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The pathophysiology of blepharospasm is incompletely understood. Current concepts suggest that blepharospasm is a network disorder, involving basal ganglia, thalamus, cortex, and, possibly, the cerebellum. Tracing, imaging, and clinical studies revealed that these structures are also concerned with olfaction and taste. Because of this anatomical overlap, dysfunction of the chemical senses in blepharospasm is expected. Injections of botulinum toxin into the eyelid muscles are the first-line treatment of blepharospasm. Yet, the effects of botulinum toxin on the chemical senses have not been systematically assessed. To contribute to a better understanding of blepharospasm, olfactory and gustatory abilities were assessed in 17 subjects with blepharospasm and 17 age-/sex-matched healthy controls. Sniffin Sticks were used to assess odor threshold, odor discrimination, and odor identification. Results of these three Sniffin Sticks subtests were added to the composite olfactory score. The Taste Strips were applied to assess taste. In an adjacent study, we assessed the sense of smell and taste in eight subjects with blepharospasm before and 4 weeks after botulinum toxin treatment. Subjects with blepharospasm had significantly lower (= worse) scores for odor threshold and for the composite olfactory score than healthy controls, while odor discrimination, odor identification, and the composite taste score were not different between groups. The adjacent study revealed that botulinum toxin did not impact the chemical senses. In this study, subjects with blepharospasm had a lower (= worse) odor threshold than healthy controls. As olfaction is important in daily life, findings justify further research of olfaction in blepharospasm. Supplementary Information The online version contains supplementary material available at 10.1007/s00702-021-02366-4.

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO2 during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO2 responses were observed in premanifest and early manifest HD patients compared to controls ( P 2 = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO2 response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.

The pathophysiology of cervical dystonia is not completely understood. Current concepts of the pathophysiology propose that it is a network disorder involving the basal ganglia, cerebellum and sensorimotor cortex. These structures are primarily concerned with sensorimotor control but are also involved in non-motor functioning such as the processing of information related to the chemical senses. This overlap lets us hypothesize a link between cervical dystonia and altered sense of smell and taste. To prove this hypothesis and to contribute to the better understanding of cervical dystonia, we assessed olfactory and gustatory functioning in 40 adults with idiopathic cervical dystonia and 40 healthy controls. The Sniffin Sticks were used to assess odor threshold, discrimination and identification. Furthermore, the Taste Strips were applied to assess the combined taste score. Motor and non-motor deficits of cervical dystonia including neuropsychological and psychiatric alterations were assessed as cofactors for regression analyses. We found that cervical dystonia subjects had lower scores than healthy controls for odor threshold (5.8 ± 2.4 versus 8.0 ± 3.2; p = 0.001), odor identification (11.7 ± 2.3 versus 13.1 ± 1.3; p = 0.001) and the combined taste score (9.5 ± 2.2 versus 11.7 ± 2.7; p p = 0.097). Regression analysis suggests that age is the main predictor for olfactory decline in subjects with cervical dystonia. Moreover, performance in the Montreal Cognitive Assessment is a predictor for gustatory decline in cervical dystonia subjects. Findings propose that cervical dystonia is associated with diminished olfactory and gustatory functioning.

(1) Background: Headache disorders are among the most disabling medical conditions but the supply with experienced providers is outpaced by the demand for service. It is unclear to what extent particularly patients in rural regions are affected by limited access to comprehensive care. Furthermore, it is unknown what role general practitioners (GPs) play in headache care. (2) Methods: First-time consultations to a specialised headache clinic at a tertiary care centre were asked to participate. Their socio-demographic background, general and headache-specific medical history, disability and quality of life (QoL) were assessed. Additionally, 176 GPs in neighbouring districts were contacted regarding headache management. (3) Results: We assessed 162 patients with first-time consultations (age 46.1 ± 17.0 years, 78.1% female), who suffered from migraine (72%), tension type, cluster and secondary headaches (each 5–10%). About 50% of patients received a new headache-diagnosis and 60% had treatment inconsistent with national guidelines. QoL was significantly worse in all domains compared to the general population. About 75% of GPs see headache patients at least several times per week, and mostly treat them by themself. (4) Conclusions: More than every second headache patient was neither correctly diagnosed nor received guideline adherent treatment. Headache-related disability is inferior to what is expected from previous studies. Access to specialised health care is more limited in rural than in urban regions in Germany and GPs request more training.

Dystonia is a heterogeneous group of hyperkinetic movement disorders. The unifying descriptor of dystonia is the motor manifestation, characterized by continuous or intermittent contractions of muscles that cause abnormal movements and postures. Additionally, there are psychiatric, cognitive, and sensory alterations that are possible or putative non-motor manifestations of dystonia. The pathophysiology of dystonia is incompletely understood. A better understanding of dystonia pathophysiology is highly relevant in the amelioration of significant disability associated with motor and non-motor manifestations of dystonia. Recently, diminished olfaction was found to be a potential non-motor manifestation that may worsen the situation of subjects with dystonia. Yet, this finding may also shed light into dystonia pathophysiology and yield novel treatment options. This article aims to provide background information on dystonia and the current understanding of its pathophysiology, including the key structures involved, namely, the basal ganglia, cerebellum, and sensorimotor cortex. Additionally, involvement of these structures in the chemical senses are reviewed to provide an overview on how olfactory (and gustatory) deficits may occur in dystonia. Finally, we describe the present findings on altered chemical senses in dystonia and discuss directions of research on olfactory dysfunction as a marker in dystonia.

Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have been previously reported in pediatric cases of epileptic encephalopathy and intellectual disability. We report a case of a 17-year-old male with a prior history of epilepsy, autism, intellectual disability, and the abrupt onset of choreo-athetotic movements. The patient was diagnosed with an EEF1A2 variant by whole exome sequencing. His movement disorder responded dramatically to treatment with tetrabenazine. To the best of our knowledge, this is the first report of successful treatment of a hyperkinetic movement disorder in the setting of EEF1A2 mutation. A trial with tetrabenazine should be considered in cases with significant choreoathetosis.

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.

Department of Neurology, Medical Faculty, RWTH University, Aachen, Germany Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada Vision Science Research Program, Toronto Western Research Institute, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada

It is widely assumed that the thalamus is not involved in olfaction. The ventrolateral thalamus is, however, closely connected to the contralateral cerebellum, which is involved in the sense of smell based on findings from functional imaging studies and findings of olfactory deficits in patients with cerebellar disease. We hypothesized that olfactory deficits following lesions of the ventrolateral thalamus may be similar to olfactory deficits following cerebellar lesions. Fifteen patients with a focal thalamic lesion involving the ventrolateral thalamus were examined and compared to 15 patients with a focal cerebellar lesion and 15 healthy controls. A detailed olfactory test ("Sniffin' Sticks") was used to assess different olfactory functions separately for each nostril. In the group of patients with a lesion of the ventrolateral thalamus, an impairment of the odor threshold was found at the ipsilateral nostril, consistent with the unilateral orientation of the olfactory system in the telencephalon. In the group of patients with a cerebellar lesion, an olfactory deficit at the contralesional nostril emerged. In controls, no significant side difference was found. The involvement of the ventrolateral thalamus in olfaction is comparable to that of the cerebellum in respect to odor threshold. Further study is needed to assess if these findings are related to an impairment of an olfactomotor loop. Present evidence for this hypothesis is indirect. Effects were subclinical as none of the patients reported olfactory disturbance. The results suggest that the cerebello-thalamic axis plays an adjuvant role in olfaction.

Tourette syndrome is a chronic tic disorder characterized by motor and vocal tics. Comorbidities such as attention deficit hyperactivity disorder and obsessive compulsive disorder can be found. The overlap between neuroanatomical regions and neurotransmitter systems in the olfactory system and the pathophysiology of Tourette syndrome let us hypothesize altered olfactory performance in Tourette syndrome. The main objective of this study was to systematically assess olfactory functioning in subjects with Tourette syndrome and to compare it to healthy controls. We assessed 28 adults with Tourette syndrome (age 33.1±9.4 years, disease duration 23.7±9.7 years) and 28 healthy controls (age 32.9±9.0 years) matched in regard to age, sex, education and smoking habits. The ""Sniffin Sticks"" test battery was applied to assess odor threshold, discrimination, and identification. Additionally, the combined score of the odor threshold test, the odor discrimination test and the odor identification test of the ""Sniffin Sticks"" test battery was calculated. Although it was not the primary aim of this study, we assessed whether tics and comorbidity could contribute to olfactory alterations in adults with Tourette syndrome. Therefore, clinical scores were used to assess severity of tics and co-morbidity such as attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety and depression in subjects with Tourette syndrome. Pathology of the nasal cavities was excluded with rhinoendoscopy. Independent sample t-tests were applied to compare performance in olfactory tests. In the case of statistically significant differences (critical p-value: 0.05), multiple linear regression analysis was carried out to explore whether tic severity, social impairment, co-morbidity or medical treatment had an impact on the differences found. Descriptive values are reported as mean ± standard deviation. Tourette syndrome subjects showed lower combined scores (Tourette syndrome subjects 31.9 ± 5.1 versus healthy controls 35.0 ± 3.1; p = 0.007), odor identification scores (Tourette syndrome subjects 12.4 ± 2.0 versus healthy controls 13.7 ± 1.4; p = 0.008) and odor discrimination scores (Tourette syndrome subjects 12.1 ± 2.1 versus healthy controls 13.2 ± 1.6; p = 0.041) in comparison to healthy subjects, while there was no difference in odor threshold (Tourette syndrome subjects 7.3 ± 2.7 versus healthy controls 8.1 ± 2.2; p = 0.22). Seven out of 28 Tourette syndrome subjects (25%) scored in the range of the age- and sex-dependent combined score for hyposmia, while two of 28 healthy controls (7%) had a similar low combined score. None of the participants were found to have functional anosmia. Multiple linear regression analyses suggest that social impairment may a predictor for low combined score and odor identification score in Tourette syndrome subjects (p = 0.003). Compared to healthy controls, altered olfaction in adults with Tourette syndrome was found in this study. Normal odor threshold level but lower scores at tasks involving supra-threshold odor concentrations point towards a central-nervous alteration in the processing of olfactory information in Tourette syndrome.

As a result of demographic change the average age of many western populations increases, accompanied with age-related disease patterns. Especially tremor symptoms rise accordingly, aggravating a barrier free interaction with information systems. In order to maintain a self determined lifestyle at home, new technologies and methods need to be introduced, especially for application in health care and telemedical scenarios. Hence, a new direct input technique based on wiping movements on touch screens has been developed. The combination of a new input concept and applying regular commercially available technologies helps to avoid high costs for acquisition and therefore makes it marketable. While making an input on the touch screen the precise characteristics of every wiping movement can be tracked and is used for computation of the desired entry. The efficacy of this approach was evaluated within a clinical study with n=15 subjects. The results show that the error ratio for inputs by tremor patients can be significantly reduced in comparison to a virtual keyboard, depending on tremor strength and form. The learning curve for first time users is very steep and tends to result in inputs that are only slightly steady than purposeful movements to standard buttons and keys.

Several lines of evidence point to an involvement of the olivo-cerebellar system in the pathogenesis of essential tremor (ET), with clinical signs of cerebellar dysfunction being present in some subjects in the advanced stage. Besides motor coordination, the cerebellum is critically involved in motor learning. Evidence of motor learning deficits would strengthen the hypothesis of olivo-cerebellar involvement in ET. Conditioning of the eyeblink reflex is a well-established paradigm to assess motor learning. Twenty-three ET subjects (13 males, 10 females; mean age 44.3 +/- 22.3 years, mean disease duration 17.4 +/- 17.3 years) and 23 age-matched healthy controls were studied on two consecutive days using a standard delay eyeblink conditioning protocol. Six ET subjects exhibited accompanying clinical signs of cerebellar dysfunction. Care was taken to examine subjects without medication affecting central nervous functioning. Seven ET subjects and three controls on low-dose beta-blocker treatments, which had no effect on eyeblink conditioning in animal studies, were allowed into the study. The ability to acquire conditioned eyeblink responses was significantly reduced in ET subjects compared with controls. Impairment of eyeblink conditioning was not due to low-dose beta-blocker medication. Additionally, acquisition of conditioned eyeblink response was reduced in ET subjects regardless of the presence of cerebellar signs in clinical examination. There were no differences in timing or extinction of conditioned responses between groups and conditioning deficits did not correlate with the degree of tremor or ataxia as rated by clinical scores. The findings of disordered eyeblink conditioning support the hypothesis that ET is caused by a functional disturbance of olivo-cerebellar circuits which may cause cerebellar dysfunction. In particular, results point to an involvement of the olivo-cerebellar system in early stages of ET.

PLoS one 8(4), e61786 (2013). doi:10.1371/journal.pone.0061786, Published by PLoS [u.a.], Lawrence, Kan.

A resurgence of interest in the surgical treatment of Parkinson's disease (PD) came with the rediscovery of posteroventral pallidotomy by Laitinen in 1985. Laitinen's procedure improved most symptoms in drug-resistant PD, which engendered wide interest in the neurosurgical community. Another lesioning procedure, ventrolateral thalamotomy, has become a powerful alternative to stimulate the nucleus ventralis intermedius, producing high long-term success rates and low morbidity rates. Pallidal stimulation has not met with the same success. According to the literature pallidotomy improves the “on” symptoms of PD, such as dyskinesias, as well as the “off” symptoms, such as rigidity, bradykinesia, and on-off fluctuations. Pallidal stimulation improves bradykinesia and rigidity to a minor extent; however, its strength seems to be in improving levodopa-induced dyskinesias. Stimulation often produces an improvement in the hyper- or dyskinetic upper limbs, but increases the “freezing” phenomenon in the lower limbs ...

A resurgence of interest in the surgical treatment of Parkinson's disease (PD) came with the rediscovery of posteroventral pallidotomy by Laitinen in 1985. Laitinen's procedure improved most symptoms in drug-resistant PD, which engendered wide interest in the neurosurgical community. Another lesioning procedure, ventrolateral thalamotomy, has become a powerful alternative to stimulate the nucleus ventralis intermedius, producing high long-term success rates and low morbidity rates. Pallidal stimulation has not met with the same success. According to the literature pallidotomy improves the “on” symptoms of PD, such as dyskinesias, as well as the “off” symptoms, such as rigidity, bradykinesia, and on-off fluctuations. Pallidal stimulation improves bradykinesia and rigidity to a minor extent; however, its strength seems to be in improving levodopa-induced dyskinesias. Stimulation often produces an improvement in the hyper- or dyskinetic upper limbs, but increases the “freezing” phenomenon in the lower limbs at the same time. Considering the small increase in the patient's independence, the high costs of bilateral implants, and the difficulty most patients experience in handling the devices, the question arises as to whether bilateral pallidal stimulation is a real alternative to pallidotomy.