Brainstem Midline Assessed by Transcranial Sonography in Parkinson's Disease: Further Evidence of a Different Etiopathogenesis of Alexithymia and Depression

Objective: Parkinson's disease (PD) is often characterized by altered emotional processing, such as depression and alexithymia. Alexithymic and depressive symptoms may be partially overlapping and the relative independence of these two disorders is strongly debated. Reduced echogenicity of midbrain raphe, evaluated with transcranial sonography (TCS), is a characteristic finding in depression associated with PD. No data are available on brainstem's echogenicity in alexithymic PD patients. We assessed, by means of transcranial sonography, possible differences between PD patient with or without alexithymia and/or depression. Methods: We recruited 22 PD patients among our local cohort of 200 patients referred to our Movement Disorder Center during 2014. All patients were treated with optimal dose of dopaminomimetic (L-DOPA EQ mg 499.7 ± 256.3) and underwent neuropsychological tests including Beck Depression Inventory (BDI) and Toronto Alexithymia Scale-20 (TAS-20). Motor symptoms were assessed with Unified Parkinson's Disease Rating Scale (UPDRS III) and modified Hoehn and Yahr scale (H&Y). TCS was performed, through temporal window, using a color-coded phasedarray ultrasound system (SONOS 7500), to evaluate midbrain raphe (0=absent, 1=discontinuous, 2=continuous). Results: TAS-20 and BDI identified 4 patients with depression without alexithymic symptoms (18.18%), 7 alexithymic patients without depression (31.82%), 5 PD patients with depression and alexithymia (22.73%) and 6 PD patients without any of the two disorders (27.27%). At statistical analysis hypoechogenicity correlated with BDI score and the presence of alexithymia was not significantly correlated with absent or discontinuous raphe. Conclusion: The study evidenced the presence of hypoechogenicity in the midbrain raphe in PD patient with depression. No alteration of midbrain raphe was found in PD patients with alexithymia. These findings suggest that while depression in PD may involve central component of brainstem midline, constituting the basal limbic system, called mesocorticolimbic pathway, alteration in alexithymia does not affect the midbrain. This study provides further evidence that depression and alexithymia are independent affective disorder.


Introduction
Parkinson's disease (PD) is often characterized by altered emotional processing. Depression occurs with a prevalence of 30-35% in medicated PD patients and alexithymia with a prevalence of 21% in PD patients [1,2]. Salient features of alexithymia are the inability to distinguish one's feelings from the associated bodily sensations with a tendency to amplify the somatic sensations accompanying emotional arousal, the inability to communicate feelings to others and an externally oriented cognitive style, reflecting reduced inner thoughts and fantasies [3].
Alexithymic and depressive symptoms may be partially overlapping and the relative independence of the two disorders is strongly debated [2][3][4][5]. Previous studies show that alexithymic features may be relevant in PD patients and may be associated with the severity of depression [2], but depressive symptoms do not completely explain the difficulty in describing and communicating emotions in this group of patients.
Both depression and alexithymia seem to find their pathophysiological correlate in limbic system dysfunction.
Depression has been associated to morphological alterations of the midbrain raphe [6,7].
A tool to assess the anatomy of the midbrain raphe is transcranial sonography (TCS). This allows a 2D visualization of brain parenchyma [6].
In the present study, we aimed to disentangle the possible pathogenetic background of alexithymia and depression, by evaluating, by means of TCS, a group of PD patients with depression in comparison with a group of PD patients with alexithymia and with a group of PD patients without any of the two symptoms.

Materials and Methods
We recruited 22 consecutive PD patients, among a local cohort of 200 patients referred to our institution during 2014. All patients gave their written informed consent to participate and fulfilled research diagnostic criteria for idiopathic PD (UK Brain Bank Criteria [11]).
All the patients were treated with optimal dose of dopaminomimetics. The global cognitive status was assessed with the Mini-Mental State Examination (MMSE). The presence and severity of depression was assessed by Beck Depression Inventory (BDI) which classifies depressive symptoms as mild mood disturbance (score from 11 to 16), borderline clinical depression (score [17][18][19][20], moderate depression (score 21-30), severe depression (score 31-40), extreme depression (score over 40).
TCS was performed by an experienced and certified ultrasound physician (RDG) using a color-coded phased-array ultrasound system (SONOS 7500). Patient lied in supine position; the ultrasound probe was pressed on the temporal window, at the temporal squama before the ear as recommended else-where [15]. Axial plane on orbitomeatal line was assessed to evaluate midbrain raphe [16]. A dynamic range of 45 dB, image brightness and time-gain compensation were adapted as needed for each examination. Echogenicity of the brainstem midline was rated in comparison with the echogenicity of the tectum of the mesencephalus and classified as grade 0=absent, 1=discontinuous, 2=continuous [8,15] ( Figure 1A example of absent raphe, Figure 1B example of continuous raphe). Grade 0 and grade 1 are classified as hypoechogenic. Continuous echogenicity of the raphe is the normal finding in the general population [8][9][10]. Neuropsychological tests and TCS were performed and analysed in different settings and by examiners blind to diagnosis of depression/alexithymia.

Results
Demographic, clinical and pharmacological findings, neuropsychological and TCS results are reported in Table 1 and compared in Table 2.

PD (n=6) PD-D (n=4) PD-A (n=7) PD-DA (n=5) p-value b f-value
Age (Mean ± SD) 63. 17    Three PD-D and 5 PD-DA patients showed the presence of hypoechogenicity in the midbrain raphe: hypoechogenicity correlated with BDI score (Pearson's Correlation: t=-3.9103, df=20, p<0.001). Among 7 PD-A patient's only one showed discontinuous raphe and no one showed absent raphe. At statistical analysis, the presence of alexithymia was not significantly correlated with absent or discontinuous raphe (Pearson's Correlation: t=-0.67542, df=20, p=0.507). Two patients of 6 PD patients without depression or alexithymia had absent raphe, one of these showed BDI score equal to 10 and clinical features of depression.
Among demographic characteristics, only disease duration was different between PD-D and PD-A groups. This finding should not affect our observation, because age, disease severity (mH&Y, LED) and clinical features (UPDRS) of the patients were no different. In addition, echogenicity of midbrain structures seems to remain constant over time [17].

Discussion and Conclusion
In the present study, we found a different TCS pattern in PD patients with depression as compared to PD patients with Alexithymia.
We confirmed the presence of hypoechogenicity in the midbrain raphe in PD patient with depression. This alteration may be due to a distinct disruption of fibre tracts and raphe nuclei of the brainstem in depressed patients, as highlighted by neuropathological [18] and MRI findings [6].
In contrast, no alterations of midbrain raphe were found in alexithymic PD patients.
Previous research has generated controversy as to whether alexithymia and depression are distinct or overlapping constructs [4,19,20]. The disentanglement of the two disorders is important because alexithymic patients do not seem to respond satisfactorily to antidepressants and should be directed to psychotherapies involving specific techniques to enhance emotional awareness and integrate symbolic and subsymbolic elements of emotion schemas [21,22]. On the other hand, patients with hypoechogenic raphe seem to respond better to selective serotonin reuptake inhibitor (SSRI) therapy than those with normal echogenicity [23].
Our findings confirmed that depression and alexithymia in PD may recognize different mechanisms. Depression seems to involve central component of brainstem midline, constituting the mesocorticolimbic pathway and involving, mainly, serotoninergic system. On the other hand, the presence of alexithymia is not associated with midbrain alterations. This latter result found a significant positive confirmation in several studies, which showed that alexithymia may involve mainly cortical dysfunctions [24][25][26]. In a recent work evaluating the default mode network (DMN) in alexithymic patients, a higher connectivity was found within right prefrontal and sensory areas. These areas have been associated with emotion suppression and a more action-oriented behavior. Furthermore, the alexithymic group showed reduced connectivity within the frontal areas of the DMN, which could be related to the reduced emotional awareness of alexithymic patients [27].
Furthermore, we note that depressed mood occurs with a prevalence of 40% and alexithymic symptoms were present with a prevalence of 54.55% in our sample. These values were higher than reported in the literature [1,2]. This can be due to the small sample size or to the fact that, at difference with previous reports [2], we included, in the prevalence evaluation, also slightly symptomatic patients (borderline alexithymic patients and mild depressed mood).
The main limitations of our study are the small sample size of patients tested and the semi-quantitative analysis of signal intensity. Moreover, despite we are supported by the abundant literature about consistency of TCS technique [6][7][8]28], the reliability of this technique is dependent on the quality of the ultrasonography system and on the qualification of the investigator.
In conclusion, the brainstem midline echogenicity would be highly interesting to perform in the future to disentangle these two disorders and, toward this aim, study on non-parkinsonian subjects with and without alexithymia is advisable.