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![(A) The locus coeruleus (LC) and its related structure, a major cortical glutamatergic afferent from orbitofrontal cortex (OFC) [a], may play a role in the pathogenesis of ET through the coerulo-cerebellar pathway [b]. (B) The cerebello–thalamo–cortical loop [c] is also an important pathway implicated in ET. These two distinct structures are consistent with heterogeneous neuropathologies (Changes in the brainstem and cerebellum, respectively) demonstrated in previous postmortem studies. Beta blockers seem to act centrally via Renshaw cells [d], and the LC is a strong candidate for mediating the beta-adrenergic effects to this pathway.](profile/Jin-Hong-19/publication/259396327/figure/fig3/AS:213416699535365@1427893914949/A-The-locus-coeruleus-LC-and-its-related-structure-a-major-cortical-glutamatergic.png)
(A) The locus coeruleus (LC) and its related structure, a major cortical glutamatergic afferent from orbitofrontal cortex (OFC) [a], may play a role in the pathogenesis of ET through the coerulo-cerebellar pathway [b]. (B) The cerebello–thalamo–cortical loop [c] is also an important pathway implicated in ET. These two distinct structures are consistent with heterogeneous neuropathologies (Changes in the brainstem and cerebellum, respectively) demonstrated in previous postmortem studies. Beta blockers seem to act centrally via Renshaw cells [d], and the LC is a strong candidate for mediating the beta-adrenergic effects to this pathway.
Source publication
Recent studies have suggested that essential tremor (ET) is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM) changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying th...
Similar publications
Essential tremor (ET) is one of the most prevalent movement disorders. Being that it is a common disorder, its diagnosis is considered routine. However, misdiagnoses may occur regularly. Over the past decade, several studies have identified brain morphometric changes in ET, but these changes remain poorly understood. Here, we tested the informative...
Citations
... These abnormalities could be a logical functional consequence of cerebellar pathology, or alternatively reflect a wider structural degenerative process beyond the cerebellum. Thus far, the cortical changes in ET and their association with cerebellar degeneration are not well characterized in neuroimaging studies and lacks consensus 11,[24][25][26][27][28][29] . In addition to possible decreases in volume, some studies even suggest an increase in gray matter in the supplementary motor area of ET patients based on a VBM analysis 30 . ...
Essential tremor (ET) is the most prevalent movement disorder with poorly understood etiology. Some neuroimaging studies report cerebellar involvement whereas others do not. This discrepancy may stem from underpowered studies, differences in statistical modeling or variation in magnetic resonance imaging (MRI) acquisition and processing. To resolve this, we investigated the cerebellar structural differences using a local advanced ET dataset augmented by matched controls from PPMI and ADNI. We tested the hypothesis of cerebellar involvement using three neuroimaging biomarkers: VBM, gray/white matter volumetry and lobular volumetry. Furthermore, we assessed the impacts of statistical models and segmentation pipelines on results. Results indicate that the detected cerebellar structural changes vary with methodology. Significant reduction of right cerebellar gray matter and increase of the left cerebellar white matter were the only two biomarkers consistently identified by multiple methods. Results also show substantial volumetric overestimation from SUIT-based segmentation—partially explaining previous literature discrepancies. This study suggests that current estimation of cerebellar involvement in ET may be overemphasized in MRI studies and highlights the importance of methods sensitivity analysis on results interpretation. ET datasets with large sample size and replication studies are required to improve our understanding of regional specificity of cerebellum involvement in ET.
Protocol registration
The stage 1 protocol for this Registered Report was accepted in principle on 21 March 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.6084/m9.figshare.19697776.
... It is a common observation in clinical trials that responsiveness to medication is not uniform across patients and that there tend to be responders and non-responders and that the proportion of the latter is sizable (80). Several studies have shown that patients with specific phenotypic, electrophysiologic, or neuroimaging features respond more favorably to propranolol (74,81). ...
... In ET, current knowledge of genetic causes and pathophysiology are quite rudimentary, making it difficult at this juncture to define etiological-pathophysiological-clinical entities (i.e., "diseases") that exist within "the essential tremors, " but it is only a matter of time before such links are observed. Preliminary work suggest that certain anatomic features of ET are linkable to pharmacological response phenotype, for example (81), and that certain clinical features (i.e., older onset) are associated with more degenerative pathology in ET (90). ...
The past 10 years has seen a remarkable advance in our understanding of the disease traditionally referred to as “essential tremor” (ET). First, the clinical phenotype of ET has been expanded from that of a bland, unidimensional, and monosymptomatic entity to one with a host of heterogeneous features. These features include a broader and more nuanced collection of tremors, non-tremor motor features (e.g., gait abnormalities) and a range of non-motor features, including cognitive, psychiatric, sleep, and other abnormalities. The natural history of these features, as well as their relationships with one another and with disease duration and severity, are better appreciated than they were previously. Studies of disease etiology have identified a number of candidate genes as well as explored several environmental determinants of disease. In addition, the decade has seen the beginnings and expansion of rigorous postmortem studies that have identified and described the postmortem changes in the brains of patients with ET. This emerging science has given rise to a new notion that the disease, in many cases, is one of cerebellar system degeneration. Across all of these studies (clinical, etiological, and pathophysiological) is the observation that there is heterogeneity across patients and that “essential tremor” is likely not a single disease but, rather, a family of diseases. The time has come to use the more appropriate terminology, “the essential tremors,” to fully describe and encapsulate what is now apparent. In this paper, the author will review the clinical, etiological, and pathophysiological findings, referred to above, and make the argument that the terminology should evolve to reflect advances in science and that “the essential tremors” is a more scientifically appropriate term.
... These changes include increased heterogenicity of axon FA (myelination) with preserved tract density (fiber number) which results in decreased synchrony of impulses transduction. These results are passing with that of Chung and colleagues, 2013 [23] who identified that ET induces heterogeneous cortical thinning and white matter alteration with a resultant alteration in the rate of disease progression as well as clinical response to propranolol. ...
Background
Essential tremor (ET) is now considered as a slowly progressive neurodegenerative disorder with a variety of motor and non-motor manifestations. The objectives of this work were to study the existence of cognitive, mood, olfactory, and balance dysfunctions in ET patients and their relation to tremor severity as well as patients’ activity of daily livings.
Methods
This study was performed on 36 ET patients and 24 healthy controls subjects (HCS) submitted to The Essential Tremor Rating Assessment Scale (TETRAS), advanced activity of daily living scale (AADLs), Montreal cognitive assessment scale (MoCA), Montgomery–Åsberg Depression Rating Scale (MADRS), auditory mismatch negativity (MMN), Sniffin’ Sticks test (SST), computerized dynamic posturography (CDP), and brain MRI diffusion tensor tractography (DTT).
Results
ET patients showed significant decrease in AADLs, MoCA, SST (threshold, identification, and discrimination subscales) as well as visual and vestibular ratios of CDP compared to HCS. Auditory MMN showed significant reduction in the amplitude and prolongation of latencies while corticospinal tracts, thalamo-cortical connectivity, and middle cerebellar peduncles DTT revealed reduced fractional anisotropy in ET patients with normal tracts densities.
Conclusion
ET patients exhibit a wide variety of non-motor manifestations including cognitive impairment, depressive symptoms, hyposmia, and increased risk of falls with consecutive reduced activity of daily living beyond the deleterious effects of the kinetic tremor.
... These changes include increased heterogenicity of axon FA (myelination) with preserved tract density (fiber number) which results in decreased synchrony of impulses transduction. These results are passing with that of Chung and colleagues, 2013 [23] who identified that ET induces heterogeneous cortical thinning and white matter alteration with a resultant alteration in the rate of disease progression as well as clinical response to propranolol. ...
Background: Essential tremor (ET) is now considered as a slowly progressive neurodegenerative disorder with a variety of motor and non-motor manifestations. The objectives of this work were to study the existence of cognitive, mood, olfactory and balance dysfunctions in ET patients and their relation to tremor severity as well as patients’ activity of daily livings. Methods: This study was performed on 36 ET patients and 24 healthy controls subjects (HCS) submitted to The Essential Tremor Rating Assessment Scale (TETRAS), advanced activity of daily living scale (AADLs), Montreal cognitive assessment scale (MoCA), Montgomery–Åsberg Depression Rating Scale (MADRS), auditory mismatch negativity (MMN), Sniffin’ Sticks test (SST), computerized dynamic posturography (CDP) and brain MRI diffusion tensor tractography (DTT). Results: ET patients showed significant decrease in AADLs, MoCA, SST (threshold, identification and discrimination subscales) as well as visual and vestibular ratios of CDP compared to HCS. Auditory MMN showed significant reduction in the amplitude and prolongation of latencies while Corticospinal tracts, thalamo-cortical connectivity and middle cerebellar peduncles DTT revealed reduced fractional anisotropy in ET patients with normal tracts densities. Conclusion: ET patients exhibit a wide variety of non-motor manifestations including cognitive impairment, depressive symptoms, hyposmia and increased risk of falls with consecutive reduced activity of daily living beyond the deleterious effects of the kinetic tremor.
... Corticothalamic feedback neurons reside in cortical layer 6 and give rise to axons that terminate both in the thalamus and in the layers of the cortex receiving thalamic input (Sherman, 2005;Wearden et al., 2006). Recently, several studies have suggested that cortical thickness could be used as an ET diagnosis with a high accuracy ( Chung et al., 2013;Cerasa et al., 2014;Serrano et al., 2017;Benito- León et al., 2019), which may partly reflect a decrease in the amount of corticothalamic connections. In the study of connectivity for the cerebello-thalamo-cortical network in humans, when tremor is severed, M1 has reduced cerebellar functional connectivity, whereas the thalamus has increased cerebellar functional connectivity ( Lenka et al., 2017). ...
Although deep brain stimulation (DBS) is a clinically effective surgical treatment for essential tremor (ET), and its neurophysiological mechanisms are not fully understood. As the motor thalamus is the most popular DBS target for ET, and it is known that the thalamic nucleus plays a key role in relaying information about the external environment to the cerebral cortex, it is important to investigate mechanisms of thalamic DBS in the context of the cerebello-thalamo-cortical neuronal network. To examine this, we measured single-unit neuronal activities in the resting state in M1 during VL thalamic DBS in harmaline-induced tremor rats and analyzed neuronal activity patterns in the thalamo-cortical circuit. Four activity patterns – including oscillatory burst, oscillatory non-burst, irregular burst, and irregular non-burst – were identified by harmaline administration; and those firing patterns were differentially affected by VL thalamic DBS, which seems to drive pathologic cortical signals to signals in normal status. As specific neuronal firing patterns like oscillation or burst are considered important for information processing, our results suggest that VL thalamic DBS may modify pathophysiologic relay information rather than simply inhibit the information transmission.
... MRI scans were acquired using a Philips 3.0 T scanner (Philips Achieva; Philips Medical Systems, Best, The Netherlands) with a SENSE head coil (SENSE factor = 2) as described in our previous work (Baik et al., 2014;Chung et al., 2013;Sunwoo et al., 2015). The highresolution axial T1-weighted MRI data were obtained using a 3D T1-TFE sequence with the following parameters: 224 × 224 axial acquisition matrix; 256 × 256 reconstructed matrix with 170 slices; voxel size, 0.859 × 0.859 × 1 mm 3 ; field of view, 220 mm; echo time, 4.6 ms; repetition time, and 9.8 ms; flip angle, 8 . ...
This study aimed to investigate the cortical neural correlates of dementia conversion in Parkinson's disease with mild cognitive impairment (PD‐MCI). We classified 112 patients with drug‐naïve early stage PD meeting criteria for PD‐MCI into either PD with dementia (PDD) converters (n = 34) or nonconverters (n = 78), depending on whether they developed dementia within 4 years of PD diagnosis. Cortical thickness analyses were performed in 34 PDD converters and 34 matched nonconverters. Additionally, a linear discriminant analysis was performed to distinguish PDD converters from nonconverters using cortical thickness of the regions that differed between the two groups. The PDD converters had higher frequencies of multiple domain MCI and amnestic MCI with storage failure, and poorer cognitive performances on frontal/executive, memory, and language function domains than did the nonconverters. Cortical thinning extending from the posterior cortical area into the frontal region was observed in PDD converters relative to nonconverters. The discriminant analysis showed that the prediction model with two cortical thickness variables in the right medial superior frontal and left olfactory cortices optimally distinguished PDD converters from nonconverters. Our data suggest that cortical thinning in the frontal areas including the olfactory cortex is a marker for early dementia conversion in PD‐MCI.
... Only three studies have assessed the pattern of cortical thickness in ET. [6][7][8] Chung et al. 6 studied the pattern of cortical thickness in 18 ET patients who had responded to propranolol and 14 who had not. The non-responder group had more severe thinning in the left orbitofrontal cortex and right temporal cortex. ...
... Only three studies have assessed the pattern of cortical thickness in ET. [6][7][8] Chung et al. 6 studied the pattern of cortical thickness in 18 ET patients who had responded to propranolol and 14 who had not. The non-responder group had more severe thinning in the left orbitofrontal cortex and right temporal cortex. ...
... The non-responder group had more severe thinning in the left orbitofrontal cortex and right temporal cortex. 6 In a voxel-based morphometry and cortical thickness study involving 14 ET patients, 12 dystonia patients, and 23 age-and sexmatched healthy control subjects, Cerasa et al. 7 reported subtle thinning of the anterior cerebellar cortex in the ET patients. Serrano et al., 8 tested the informativeness of measuring cortical thickness for the purposes of ET diagnosis, applying feature selection and machine learning methods to study a sample of 18 patients with ET and 18 age-and sex-matched healthy control subjects. ...
Objective
Although the cerebello‐thalamo‐cortical network has often been suggested to be of importance in the pathogenesis of essential tremor (ET), the origins of tremorgenic activity in this disease are not fully understood. We used a combination of cortical thickness imaging and neurophysiological studies to analyze whether the severity of tremor was associated with anatomical changes in the brain in ET patients.
Methods
Magnetic resonance imaging (MRI) and a neurophysiological assessment were performed in 13 nondemented ET patients. High field structural brain MRI images acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Cortical reconstruction and volumetric segmentation was performed with the FreeSurfer image analysis software. We used high‐density surface electromyography (hdEMG) and inertial measurement units (IMUs) to quantify the tremor severity in upper extrimities of patients. In particular, advanced computer tool was used to reliably identify discharge patterns of individual motor units from surface hdEMG and quantify motor unit synchronization.
Results
We found significant association between increased motor unit synchronization (i.e., more severe tremor) and cortical changes (i.e., atrophy) in widespread cerebral cortical areas, including the left medial orbitofrontal cortex, left isthmus of the cingulate gyrus, right paracentral lobule, right lingual gyrus, as well as reduced left supramarginal gyrus (inferior parietal cortex), right isthmus of the cingulate gyrus, left thalamus, and left amygdala volumes.
Interpretation
Given that most of these brain areas are involved in controlling movement sequencing, ET tremor could be the result of an involuntary activation of a program of motor behavior used in the genesis of voluntary repetitive movements.
... На 32 больных с ЭТ (группа 1 -18 человек, реагирующих на пропранолол, и группа 2 -14 человек, которые не реагировали на пропранолол) было показано, что пациенты второй группы имели более выраженную атрофию коры левой орбитофронтальной и правой височной областей. Однако у пациентов, реагирующих на пропранолол, выявлено более выраженное истончение коры в лобных областях, мозолистом теле и белом веществе правой теменной области [10]. ...
Introduction. Essential tremor (ET) is one of the most common movement disorders. It is mainly characterized by postural and kinetic tremor, affecting arms and other body parts. Progression of ET violates social activity, lowers self-esteem, and occasionally leads to the patient’s disability. Selection of an effective drug therapy for ET is mostly carried out empirically and takes long time, which causes additional negative psycho-emotional effects, distrust of the doctor and abandonment of the treatment. Present study is aimed at the implementing a novel approach to the segregation of ET subtypes based on the heterogeneity of the pharmacological response. Results. Neuroanatomical, electrophysiological and biochemical data published to date are outlined in the current paper, to designate parameters for identification of ET subtypes with deterministic pharmacological response. Before prescribing pharmacotherapy for patients with ET, it is necessary to perform asurface electromyography to identify the patterntype of antagonist muscles contractions. In addition, the concentration of glutamate and gamma-aminobutyric acid in peripheral blood should be determined. Conclusion. The heterogeneity of pharmacological response among patients with ET necessitates a more subtle classification within the syndrome by neuroanatomical, electrophysiological and biochemical indicators. The approach proposed in the review will increase the effectiveness of therapy and improve the lifequality of patients with ET. (For citation: Muruzheva ZM, Karpenko MN, Klimenko VM. The heterogeneity of drug response as the basis of identificationof essential tremor subtypes. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(1):54-59. doi: 10.17816/RCF16154-59).
... Janicki and colleagues [18] found significant correlation between cognitive decline and patients' age probably due to inclusion of late onset ET patients. Chung and colleagues [19] agreed with that cognitive decline is more common among non-propranolol responders. ...
Background: Essential tremor (ET) is no longer considered as tremor genic mono symptomatic movement disorder but it has several non-motor manifestations including cognitive dysfunctions. Objectives: to study the cognitive abnormalities in ET patients and their relation to the tremor severity. Methods: This study was performed on 30 ET patients and 15 healthy controls subjected to history taking, neurological examinations with tremor severity assessment using The Essential Tremor Rating Assessment Scale (TETRAS). They were also submitted to the Montreal Cognitive Assessment Scale (MoCA), Stroop Color Word Test, subtest of Wechsler Adult Intelligence Scale IV (WAIS-IV), Wisconsin Card Sorting Test (WCST), brain MRI volumetry and event related potential mismatch negativity (MMN). Results: the neuropsychological tests revealed significant impairment in the global cognitive evaluation, executive functions, attention and working memory of ET patients. Brain MRI volumetry showed significant reduction in cerebellar cortical and white matter volumes, thalamic volume and total white matter volume. Patients also had either absent or diminished amplitude and delayed MMN. Conclusion: Cognitive impairment is a common underdiagnosed ET manifestation affecting patients' socio–occupational career and should be respected in the management plan.
... Specifically, an assessment of cortical thickness provides a directly interpretable metric, allows for detection of sub-voxel changes 19 while being less sensitive to inaccuracies of spatial normalization and smoothing 20 , and has been well validated 21 . Only two studies have assessed the pattern of cortical thickness in ET 22,23 . Chung et al. 22 analyzed the pattern of cortical thickness in 18 ET patients who had responded to propranolol and 14 who had not. ...
... Only two studies have assessed the pattern of cortical thickness in ET 22,23 . Chung et al. 22 analyzed the pattern of cortical thickness in 18 ET patients who had responded to propranolol and 14 who had not. Relative to responders, the non-responder group had more severe atrophy in the left orbitofrontal cortex and right temporal cortex 22 . ...
... Chung et al. 22 analyzed the pattern of cortical thickness in 18 ET patients who had responded to propranolol and 14 who had not. Relative to responders, the non-responder group had more severe atrophy in the left orbitofrontal cortex and right temporal cortex 22 . In a voxel-based morphometry and cortical thickness study involving 14 ET patients, 12 dystonia patients, and 23 age-and sex-matched healthy control subjects, Cerasa et al. 23 reported subtle atrophy of the anterior cerebellar cortex in the ET patients. ...
Essential tremor (ET) is one of the most prevalent movement disorders. Being that it is a common disorder, its diagnosis is considered routine. However, misdiagnoses may occur regularly. Over the past decade, several studies have identified brain morphometric changes in ET, but these changes remain poorly understood. Here, we tested the informativeness of measuring cortical thickness for the purposes of ET diagnosis, applying feature selection and machine learning methods to a study sample of 18 patients with ET and 18 age- and sex-matched healthy control subjects. We found that cortical thickness features alone distinguished the two, ET from controls, with 81% diagnostic accuracy. More specifically, roughness (i.e., the standard deviation of cortical thickness) of the right inferior parietal and right fusiform areas was shown to play a key role in ET characterization. Moreover, these features allowed us to identify subgroups of ET patients as well as healthy subjects at risk for ET. Since treatment of tremors is disease specific, accurate and early diagnosis plays an important role in tremor management. Supporting the clinical diagnosis with novel computer approaches based on the objective evaluation of neuroimage data, like the one presented here, may represent a significant step in this direction.
