MULTIVOKSELINĖ MRT MORFOMETRIJA PARKINSONO LIGA SERGANTIESIEMS SU NEUROPSICHIATRINIAIS SUTRIKIMIAIS ----------------------------- MRI VOXEL BASED MORPHOMETRY IN PARKINSON´S DISEASE PATIENTS WITH NEUROPSYCHIATRIC DISORDERS

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MULTIVOKSELINĖ MRT MORFOMETRIJA

PARKINSONO LIGA SERGANTIESIEMS SU

NEUROPSICHIATRINIAIS SUTRIKIMIAIS

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MRI VOXEL BASED MORPHOMETRY IN

PARKINSON´S DISEASE PATIENTS WITH

NEUROPSYCHIATRIC DISORDERS

Juan Manuel Murillo Del Viejo

Medicinos akademijos (MA)

Vientisuju Studiju Programa - Medicina

LSMUL KK Neurochirurgijos Klinika

Darbo vadovas dr. Andrius Radžiūnas

Kaunas 2018-2019

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SUMMARY

MRI Voxel based morphometry in Parkinson disease patients with neuropsychiatric disorders. Juan Manuel Murillo del Viejo

Background

Studies unifying thalamus morphometric changes on Parkinson Disease (PD) patients and their relation with depression and anxiety are lacking. For that reason, and supporting the present study on the past research articles of Dr A. Radziunas, the aim of this exploratory study is deepening actual morphometry studies investigating the possible relations of the Thalamic nuclei volume changes with the most common neuropsychiatric symptoms in PD patients.

Objectives

We reviewed the literature concerning the current knowledge of the PD and his Non-Motor Symptoms (NMSs) (i), the thalamic changes in PD and their relation with Depression or Anxiety (ii). With that background we investigated using neuroimaging techniques the morphometric thalamic changes in PD patient (iii) and with Voxel Based Morphometry (VBM) and statistical software we compared the results of the PD group between the healthy volunteers (iv). As the last steep, we evaluated using the most stablished and reliable proven questionnaires the PD

neuropsychiatric state with their forehead analysed thalamic volume changes (v)

Methods

Thirty-one (31) PD patients (Inclusion criteria of idiopathic PD longer than 5 years with good response to L-DOPA therapy) performed a depression and a Quality of Life (QoL) level questionnaires and underwent brain MRI. As a control group we used age and sex matched 17 healthy volunteers. Automated voxel-based image analysis was performed with the Freesurfer Software. SPSS was used as a statistical analysis software

Results

PD patients when compared with healthy controls didn’t show a significant difference in their thalamic nuclei volume. Between PD patients, depression was associated to a specific intralaminar nucleus and lateral nuclear group (including pulvinar nuclei) volume decrease and a global thalamic volume loss, left thalamus was most notably affected (-0.48:0.04). Anxiety followed the same trend, with an intralaminar and lateral nucleus volume loss, with a decrease of the integral thalamic volume. SF-36 and PDQ-39 questionnaires results didn’t show any influence or correlation with the thalamic volume.

Conclusions

Anxiety and Depression are among the most common Non-motor symptoms of PD. Results in this study proved being statistically significant for a thalamic volume reduction in that cases. That outcome open the doors to conceive neuroimaging studies as an affordable and non-invasive way to prognose and evaluate neuropsychiatric symptoms and tries to encourage future and more specific studies to overcome the lack of knowledge on the specific thalamic nucleus that although being proven in our results to be related with neuropsychiatric states they do not have any other clear or direct report thereon.

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ACKNOWLEDGMENTS

This study would not have been possible without the help of Dr Andrius Radziunas and his contribution to all the aspects of it.

CONFLICTS OF INTEREST

The author reports no conflicts of interest

PERMISSION ISSUED BY ETHICS COMMITTEE

Permission issued by Lietuvos Sveikatos Mokslu Universitetas Bioetikos Centras with Nr. BEC-MF-385 on date of 2019-02-20.

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ABBREVIATIONS

BC Before Christ

BDI Beck Depression Inventor CL Central lateral

CM Centromedian

CNS Central Nerve System DBS Deep Brain Stimulation

fMRI Functional Magnetic Resonance

HADS Hospital Anxiety and Depression scale IQR Interquartile range

LD Lateral Dorsal LP Lateral Posterior

MMSE Mini Mental State Examination NMSs Non-Motor Symptoms

PD Parkinson Disease

PDQ-39 Parkinson disease questionnaire 39 PuM Medial Pulvinar

PuA Anterior Pulvinar Pf, Parafascicular

PET Positron Emission Tomography PUL Pulvinar

QoL Quality of Life SF-36 Short Form 36

UPDRS – III Unified Parkinson disease rating scale motor part III VPL Ventral Posterolateral

VLa Ventral Lateral anterior VBM Voxel Based Morphometry

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TERMS

Biserial correlation: Correlation coefficient used when one variable is dichotomous

Lewy bodies: Abnormal protein aggregates that develop inside nerve cells in certain pathologies Morphometry: Quantitative study of the form, empathising in shape and size.

Neurodegenerative: Progressive loss or damage of nerve cells

Neuroimaging: Techniques to directly or indirectly image the structure or function of nerve system Neuropsychiatric symptoms: Affective and behavioural changes in the patient

Nosology: Branch of medical science that study the classification of diseases

“Off “period: Stage where PD medication is not working optimally and Parkinson symptoms return Voxel Based Morphometry: Statistical parametric mapping of the brain using MRI

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BACKGROUND

Being the 2nd most prevalent neurodegenerative disease with over 10 million people worldwide living with it [1], Parkinson disease has received during the last decades considerable attention of medical and research field in order to uncover the pathophysiology of the disease and try to develop better management approaches and improve the patient’s outcome. Nonetheless, it is relatively recent that due his prevalence and QoL repercussion, the non-motor symptoms became the main focus of study.

Yet, Originally Parkinson disease has been a disease intrinsically attached to is motor

involvement. That alteration was pictured since 1000 BC; where ancient Chinese and traditional Indian texts capture the nature of “Involuntary tremulous motions, with lessened muscular power and bending of the trunk, without have the senses or intellect injured “[2] presumably for being the most discernible symptom. Many other similar references can be noticed on Egyptian papyrus or The Bible [3]

First insights of the modern concept of PD were given by James Parkinson on is piece “An Essay on

the Shaking Palsy” (1817), where he reported and analysed 6 subjects while describing his

symptoms in order to give the first clear medical description of the disease [4]. That description was attuned by J.M. Charcot, whose studies gave the anchor in the understanding and

differentiating the disease, giving the first nosology steps of PD making the distinction between bradykinesia, rigidity and weakness among other symptomatically similar diseases. And coining the term “Parkinson Disease” 60 years after the publication of the first disease essay and in honour of his writer.

Those pioneering initial works become the landmark and onset for many fields trying to unveil the nature and causes of the manifested triad of cardinal motor symptoms who defined the disease – bradykinesia, rigidity and tremor. But it wasn’t until 1964, where the team led by Adams R.D. [5], documented the striatum affection of the disease, opening the actual understanding and research pathway of the disease

Notwithstanding the foregoing, evolution of the diagnostic methods and rise of the scientific

community and their researches have shown that the neuropathology underlying PD is not confined on the dopaminergic nigrostriatal pathway and it is a multisystem disease that affect the nervous systems as a whole

As a brief summary of the different nervous system components affected on PD, we find that in PNS systematic cytopathologic studies have shown a loss of neurons in the sympathetic ganglia and Lewy Bodies accumulation in the enteric nervous system, cardiac plexus, pelvic plexus and adrenal medulla [6]. Whilst Central Nerve System (CNS) morphometric studies in PD patients revealed an asymmetric progressive pattern. Left hemisphere Cortical thickness decline is predominantly affected in early stages of PD (fusiform, insula, olfactory sulcus, parahipocampal and precentral areas), whereas right hemisphere cortical thickness decrease its related to late stages of PD (caudal anterior cingulate, inferior supramarginal gyrus, parahipocampal and precentral) [7][8][9].

Left cerebellum shows significant grey matter reduction in the right quadrangular lobe. Superior cerebellar peduncle volume decrease has been reported [7][10][11]. Progressive asymmetrical lateral ventricular enlargement, associated to PD motor and cognitive progression has been noted in different studies [12][13][14]. Hypothalamic neural degeneration was documented in all 13 nuclei

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of the hypothalamus, with predominance in tuberomammillary nucleus and lateral and posterior hypothalamic nuclei [15].

As well, thalamus and limbic system among other CNS areas revealed a broad range of

abnormalities on PD patients. This subject will be discussed further in next sections of the present study

As we can assume, the widespread of impaired loci is the cause of the large spectrum of non-motor symptoms related to the disease. For this reason, is not surprising that almost 88% of the patient reported at least one NMS, and 60% of the patients reported 2 or more. While the quantity of that NMSs are positively related to the severity of the disease [16].

Nonmotor domain

Autonomic Sleep Neuropsychiatric Sensory and others Nonmotor Symptoms Nausea Constipation Urinary urgency Nocturia Sexual dysfunction Orthostatic hypotension Insomnia Vivid dreams Daytime sleepiness Restless legs syndrome Depression Anxiety Psychosis Compulsive behaviour Pain Auditory, Olfactory and visual dysfunctions

Table 1. Nonmotor symptoms in Parkinson's disease: classification and management [17]

From the forehead mentioned, Neuropsychiatric disturbances, including depressive states and anxiety are among the most common non-motor symptom in patients with Parkinson disease [17]. With depression and anxiety affecting 40%-50% of the PD patients [18].

The causes of this relations have been longed studied and given arise to many theories, from psychological factors, were the fears of being unable to function or being embarrassed ( especially during a sudden “off” period ) till the own biological pathognomy of the disease, where the

underproduction of dopamine can affect directly to the depressive or anxiety disorders.[19] Linking it directly with the main aim of our study, numerous studies have sought to find a morphometric correlation between the most common neuropsychiatric disturbances and the PD patient brain. Orbitofrontal and insula white matter atrophy has been confirmed to contribute to the depression in PD [20].

Likewise, Thalamus has been directly linked on the PD process and the Neuropsychiatric process. Most common reported pathoanatomical relation is based on the centromedian–parafascicular complex atrophy [21][22]. Or newer approaches like miscommunication between basal ganglia and thalamus, caused by the dopamine depletion and affecting directly to the excitatory amplitudes between them [23]. In the same way, paraventricular thalamus affections shown to be directly related to depressive disorders [24].

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AIM

Studies unifying thalamus morphometric changes on PD patients and their relation with depression and anxiety are lacking. For that reason, and supporting my study on the past research articles of Dr. A. Radziunas, the aim of this exploratory study is deepening actual morphometry studies investigating the possible relations of the Thalamic nuclei volume changes with the most common neuropsychiatric symptoms in PD patients.

RESEARCH OBJECTIVES

1 Review the literature concerning the current knowledge of the Parkinson disease and his Non-motor Symptoms.

2 Review the most actual literature about the thalamus changes in the Parkinson disease and his relation with Depression or Anxiety.

3 Investigate using Neuroimaging techniques the morphometric thalamic changes in PD patients. 4 Compare using VBM and statistical software the neuroimaging results of the PD group and healthy group to discern possible thalamic volume nuclei differences.

5 Evaluate using the most stablished and reliable proven questionnaires the PD neuropsychiatric state with their thalamic volume changes.

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METHODS

Subjects

We analysed a total of 32 PD patients from Department of Neurosurgery and Neurology of the Lithuanian University of Health Science Hospital Kaunas Clinics, Kaunas, Lithuania, In a period from January, 2015 until September, 2016. From them 14 were DBS-implanted patients. Inclusion criteria were (i) idiopathic PD with disease duration of more than 5 years; (ii) good response to L-DOPA therapy; (iii) absence of severe cognitive deficit and (iv) signed informed consent. Exclusion criteria were (i) current dopamine agonist and psychotropic drug use; (ii) active psychiatric

disorder(s); (iii) cognitive impairment (defined as Mini Mental State Examination (MMSE) score <24) and (iv) structural changes on brain MRI (subtle ischemic or lacunar infarction, brain tumours). As a control group we used 17 healthy control patients brain MRI. Patients were excluded from the analyses if semiautomated VBM software (Freesurfer) required manual brain mask correction.

Study design

Following the previous article and study of Dr A. Radziunas “Brain MRI morphometric analysis in Parkinson’s disease patients with sleep disturbances” [7] and with the intention of develop it, we requested the use of the same data used it. Consents were approved by Ethics Committee for Biomedical Research at the Lithuanian University of Health Sciences, Kaunas, Lithuania. All patients pondered on the study gave signed informed consent prior to inclusion in the study. PD patients were instructed about their eligibility to participate in the study. After signing informed consent form, patients underwent various evaluations for PD severity ( Unified Parkinson disease rating scale motor part III or UPDRS – III ), global cognitive functioning ( mini mental state examinationMSE ) depressive/anxiety symptom severity ( Hospital Anxiety and Depression scale -HADS) and generic and specific Health-related quality of life Questionnaires ( Parkinson disease questionnaire 39 - PDQ39 and Short Form 36 - SF36 ). All patients undergo brain MRI in the same admission.

Instruments

Depression Assessment

Evaluation of depressive symptom severity was measured using BDI and HADS questionnaires. Beck Depression Inventory (BDI) is a self-reporting rating inventory of 21 items (Likert scale) that measure characteristics and defined symptoms of depression (Beck, 1961). We used BDI-II version (APA, 1996) and is composed of items as hopelessness, irritability, guiltiness, feeling of being punished and physical symptoms such as fatigue, lack of sexual drive and weight loss.

BDI showed to have a high internal consistency (α=.91). [25]. And a consistent and one-week test– retest reliability (Pearson r =0.93), making it not overly sensitive to daily variations in mood. [26]

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HADS is a self-reporting scale that has been found to be reliable [27] for detecting states of anxiety and depression in the setting of an hospital practice. Validated Lithuanian version of HADS-A and HADS-D subscales were used to measure anxiety and depression severity. Each HADS subscale consist of two 7 items subscales, with score in each item ranging from 0 to 3. The higher the score, the greater severity of their respective symptoms [28].

Short-form 36 Health survey questionnaire. SF-36

Evaluation of Health quality-of-life status was measured using SF-36 and PDQ-39 questionnaires. SF-36 after more than 30 years has become one of the most used and common generic Health-related quality of life questionnaires [29]. Short Form-36 consist in 10 items with a group of eight scaled scores that the patient needs to report (Self-reported). The survey is weighted and the results are considered useful to incorporate and value the information about the Physical, Social and Emotional functions [30].

Parkinson Disease Questionnaire (PDQ-39) is a self-reported questionnaire specific for Parkinson patients. On PDQ-39 we can assess the impact across 8 dimensions of daily living, the results are valued independently, fact that can help to the revision and control of evolution of different aspects of the disease [30]

This questionnaire has shown high efficacy [31] [32] helping to develop a more holistic view of patients and has been used in evaluation of the effectiveness and adequacy of diverse treatments e.g. Neurostimulation [33].

MRI acquisition

Due the nature of the present study, all the MRI scans were kindly ceded by dr A. Radziunas in order to deepen his previous article [7].

As stated on is study;

“All scans were obtained using the 1.5 T Siemens Avanto scanner. The imaging protocol included axial T2W, T1W/mpr/p2/iso and sagittal T2W/spcp2/iso sequences of the entire brain and using the following parameters: T2W: TR 4740 ms; TE 104 ms; 2.0 mm thickness; FoV 250 (192 × 256); concatenation 2, flip angle 120; T2W/spcp2/iso: TR 3200 ms; TE 376 ms; 1.0 mm thickness; FoV 260 (256 × 256); concatenation 1; T1W/mpr/p2/iso: TR 1900 ms; TE 3.35 ms; 1.0 mm thickness; FoV 260 (192 × 256); concatenation 1, flip angle 15. No hardware or software upgrades of the MRI scanner were done during the study period” (Radziunas et al., (2018) Brain MRI morphometric analysis in Parkinson´s disease patients with sleep disturbances)

Image processing and analysis

MRI scans were received in Siemens ASL DICOM format, conversion to. nii was performed by MRIConvert software (2.0.7, University of Oregon, https://lcni.uoregon.edu). Scan were processed with an Automated voxel-based segmentation and parcellation using the software Freesurfer (Linux v6.0 x86, Harvard, MA, https://surfer.nmr.mgh.harvard.edu). Primary parcellation and

segmentation were performed using default “recon-all” script. After successive corrections, 3 subjects were excluded from the posterior analysis due not successful script output. Given the results we proceed to the segmentation of the thalamus, identifying it on 25 nuclei based on the probabilistic atlas of the thalamic nuclei proposed by Iglesias, J.E. [60] and used the Freesurfer

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module that the same author offers. The atlas was assembled using manual delineation on autopsy thalamic samples and combined with brain MRI as an adaptive tetrahedral mesh. Results were further statistically analysed in order to find significant correlations.

Statistical analysis

Before deciding which test could be used, all data were checked for normality with Smirnov-Kolmogorov test. For non-normally distributed data non parametric test was used (Spearman test). IBM SPSS 25 (IBM Corp. 2017, IBM SPSS Statistics for Windows, version 25.0) software was used for data analysis. Threshold was set at p<0.5. One-way ANOVA was used for comparison of brain morphometric characteristics of PD vs healthy controls. Significant differences were adjusted for age and gender. Point biserial correlation used in dichotomous variables with significative threshold of rpb >0.8 or <-0.8

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RESULTS

Our results are based on the study of 32 PD patients, 17 males and 15 females, with a mean age of 59yr and interquartile range from 56.7yr till 64yr. They are compared with a healthy control group 17 persons, 6 males and 11 females, with mean age of 56.6yr (IQR of 50-69yr).

Healthy control

PD patients shown no significant statistical difference in the thalamic nuclei volume in comparation with the healthy control subjects. Analysis done with point biserial correlation did not arrive to a significant value (rpb greater than 0.8 or less than -0.8)

DEPRESSION

PD patients evaluated with HADS-D with positive depression symptoms had smaller thalamic nucleus volumes (PuM, VPL, PuA, Pf, CL, LP and LD) on the right and left thalamus. Left

Thalamus was statistically significant reduced (r=-0.48 with p=0.04) while right thalamus (p= 0.1) did not arrive to the significance level required to be accepted on the study (p=<0.05).

ANXIETY

Thalamus nucleus volume analysis demonstrate a strong anticorrelation on the Parkinson disease patients with anxiety symptoms evaluated with HADS-A. Decreased thalamus volume on the left thalamus (PuM, VLa, Pf, CL, LP and LD) and on the right thalamus (LP Nucleus) has been shown to be statistically significant on our study. Whole thalamus analysis showed as well a reduced

Variable Controls PD patients Total Participants 17 32

Age (years) 56.6 (IQR 50-60) 59 (IQR 56.7-64) Male/Female (number) 6/11 17/15

Table 1 Baseline demographics of the study patients and controls Age calculated by mean and noted in years

PD vs Healthy Left thalamus rpb Right Thalamus rpb

Correlation Coefficient

-0.071 0.004

Table 2 Comparison Thalamic Volume for PD patients and Controls

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volume (r=-0.48;0.02) while the right thalamus (p:0.1) did not arrive to the significance level required to be accepted on the study.

In this case, Left CM and VLA nucleus and Right CL and LD nucleus, despite shown a decrease on volume were not significant (p<0.05)

Thalamus Nucleus HAD overall score r;p

Depression r:p Anxiety r:p BDI r:p Left PuM -6.62:0.003 -0.49:0.02 -0.61:0.003 -0.43:0.04 VPL -0.48:0.02 -0.32:0.15 -0.51:0.01 -0.37:0.09 CM -0.46:0.03 -0.4:0.07 -0.4:0.06 -0.33:0.12 VLa -0.49:0.02 -0.45:0.03 -0.41:0.06 -0.4:0.06 PuA -0.54:0.01 -0.38:0.08 -0.55:0.01 -0.46:0.06 Pf -0.59:0.005 -0.59:0.004 -0.47:0.03 -0.38:0.07 CL -0.55:0.01 -0.6:0.004 -0.45:0.04 -0.5:0.01 LP -0.7:<0.001 -0.68:0.001 -0.59:0.004 -0.57:0.005 LD -0.5:0.01 -0.58:0.005 -0.47:0.03 -0.51:0.01 Whole Thalamus -0.51:0.03 -0.48:0.04 -0.48:0.02 -0.41:0.05 Right CL -0.45:0.04 -0.58:0.006 -0.25:0.2 -0.51:0.01 LP -0.57:0.007 -0.6:0.004 -0.41:0.06 -0.53:0.01 LD -0.46:0.03 -0.62:0.003 -0.26:0.2 -0.46:0.03 Whole Thalamus -0.39:0.07 -0.34:0.1 -0.36:0.1 -0.34:0.1 Table 3 Comparison of thalamic nuclei volumes with depression and anxiety symptoms

p Non parametric Spearman test. Smirnov Kolmogorov check for normality

Health-related quality of life Questionnaires

After both health-related quality of life questionnaires used on the study were filled (Parkinson specific PDQ-39 and the generic SF-36), we collect the total results on each of them and search a possible relation between the global thalamic volume using a bivariate Pearson correlation test. Our statistical analysis did not arrive to the Sig 2-tailed threshold (≤.05) needed to be accepted as a significant. For this reason, we can assume that there is no direct relation between the PDQ-39 and SF-36 questioner total scores and the thalamic volume.

Left Thalamic Volume Right Thalamic Volume

PDQ-39 p:s -0.27:0.18 -0.20:0.33

SF-36 p:s -0.39:0.37 -0.32:0.95

Table 4 Comparison of Thalamic volume with PDQ-39 and SF-36 QoL questionnaires p: Pearson correlation s: Sig. 2-tailed. Smirnov Kolmogorov check for normality

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DISCUSSION

PD pathophysiological changes on the thalamus are not fully understood till the date, and all approaches gravitate around the loss of inhibitory synaptic outputs from the Basal ganglia [34]. This low inhibitory state induces a thalamic neuron surge of action potentials, which after a certain threshold is reached will initiate Parkinson-like muscular contractions [35]. This theory is

supported by the fact that dopamine replacement therapies largely alleviate these motor circuit abnormalities. Thalamus has also been related to Lewy bodies accumulation [36].

Oppositely, morphometric analysis are not homogenous, and the subject is tackled from different angles. Many studies relate the PD with a direct thalamic atrophy or cell loss. Centre median parafascicular complex can experience a 30%-40% cell loss with non-parvalbumin containing neurons arriving up to 70% average decrease [37] producing a significant volume decline in the thalamus, [38][39], situation that its directly related with the disease progression and NMS frequency [40].

Differing from that statements, our findings did not appreciate a significant thalamic volume difference between the healthy control and PD patients in either left and right thalamus. But far from being an isolated case, results are consistent with the study led by M. McKeown where after the application of similar computer thalamic segmentation analysis, were not found any significant volumes changes and the PD morphometric changes were tied only to the shape of the thalamus. We can assume that being affected only determined nucleus (like the previously mentioned CM Perifascicular complex or the intralaminar nuclei) are not sufficient enough to lead an overall loss of the thalamic volume. Other explanations can be given to the compensatory effects of the thalamus, where contiguous loci of the thalamus can hypertrophy [41].

Anxiety and depressive symptoms are strongly associated to PD [18]. As all the emotional process, the neural network and specific modulation responsible of them are complex. But with the access of newer and more advanced neuroimaging instruments (fMRI or PET as the most prevailing)

neuroscientists had the chance to unveil this relation and try to give some clues for understanding that systems. From a neuroimaging point of view, anxiety and mood disorders are usually treated together because the circuits involved are difficult to distinguish [42]. Neuroimaging abnormalities found in patients with mood disorders shown that there are mainly 2 circuits involved. First of them is the orbital prefrontal network, located in the central orbital cortex, that connect with several sensory related cortical areas, with the main known function of anticipate reward and assessing objects [43]. The second and most related to mood disorders is the Amygdala-medial prefrontal system, that involves a wider network with other cortical areas as the temporal and posterior cingulate cortex, and some subcortical structures in ventral striatum, brainstem, hypothalamus and medial thalamus [44].

Brain morphometric influence has been widely described too, Mujeeb U. using a voxel-based morphometry method resembling to our study, demonstrate a bilateral decrease on grey matter volume in the frontal lobe and caudate nucleus and right superior and middle temporal gyri [45]. Other studies relate a significant increase in neurons in the mediodorsal and

anteroventral/anteromedial nuclei [46].

Interestingly the studies that link neuropsychiatric aspects of PD with the thalamus volume analysis (not function) are lacking. Has been observed a bilateral white matter reduction in the mediodorsal

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thalamic area, (negatively correlated with the scores of depression severity) [47] and an increased volume in mediodorsal nuclei [48].

Our data have shown a wider range of affected nuclei, not included in previous studies, some of the most significant are:

Pulvinar nuclei (PUL), is a collection of cell bodies located on the thalamus traditionally divided into four nuclei; Anterior, inferior, lateral and medial nucleus. Their lesions can induce attentional and neglect deficits [49] and affect the visual-motor behaviours [50]. Major depression has been related to increase in PUL size (due SERT-ss genotype) [51] and connectivity disorders with the insula [52]. Our study showed a decrease of volume on the left medial (-0.48;0,02) and anterior Pulvinar nucleus (-0.54;0.01) on PD Patients with Depression and Anxiety, situation that can be caused due the weakened connective loops with the insula as we mentioned on the amygdala-medial prefrontal neural network, or direct PD affectation.

Intralaminar nuclei of thalamus is a cluster of cell bodies located on the thalamus, divided in anterior and posterior group who form an extensive cortico-thalamo-cortical pathway [53]. The centromedian nucleus (CM) is the most important and commonly related on PD. Functionally related to the sensorimotor coordination, cognition, arousal and pain processing is one of the main neuromodulation therapy targets (Deep brain stimulation) in PD and other neurologic diseases [54]. New studies suggest that therapeutic treatment of tremor with DBS on CM is more effective than more classical targets like subthalamic nucleus and globus pallidus [55]. Suggested main reason of this can be the documented neurodegeneration of CM in PD [56]. Intralaminar nuclei loop

disfunctions has been directly related with neuropsychiatric states, like anxiety [57]. That argument is consistent with the results of our study, left CM shown a decrease on volume (-0.46;0.02) among the patients with Anxiety and Depression using the HAD score. Left

Parafascicular nucleus (PF) and bilateral central lateral nucleus (CL) followed the same trend (-0.55 and -0.7 respectively with r<0.05)

Ventral nuclear group is the biggest array of nuclei in the thalamus. Located ventrally include ventral anterior, ventral lateral, ventral posterior, lateral geniculate and medial geniculate nuclei. Ventral posterolateral nucleus (VPL) is an extensive lateral portion of the VP nucleus that receives information from the trunk and limbs via the spinothalamic tracts and medial lemniscus and projects to the primary somatosensory cortex. Post-mortem studies shown no direct relation with the PD disease and VPL pathology [58] and no studies can be found relating VPL and anxiety or depression. Nevertheless, our results observed a direct relation with left VPL volume loss and anxiety (-.61;0.003) or depression (-0.49;0.02) in the PD patient.

Lateral Posterior (LP) and Lateral dorsal (LD) nucleus form with PUL nuclei the lateral nuclear group. They act in concert with PUL and anterior nuclei of thalamus respectively to receive sensory input and redirect it to the limbic forebrain nuclei in order to conduct emotional and behavioural functions [59]. As with the VPL, the LD and LP are lacking of a deep functional knowledge or documented studies, and is hard to find any cited relation with depressive or anxiety disorders. Despite that, our study shown a clear direct relation between the LP and LD nuclei (bilaterally) with the depression and anxiety symptoms.

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LIMITATIONS AND STRENGTHS OF THE STUDY

Following the earlier observation, here we face one of the biggest problems of this and other similar studies, the limited knowledge we have about the thalamus. Despite having small weight (20 grams) and size (2,5cm x2cm) the functions and complexity of the thalamus are enormous. Till the point that there is not a clear or definitive division of the Thalamic nuclei, and periodically new functions are added to them.

Thus, while some of our findings have a target with an abundant background of research articles, like intralaminar nucleus volume loss, that help to originate and propitiate a proper an acceptable explanation to our results, in others loci as the LD and LP we have limited knowledge, fact that makes difficult to give a proper interpretation to our analysis outcomes.

Being more specific with our study, the limited sample size and the own nature of the

neuropsychiatric disorders are the major limitations. Depression and anxiety among them, lack of a standardised way for diagnose them, and we needed to adapt to various self-reported questionnaires in order to determine the availability for the study, will all the bias and non-homogeneity that can produce a subjective filling of the survey.

Following the same line, Freesurfer software is a community evolving and a relatively new

program, specially about his thalamic nucleus analysis modules (2018). Due that incipient situation, is expected that the histologic atlas that is based on and the program module will suffer many changes and corrections.

That incipient state of the subject and studies become the main strength of this study. There are few studies tackling the relation of depression and the thalamic changes. Especially on the background of a neurodegenerative environment of the Parkinson disease.

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CONCLUSION

1 Among any other comparable chronic disabling disease, PD patients are on the top of developing neuropsychological symptoms. Depression being the most common, affecting up to the 50% of PD patients.

2 Related changes of the thalamus in PD patients are various, and differ depending the approach taken. Most important and analysed assumption is based on the loss of inhibitory synaptic outputs from the Basal ganglia that induces a thalamic neuron surge of action potentials, which after reaching the threshold will initiate Parkinson-like muscular contractions. In relation of

neuropsychiatric symptoms on the PD patient, the Amygdala-medial prefrontal system neural network in connection with medial thalamus seems to be the key for the appearance of mood disorders.

3 In those cases, thalamus has shown to have specific morphometric changes in Intralaminar Nucleus and Lateral nuclear group (including Pulvinar nucleus) that can be assessed using neuroimaging.

4 Despite aforementioned, our study did not show a significant difference in thalamic nuclei volume when compared with healthy controls.

5 PD patients who were assessed for Depression and Anxiety shown a decrease of various Thalamic nuclei (PUL, VPL, LP, LD and intralaminar nuclei), these changes were mostly significant on left thalamus.

6 Although the reason of those changes are not always clear, this study opens the doors and tries to encourage future new analysis to overcome that lack of knowledge in order to be able to offer an affordable and non-invasive way to evaluate neuropsychiatric symptoms and give a better understanding of the PD as a whole and his related non motor symptoms.

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MULTIVOKSELINĖ MRT MORFOMETRIJA PARKINSONO LIGA SERGANTIESIEMS SU NEUROPSICHIATRINIAIS SUTRIKIMIAIS ----------------------------- MRI VOXEL BASED MORPHOMETRY IN PARKINSON´S DISEASE PATIENTS WITH NEUROPSYCHIATRIC DISORDERS