The paper has applied statistical analysis and machine learning methods to identify the biomarkers of ET and PD. Based on statistical analysis, widespread alterations have been found in ET patients and there are no gray matter differences in PD patients. While the alterations have been found for both ET and PD patients based on machine learning and the abnormal brain regions are overlapped, which is consistent with the findings in [10], and is helpful to explain the difficulties to discriminate ET and PD. However, it is notable that the abnormal brain regions of ET are broader than PD, which is consistent with [28]. From the perspective of functional imaging, it has been pointed out that ET can lead to subtle morphological changes of multiple neural networks, involving the cerebellum, brainstem, frontal lobe and thalamus [28].
Clinically, it is considered that PD and ET are two different diseases. But it is easy to misdiagnose PD as ET due to their same clinical symptoms, and some patients with ET will be transformed into PD [29]. Autopsy and pathological studies have shown that the loss of melatonin dopamine neurons and increased iron deposition in the basal ganglia have happened in PD, so PD mostly involved the abnormalities of the basal ganglia. However, due to the limited sample size, the brain markers of ET cannot be identified at present. However, radiotracer imagings have shown that patients with ET retain dopaminergic energy to a large extent, and most studies also have shown that the measurement of iron content in substantia nigra and neuromelanin in patients with ET is not significant. Therefore, dopaminergic and iron imaging has shown that there is no substantial overlap between the pathophysiology of ET and PD.
Due to non-invasive advantages of neuroimaging, researchers have carried out various studies on ET and PD based on neuroimaging to clarify the neuroimaging markers of the two diseases and explore their pathological mechanism. However, the findings based on structural images are inconsistent, and even contradicted [30], it has been pointed out that the findings of gray matter abnormalities in ET are unreliable [31]. On the one hand, T1 structural image has high image contrast in cortex and basal ganglia, while image contrast decreases due to the increase of iron content in the midbrain area for PD patients, so it is impossible to accurately detect brain abnormalities; On the other hand, it has been believed that ET is not only a simple disease, but a general term of a class of diseases with individual heterogeneity. Therefore, heterogeneity in data often leads to inconsistent findings.
Although the pathogenesis and neural mechanism of PD and ET are still not clear, a large number of studies have found that some brain regions might be related to their common symptom—tremor, and the most consistent finding is the cerebellum. Compared with the inconsistent results in traditional MRI studies, most findings based on diffusion tensor imaging (DTI) have pointed out the microstructure changes of cerebellar. As a consequence, cerebellar abnormalities have been considered as the direct cause of tremor. The cerebellar abnormalities in patients with ET and PD were both found in [9, 30], but it is still controversial whether the gray matter volume of the cerebellum increases or decreases. Although statistical analysis in the paper did not find cerebellar abnormalities in PD patients, it was found that the cerebellar gray matter of ET patients increased, which is consistent with [32], which has believed that the increase of cerebellar for gray matter in ET patients may be the compensatory result of cerebellar dysfunction. In addition, machine learning analysis in the paper found that both ET and PD patients had cerebellar abnormalities, and the larger area of cerebellum abnormalities in ET patients also partially supported the point that cerebellar abnormalities existed in ET and PD.
In order to further explore the role of the cerebellum, it has been found that missing Purkinje cells in the cerebellum for most ET patients through autopsy [33]. The possible reason is that Purkinje cells are inhibitory neurons and participate in the processes of motor control and learning. Therefore, the loss of Purkinje cells may lead to excessive activity of the cerebellum, which results in tremor. It has also been suggested that the pathological changes of locus coeruleus lead to the changes of Purkinje cells, because Lewy bodies are concentrated in locus coeruleus, and locus coeruleus are the important source of noradrenaline in the brain and has a main efferent connection with Purkinje cells in the cerebellum [33]. On the other hand, it has been pointed out that cerebellar abnormalities may be related to cognitive impairment from the perspective of neuropsychological symptoms, and this kind of abnormality may be caused by the interruption of communication pathway from cerebellum to prefrontal cortex through parietal lobe, temporal lobe and limbic system [34]. Especially through machine learning method, it was found abnormalities in CrusI for both ET and PD. It has been pointed out that most areas of CrusI are related to default mode network and control network [9], while the default mode network is responsible for emotion, self reference and projection, so patients with PD and ET will appear depression and cognitive impairment. It has also been pointed out that the cognitive decline of ET patients was faster than that of age-matched healthy subjects [35].
Based on machine learning, the paper also found that an abnormality of lobule VIII for ET, but PD did not, which is consistent with [36]. Through correlation analysis between the clinical tremor score and the gray matter volume of each region of the cerebellum, it has been found that tremor severity of ET is negatively correlated with the volume of lobule VIII [36]. Moreover, compared with PD, more extensive cerebellar regions have been found for ET, including lobules 3, 4, 5, 7, 8, 9, crusI and vermis 3. Among them, lobules 4, 5, 6 and 8 involved sensorimotor regions, which not only showed that tremor symptoms of PD and ET were related to the sensorimotor function of cerebellum, but also explained that the tremor symptoms of ET were related to a wider range of sensory dysfunction.
In the past 10 years, most studies have found abnormalities in different parts of the cerebellum in patients with ET [37, 38]. At present, it is necessary to clarify whether ET affects the whole cerebellum or only some specific areas of the cerebellum. Because the anterior part of the cerebellum is related to movement, its posterior part is related to cognition [33] . In particular, neural activation patterns between frontal lobe, cerebellum and dentate nucleus are related to executive function and language working memory [39]. It has been pointed out that ET may first affect the anterior part of the cerebellum, and then affect the posterior part of the cerebellum with the development of the disease, resulting in the defect of cognitive function [33]. However, it is unclear whether ET patients with severe cognitive impairment are accompanied by more severe abnormalities in the posterior cerebellum. However, it has been suggested that cerebellar cortical abnormalities may be potential neuroimaging markers of ET [37].
In order to explain the occurrence and duration of tremor, it has been believed that the tremor signal of ET patients originated from the cerebellum, transmitted to the relay station-thalamus, and finally reached the motor cortex of the forebrain [40]. This pathway is also known as the cerebello-thalamo-cortical pathway (CTC). Ref. [41] also has supported that the abnormality of CTC is involved in the generation and transmission of tremor. For PD, it has been suggested that the tremor in PD patients is related not only to the pathophysiological changes of the CTC motor circuit, but also to the basal ganglia [42]. While they believed that the tremor of PD patients first occurred in the basal ganglia and then spread to the CTC circuit through the motor cortex [43]. The paper based on statistical analysis found that the atrophy of bilateral thalamus and increased gray matter volume of cerebellar in ET. Meanwhile, machine learning in the paper also found that the abnormalities of bilateral thalamus in both ET and PD, which may confirm that the compensatory effect on the CTC circuit and the occurrence of tremor is related to the abnormality of the CTC circuit. Moreover, this paper also found abnormalities of basal ganglia of ET and PD (such as putamen and caudate) with machine learning, which is consistent with [12, 44]. In addition, the increase of gray matter volume of MTG in the paper is partially consistent with [10], which has proposed that the function of MTG involved motion perception and eye movement, and some ET patients have long-term head tremor, which may need to be supplemented by maintaining visual stability. As a consequence, the MTG of ET may be continuously activated, which lead to increasing gray matter volume to keep coordination and balance between head and eyes.
Recently, the tremor behavior of ET patients with gamma aminobutyric acid (GABA) hypothesis has been tried to explain [45]. GABA is a molecule produced by the brain. It mainly acts as a chemical messenger or neurotransmitter to control some activities of the brain. GABA can regulate the excessive excitation of brain nerve cells, so it is also called inhibitory neurotransmitter. In the CTC, nerve cells in the cerebellum can produce and release GABA, which are responsible for regulating and controlling movement. For ET patients, the abnormal cerebellar leads to the reduction of GABA molecules, which makes the activity of deep cerebellar neurons abnormally excited, and leads to the acceleration of the rhythm of the thalamus and its pathway and produces tremor. However, the abnormal evidence of the GABAergic neurotransmitter system in patients with ET obtained with positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) is limited.
In addition, the paper has found increased gray matter related to visual processing function, such as BA17, BA18, BA19, BA21 and BA37. It has long been suspected that the increase of visual information will lead to the severity of tremor, this hypothesis has been confirmed [46], and it has been found that increasing visual feedback may aggravate tremor. It also has been found that expect for CTC, striatum (V3/V5) and IPL are related to the severity of tremor and pointed out that ET is not only manifested as tremor, but also as a variety of non motor manifestations, including cognitive impairment, depression, anosmia and possible increased risk of falls, which is consistent with the findings of this paper [47]. More than that, the paper also found the abnormalities related to cognition, language, hearing, memory, vision, smell and spatial cognition.
Although some results have been identified in our study, it can not be denied that there are some limitations in the paper. Firstly, in the stage of model-level and feature-level assessment, we have achieved superior classification performance. However, since maybe there are limited number of samples, 100% accuracies have been obtained. Therefore, it is necessary to collect sufficient samples of PD and ET patients to verify the founds in the paper further. Secondly, we have only investigated the classification results on GM, multi-modality and multi-center data will be helpful find more meaningful and interesting results from different aspects in the future.