gene carriers from control cases and also that alterations in gray matter contents in the hypothalamic region occur at least a decade before clinical diagnosis in HD. Our study also found significant atrophy of the hypothalamus. Earlier studies have shown, reduced striatal volumes and that the left-sided volumes were smaller than right-sided volumes in HD patients. This volume loss was significantly correlated with CAG repeat number.
In a VBM and DTI study involving 15 HD and 15 controls, in addition to neostriatum and cortical GM volume loss, individuals with HD showed volume loss in the genu of the internal capsule and subcortical frontal WM bilaterally, the right splenium of the CC, and the left corona radiata. Areas of WM atrophy, decreased FA, and increased MD correlated with the severity of the motor and cognitive dysfunction, whereas only the areas with increased MD correlated with disease duration. Smaller volumes of the caudate nucleus, putamen and whole-brain (P < 0.001 for all) was observed in HD carriers in one study. A particular pattern of atrophy that includes thinning of the GM in the insula, inferior frontal gyrus, caudate, lentiform nucleus, and thalamus, bilaterally, in the left middle frontal, middle occipital, and middle temporal gyri, and of periventricular, subinsular, right temporal lobe, and left internal capsule WM has also been described.
WM degeneration within interhemispheric pathways plays an important role in the deterioration of cognitive and motor functions. Hypothalamus, thalamus, fornix is part of the limbic system which are involved in our patients. Also, the thalamus, caudate, putamen, and globus pallidum, which are part of the cognitive circuit of the cortical-basal ganglia loop, are involved in our patients. Thalamus is involved in the socio-emotional cognition that mediates envy and jealousy. Superior temporal gyrus is associated with dispositional envy. Involvement of these anatomical structures may explain the neuropsychiatric features observed in patients with HD. Structural MRI studies in patients with depression have shown the reduced volume of the hippocampus and volume reduction of the dorsal anterior insula, cingulate cortex, and superior frontal gyrus., In a recent study that included 43 HD mutation carriers (both manifest and premanifest HD), subjects with impairment in cognitive and motor domains shared a common neurobiological basis (GM and WM tracts involved in executive functions, language, visuospatial and sensorimotor processing) and subjects with psychiatric symptoms had abnormalities in the cortical and WM tract associated with emotional processing. The cortical thickness was reduced in limbic and paralimbic regions, left ventromedial prefrontal cortex, and bilateral insula. Also, reduced cortical thickness was observed in left superior frontal gyrus, left middle temporal gyrus, left anterior and posterior cingulate cortex (regions of default mode network).[Figure 3] shows a schematic diagram of the gray matter atrophic areas and WM abnormalities associated with psychiatric symptoms in patients with HD.
|Figure 3: Schematic diagram showing the gray matter and WM abnormalities in patients with HD that are associated with psychiatric symptoms|
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It is thus obvious that apart from the usual MRI changes, HD patients have significant atrophy of GM and associated WM tract abnormalities that underlie the psychiatric disturbances observed in these patients.
Our study has some limitations such as a small sample size. However, our results are comparable with other published studies. Our study lacked the cognitive testing that could have been useful in correlating the cognition with imaging. Also, we do not have a group without psychiatric symptoms that would have helped confirm the anatomical substrates.
In addition, correlation of brain atrophy with the severity of psychiatric symptoms was not possible as psychiatric scale was not used and also due to the small sample size.
| Conclusions|| |
There was significant atrophy of bilateral caudate nuclei in patients with HD. Also, these patients have atrophy of the hypothalamus, right precuneus, superior temporal gyrus, globus pallidus and left culmen and also the involvement of cerebral WM and thalamus. Involvement of these structures suggests disruption of the frontal subcortical circuits and several other regions that leads to psychiatric and cognitive symptoms in addition to motor symptoms in these patients. However, due to small sample size and lack of another group of HD patients without psychiatric manifestations makes it difficult to draw conlusions. Hence, larger studies are required to confirm our findings.
The authors have no acknowledgement to declare.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]