Associations Among Tremor Amplitude, Activities of Daily Living, and Quality of Life in Patients with Essential Tremor.

Background: Essential tremor (ET) is a disabling syndrome consisting of tremor, primarily in the upper limbs. We assessed the correlation of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Item 4 ratings of upper limb tremor with the TETRAS activities of daily living (ADL) subscale and with 2 quality of life (QoL) scales. Methods: This noninterventional, cross-sectional, point-in-time survey of neurologists(n = 60), primary care physicians (n = 38), and their patients with ET (n = 1,003) used real-world data collected through the Adelphi ET Disease Specific Programme™. Physician-reported measures (TETRAS Performance Item 4 and TETRAS ADL total) and patient-reported QoL measures (generic EuroQol-5 Dimension 5 Level [EQ-5D-5 L] and ET-specific Quality of Life in Essential Tremor Questionnaire (QUEST)) were assessed with bivariate and multivariable analyses. Sensitivity analyses were also conducted. Results: The bivariate association between TETRAS Performance Item 4 score and TETRAS ADL total score was high (Pearson r = 0.761, P < 0.001). The bivariate associations between TETRAS Performance Item 4 score and EQ-5D-5 L index score (r = -0.410, P < 0.001) and between TETRAS ADL total score and EQ-5D-5 L index score (r = -0.543, P < 0.001) were moderate. The bivariate associations between TETRAS Performance Item 4 score and QUEST total score (r = 0.457, P < 0.001), and between TETRAS ADL total score and QUEST total score (r = 0.630, P < 0.001) were also moderate. These associations were unaltered by the inclusion of covariates. Discussion: This study showed that greater tremor severity (TETRAS Performance Item 4) was positively correlated with ADL impairment (TETRAS ADL) and negatively associated with QoL (EQ-5D-5 L and QUEST). TETRAS Performance Item 4 score is a robust predictor of TETRAS ADL total score, and TETRAS Performance Item 4 and TETRAS ADL total scores were robust predictors of the 2 QoL scales. The results demonstrate the value of TETRAS scores as valid endpoints for future clinical trials. Highlights: This real-world study assessed TETRAS scores as predictors of impaired QoL in ET. TETRAS Performance Item 4 and ADL were associated with EQ-5D-5 L and QUEST. TETRAS scores may serve as valid endpoints for future clinical trials.

Validation of a New Patient-Reported Outcome Measure of the Functional Impact of Essential Tremor on Activities of Daily Living.

Background: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Objective: Develop and validate a TETRAS PRO subscale. Methods: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. Results: TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). Conclusions: TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.

Sleep problems as predictors of cognitive decline in essential tremor: A prospective longitudinal cohort study.

BACKGROUND: There is growing evidence that essential tremor (ET) patients are at high risk of cognitive impairment. Predictors of cognitive impairment have not been studied extensively. There is evidence from cross-sectional studies that sleep dysregulation is associated with cognitive dysfunction in ET, but longitudinal studies of the impact of sleep disruption on cognitive change have not been conducted. We investigated the extent to which sleep problems predict cognitive change in patients with ET. METHODS: ET cases enrolled in a prospective, longitudinal study of cognitive performance. Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Cognitive abilities across five domains (memory, executive function, attention, language, and visuospatial ability), and a global cognitive score (mean of the domains) were extracted from an extensive neuropsychological assessment. Generalized estimated equations were used to examine the association between baseline sleep problems and cognitive changes over three follow-up assessments each spaced 18 months apart. RESULTS: The 188 non-demented ET cases had a mean age of 77.7 ± 9.5 years. Longer sleep latency was associated with longitudinal decline in executive function (p = 0.038), and marginally with longitudinal decline in global cognitive performance (p = 0.075). After excluding 29 cases with mild cognitive impairment, results were similar. CONCLUSION: Cognitively healthy people with ET who have longer sleep latency had greater declines in executive function during prospective follow-up. Early detection of, and possibly intervention for, abnormal sleep latency may protect against certain aspects of cognitive decline in ET patients.

"Benign" tremor? A serial case report of 2.5 year progression from mild cognitive impairment to amnestic dementia following deep brain stimulator placement for essential tremor.

Essential tremor (ET) is a prevalent neurological disorder with associated neuropsychological sequalae. Although cognitive deficits associated with ET are traditionally conceptualized as attention, processing speed, and executive impairments attributed to underlying frontal-subcortical dysfunction, emerging literature highlights the elevated frequency of progressive amnestic memory impairments in patients with ET. This case study centers around a 75-year-old woman with a 15-year history of ET who underwent deep brain stimulation (DBS) as well as three neuropsychological evaluations, one pre-surgically and two post-surgically at one and two-years post successful DBS surgery. Neuropsychological evaluation results revealed circumscribed mild and variable memory deficits pre-surgically and one-year post-surgically, However, two-years post-DBS, reliable change indices revealed significant declines in verbal/visual memory, consistent with an amnestic presentation, in addition to executive functions, aspects of higher-level language abilities, and overall IQ. This case study adds to a growing literature identifying a subset of ET patients with a neurodegenerative cognitive trajectory characterized by progressive, amnestic memory impairment. The case also highlights the importance of serial monitoring of cognition beyond the pre-surgical DBS workup to monitor for clinically significant decline(s).

Neuropsychological outcomes after thalamic deep brain stimulation for essential tremor.

INTRODUCTION: Non-motor DBS outcomes have received little attention in ET relative to PD. This study examines neuropsychological outcomes in ET following thalamic VIM DBS. METHODS: Fifty patients completed neuropsychological evaluations preoperatively and approximately seven months postoperatively. Cognition and mood changes were analyzed at the group level and individual level. Additional associations with treatment, disease, and demographic characteristics were assessed. RESULTS: Significant cognitive decline was not observed at the group level. At the individual level, 46% of patients demonstrated at least subtle overall cognitive decline (≥1SD on at least one test within at least two domains). Mild decline (≥1SD) was seen in 10%-29.17% of patients on individual tests across all cognitive domains, with highest rates in verbal memory. Substantial cognitive decline (≥2SD) occurred in less than 9% of the sample across all tests. Factors related to cognitive decline included higher DBS parameter settings, older age of ET onset, intracranial complications, and inability to reduce ET medications postoperatively. Depression and anxiety did not change when accounting for questionnaire items that could be falsely elevated by tremor. CONCLUSION: Substantial cognitive decline after VIM DBS is rare in patients with ET. However, subtle decrements can occur across cognitive domains and particularly in verbal memory. DBS parameter settings may relate to cognitive decline. Further research is needed to better understand possible associations with electrode lateralization and other variables that could also relate to disease progression and test-retest effects. Symptoms of depression and anxiety remain stable.

Altered local and matrix functional connectivity in depressed essential tremor patients.

BACKGROUND: Depression in essential tremor (ET) has been constantly studied and reported, while the associated brain activity changes remain unclear. Recently, regional homogeneity (ReHo), a voxel-wise local functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging, has provided a promising way to observe spontaneous brain activity. METHODS: Local FC analyses were performed in forty-one depressed ET patients, 49 non-depressed ET patients and 43 healthy controls (HCs), and then matrix FC and clinical depression severity correlation analyses were further performed to reveal spontaneous neural activity changes in depressed ET patients. RESULTS: Compared with the non-depressed ET patients, the depressed ET patients showed decreased ReHo in the bilateral cerebellum lobules IX, and increased ReHo in the bilateral anterior cingulate cortices and middle prefrontal cortices. Twenty-five significant changes of ReHo clusters were observed in the depressed ET patients compared with the HCs, and matrix FC analysis further revealed that inter-ROI FC differences were also observed in the frontal-cerebellar-anterior cingulate cortex pathway. Correlation analyses showed that clinical depression severity was positively correlated with the inter-ROI FC values between the anterior cingulate cortex and bilateral middle prefrontal cortices and was negatively correlated with the inter-ROI FC values of the anterior cingulate cortex and bilateral cerebellum lobules IX. CONCLUSION: Our findings revealed local and inter-ROI FC differences in frontal-cerebellar-anterior cingulate cortex circuits in depressed ET patients, and among these regions, the cerebellum lobules IX, middle prefrontal cortices and anterior cingulate cortices could function as pathogenic structures underlying depression in ET patients.

Botulinum Toxin Monotherapy for the Treatment of Essential Tremor: Life Quality Effect.

AIM: This study aims to evaluate the effectiveness of botulinum toxin therapy, as a monotherapy, and its effect on quality of life in patients with essential tremor (ET) who are resistant to medical treatment or cannot tolerate optimum drug doses in the population. METHOD: This retrospective research was conducted between February 2019 and December 2019 with 15 adult patients (9 men and 6 women) in the 50-to-70 age group, who had a definite diagnosis of ET as evaluated by the same clinician. With the help of electroneuromyography, intramuscular onabotulinum toxin A (BoNT-A) injection was administered to the related muscles, not exceeding 100 U in total. Demographic characteristics and duration of disease of all patients were recorded. The tremor severity of patients before the injection, 1 month after the injection, and 3 months after the injection was assessed by the Fahn-Tolosa-Marín Tremor Rating Scale (FTM-TRS), applied by the same clinician during the face-to-face interviews, in addition to the Questionnaire for Essential Tremor (QUEST), which was filled out by participants. RESULTS: The first month and third month mean QUEST and FTM-TRS scores were statistically lower than that before the procedure in patients with ET after BoNT-A injection (P = 0.001, P = 0.001, P = 0.001, and P = 0.001). In addition, the mean FTM-TRS and QUEST scores for the first month after the procedure were significantly lower than the mean FTM-TRS and QUEST scores for the third month (P = 0.005 and P = 0.007). CONCLUSION: We believe that our study is valuable because there is no research on the effect of BoNT-A administration on ET treatment in the our country population and because the effect of BoNT-A treatment on quality of life in patients with ET was evaluated using the ET-specific QUEST scale.

Alexithymia is a non motor symptom of essential tremor regardless of the presence of depression and anxiety.

OBJECTIVE: Essential tremor (ET) is one of the most common movement disorders. Aside from tremor, patients may exhibit other motor features as well as non-motor features, including neuropsychiatric symptoms. The cerebellum and cerebellar connections are thought to play a key role in the pathophysiology of ET. Cognitive and affective disturbances can occur in the context of cerebellar disease. Our aim was to study the prevalence and clinical correlates of alexithymia and its relationship to depression and anxiety in ET patients and control subjects (CS). METHOD: We enrolled 100 ET patients and 100 age- and gender-matched CS. The Toronto Alexithymia Scale-20 (TAS-20), the Beck depression inventory-II and the Beck anxiety inventory were administered. RESULTS: Alexithymia levels were significantly higher in ET patients than CS (respective mean TAS-20 scores = 50.63 ± 9.79 vs. 44.05 ± 12.51, p < 0.001).  There were robust associations between alexithymia, depressive symptoms, and anxiety but, after excluding the ET patients and the CS who had moderate or severe depression or who had moderate or severe anxiety, the total alexithymia score remained significantly higher in the ET than the CS group (46.78 ± 9.19 vs. 41.18 ± 11.79, p ≤ 0.01). CONCLUSION: This study suggests that prevalence of alexithymia is significantly higher in ET patients. Alexithymia might be another non-motor neuropsychiatric symptom of the disease.  Further studies are needed to confirm and expand upon our findings.

Long-term efficacy and cognitive effects of voltage-based deep brain stimulation for drug-resistant essential tremor.

OBJECTIVES: To analyze the long-term efficacy and cognitive effects of voltage-based deep brain stimulation (DBS) for drug-resistant essential tremor (ET). PATIENTS AND METHODS: Patients with drug-resistant ET and treated by voltage-based DBS of the ventral intermediate nucleus (VIM-DBS) were continuously enrolled. Seizure outcomes were assessed by blinded observers using the Tremor Rating Scale (TRS). The full-scale intelligence quotient, full-scale memory quotient, Hamilton Depression Scale, Hamilton Anxiety Scale, and Quality of Life in Essential Tremor Questionnaire were assessed as measures of cognitive function. RESULTS: Eleven patients met the inclusion criteria, and two of them were excluded because of loss to follow-up. The patient follow-up times ranged from 48 to 66 months (median 51 months). TRS scores decreased by 60.4% and 46.0% at the 12- and 48-month follow-ups, respectively. Both changes were highly significant. During the follow-up period, the patients' intelligence and memory had not significantly changed; depression, anxiety, and quality of life significantly improved. After long-term follow-up, the stimulation efficacy and quality of life gradually decreased, and the depression and anxiety levels increased. CONCLUSION: For patients with drug-resistant ET, voltage-based DBS can provide acceptable benefits on tremor, cognitive function, and quality of life. However, the efficacy of VIM-DBS decreased over time.

The "Caring Giver": Emotional Caregiving in the Setting of Essential Tremor.

INTRODUCTION: Essential tremor (ET) is a common neurological disorder associated with functional impairment. Emerging evidence shows that some ET caregivers experience burden, but the unique interpersonal aspects of caregiving in the context of ET have not been fully examined. RESEARCH DESIGN: Open-ended questions were administered to 98 ET care-recipient-caregiver dyads. Responses were analyzed using conventional content analysis. RESULTS: The unique visibility of disability and feelings of embarrassment that occur with ET prompts caregivers to be highly attuned to care-recipient emotions. Providing companionship, promoting independence, and reducing embarrassment are three themes we found that describe the ET caregiving experience. DISCUSSION: Caregiving in ET often goes beyond aiding with activities of daily living; it has a significant emotional component especially in relation to independence and embarrassment. Future studies on caregiving in ET and conditions in which disability is visible should consider using a definition of caregiving that includes emotional caregiving.

Psychosocial factors and perceived tremor disability in essential tremor.

Growing evidence suggests that patients with essential tremor (ET) show impairment in psychosocial functions and subsequently increasing vulnerability to anxiety. Here we review evidence supporting a positive relationship between self-reported motor disability and psychological symptoms in ET and critically analyze evidence suggesting how psychosocial factors enhance tremor disability in ET. Theories related to motor competency, behavioral conditioning, and social anxiety have been proposed to relate self-concepts to self-reported tremor disability. We review these theories and then propose a new model in an effort to focus on the self-concepts among ET patients as a factor in tremor disability. Patients with ET exhibited cognitive abnormalities, depression, anxiety, and a higher prevalence of avoidant personality types. Although anxiety, depression and personality types may influence tremor disability in ET, self-concepts may better explain perceived tremor disability in social situations. We conclude by discussing a proposed biopsychosocial model and suggesting future research on ET specific assessment tools and intervention methods.

Demoralization in essential tremor: prevalence, clinical correlates, and dissociation from tremor severity.

OBJECTIVE: Essential tremor (ET) is associated with psychological difficulties, including anxiety and depression. Demoralization (feelings of helplessness, hopelessness, inability to cope), another manifestation of psychological distress, has yet to be investigated in ET. Our objectives are to (1) estimate the prevalence of demoralization in ET, (2) assess its clinical correlates, and (3) determine whether demoralization correlates with tremor severity. METHODS: We administered the Kissane Demoralization Scale (KDS-II) and several psychosocial evaluations (ie, scales assessing subjective incompetence, resilience, and depression [eg, Geriatric Depression Scale]) to 60 ET subjects. Tremor was assessed with a disability score and total tremor score. KDS-II >8 indicated demoralization. RESULTS: Among 60 ET subjects (mean age = 70.2 ± 6.8 years), the prevalence of demoralization was 13.3%, 95% confidence interval = 6.9-24.2%. Although there was overlap between demoralization and depression (10% of the sample meeting criteria for both), 54% of depressed subjects were not demoralized, and 25% of demoralized subjects were not depressed. Demoralization correlated with psychological factors, but demoralized subjects did not have significantly higher total tremor scores, tremor disability scores, or years with tremor. CONCLUSIONS: Demoralization has a prevalence of 13.3% in ET, similar to that in other chronic or terminal illnesses (eg, cancer 13-18%, Parkinson's disease 18.1%, coronary heart disease 20%). Demoralization was not a function of increased tremor severity, suggesting that it is a separable construct, which could dictate how a patient copes with his/her disease. These data further our understanding of the psychological and psychosocial correlates of ET.

Clinical Profile of Non-Motor Symptoms in Patients with Essential Tremor: Impact on Quality of Life and Age-Related Differences.

Background: Identifying the clinical phenotypes of non-motor symptoms (NMSs) of essential tremor (ET) among different populations is necessary due to their impact on the quality of life (QoL). This study aimed to investigate the clinical phenotype and impact of NMSs on QoL in Egyptian patients with ET. Methods: Thirty ET patients were compared to 30 matched controls. Subjects were evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale, Non-Motor Symptoms Scale (NMSS), Montreal Cognitive Assessment, Hamilton Anxiety Rating Scale, Beck Depression Inventory, Pittsburgh Sleep quality Index, and the Short Form 36 Health Survey Questionnaire. Both groups were divided into two subgroups of younger (<45 years, 14 patients) and older age (>45 years, 16 patients) groups, to investigate age-related differences. Results: ET patients showed significantly worse cognition, depression, anxiety, sleep and NMSS domains (p < 0.001), compared to controls, that negatively affected and predicted QoL. Older patients had more cognitive impairment (p = 0.003) and worse sleep/fatigue (p = 0.032) and sexual functions (p = 0.006), compared to younger group. Discussion: The study supports that NMSs are integral part of ET, negatively affect QoL, and similarly affect younger and older patients. Therefore, NMSs should be explored for proper care of ET patients.

Enfeeblement in Elders with Essential Tremor: Characterizing the Phenomenon and Its Role in Caregiver Burden.

Background: Individuals with essential tremor (ET), a common movement disorder, experience functional impairment, which contributes to burden experienced by their loved ones and caregivers. Some burdened caregivers report their loved ones as seeming debilitated or prematurely old, a concept that we have called enfeeblement. Using the Essential Tremor Enfeeblement Survey (ETES), we seek to characterize enfeeblement in elders with ET and assess its contribution to caregiver burden. Methods: We administered the ETES (range = 8-40, higher scores indicating more enfeeblement) and other scales to 98 caregivers of individuals with ET. Individuals with ET were also queried regarding tremors, cognitive abilities, and overall health. We then identified demographic and clinical correlates of ETES and modeled the contribution of ETES to caregiver burden (assessed using the Zarit 12-item Burden Interview [ZBI-12]). Results: Mean ETES score was 14.2 ± 6.2 (median = 12.0, range = 8.0-32.0); 26.5% of respondents endorsed at least one of the eight ETES items. Older age, greater tremor severity and disability, more functional and gait disability, more cognitive difficulty, and more depressive symptoms were associated with higher ETES scores. ETES was the strongest contributor to caregiver burden (ZBI-12) and substantially increased the variance explained in models of caregiver burden. Discussion: Enfeeblement seems to describe a previously unexplained component of caregiver burden in elders with ET. The presence of enfeeblement may contribute to greater burden and should be factored into assessments of patient and caregiver needs.

Graph theory analysis of resting-state functional magnetic resonance imaging in essential tremor.

Essential tremor (ET) is a neurological disease with both motor and nonmotor manifestations; however, little is known about its underlying brain basis. Furthermore, the overall organization of the brain network in ET remains largely unexplored. We investigated the topological properties of brain functional network, derived from resting-state functional magnetic resonance imaging (MRI) data, in 23 ET patients versus 23 healthy controls. Graph theory analysis was used to assess the functional network organization. At the global level, the functional network of ET patients was characterized by lower small-worldness values than healthy controls-less clustered functionality of the brain. At the regional level, compared with the healthy controls, ET patients showed significantly higher values of global efficiency, cost and degree, and a shorter average path length in the left inferior frontal gyrus (pars opercularis), right inferior temporal gyrus (posterior division and temporo-occipital part), right inferior lateral occipital cortex, left paracingulate, bilateral precuneus bilaterally, left lingual gyrus, right hippocampus, left amygdala, nucleus accumbens bilaterally, and left middle temporal gyrus (posterior part). In addition, ET patients showed significant higher local efficiency and clustering coefficient values in frontal medial cortex bilaterally, subcallosal cortex, posterior cingulate cortex, parahippocampal gyri bilaterally (posterior division), right lingual gyrus, right cerebellar flocculus, right postcentral gyrus, right inferior semilunar lobule of cerebellum and culmen of vermis. Finally, the right intracalcarine cortex and the left orbitofrontal cortex showed a shorter average path length in ET patients, while the left frontal operculum and the right planum polare showed a higher betweenness centrality in ET patients. In conclusion, the efficiency of the overall brain functional network in ET is disrupted. Further, our results support the concept that ET is a disorder that disrupts widespread brain regions, including those outside of the brain regions responsible for tremor.

Erythropoietin ameliorates harmaline-induced essential tremor and cognition disturbances.

There are conflicting reports concerning the association of motor disabilities with increased risk of mental disorders. This investigation will provide a good understanding about defining the possible association between tremor and risk of anxiety and cognitive alterations. Beside, a secondary objective of the current study was to determine the effect of erythropoietin (EPO) on harmaline-induced motor and cognitive impairments. Male Wistar rats were used for the present study. The animal model of Esential tremor (ET) was established by the intraperitoneal injection of harmaline. EPO (5000 U/kg, i.p.) administered to the animals 1 h prior to harmaline injection. Exploratory, balance, anxiety related behaviors and cognitive function were assessed using footprint, open field, wire grip, rotarod and shuttle box tests. Findings demonstrated EPO ameliorated tremor scores that was induced by harmaline. Harmaline impaired cognitive functions of the treated rats, whereas EPO showed a promising effect against the cognitive impairments induced by harmaline. EPO can be offered as a potential neuroprotective agent in the treatment of patients with ET that manifest locomotor and cognitive impairments; however, further studies are needed to clarify the exact mechanisms.

Unilateral Thalamic Deep Brain Stimulation Versus Focused Ultrasound Thalamotomy for Essential Tremor.

BACKGROUND: The predominant neurosurgical approach to medication-refractory essential tremor is thalamic deep brain stimulation (DBS). The emergence of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has reawakened the debate surrounding the use of DBS versus thalamotomy for this indication. Herein, we aimed to provide a contemporary comparison between DBS and MRgFUS. METHODS: Two controlled trials that evaluated DBS and MRgFUS for the unilateral treatment of refractory essential tremor were compared. Clinical outcomes extracted included postural tremor score in the treated upper extremity, quality of life (QoL), and incidence of adverse events (AE). RESULTS: Baseline patient characteristics were comparable in the 2 studies, except that DBS patients were younger and had more severe baseline tremor. Both DBS- and MRgFUS-treated patients had significant tremor improvement that was sustained for 1-year posttreatment, and significant improvement in QoL. The MRgFUS cohort had higher rates of persistent neurologic AE, whereas the DBS group had higher rates of surgery- and hardware-related AEs, including intracranial hemorrhage. CONCLUSIONS: In context of prior literature, both DBS and MRgFUS significantly improve tremor control and QoL. The 2 approaches are predominantly differentiated by their AE-profile. Additional head-to-head comparison on matched clinical populations are required to more accurately compare clinical efficacy and long-term outcomes.

Long Trace Eyeblink Conditioning Is Largely Preserved in Essential Tremor.

The cerebellum and the prefrontal cortex are assumed to play a role in the pathophysiology of essential tremor (ET). Trace eyeblink conditioning with a long interstimulus interval relies on an intact function of the hippocampus, prefrontal cortex (PFC), and, although marginally, of the cerebellum. The aim of the present study was to evaluate whether long trace eyeblink conditioning is impaired in patients with ET. In 18 patients with ET and 18 controls, a long trace conditioning paradigm was applied. Following 100 paired conditioned response-unconditioned response trials, 30 conditioned response alone trials were given as extinction trials. The degree of tremor and the presence of accompanying cerebellar signs were determined based on clinical scales. The acquisition of conditioned eyeblink responses was not impaired in the group of all patients compared to controls (mean total incidences of conditioned responses in patients 23.3 ± 14.5%, in controls 24.1 ± 13.9%; P = 0.88). In the subgroup of six patients with cerebellar signs, incidences of conditioned responses were numerically but not significantly lower (16.4 ± 9.9%) compared to patients without cerebellar signs (26.8 ± 15.5%; P = 0.16). Trace eyeblink conditioning with a long interstimulus interval was not impaired in subjects with ET. Patients with clinical cerebellar signs presented slightly reduced conditioning. Areas of the PFC contributing to trace eyeblink conditioning appear less affected in ET. Future studies also using a shorter trace interval should include a larger group of subjects in all stages of ET.