Third-Generation Light-Driven Symmetric Molecular Motors.

Symmetric molecular motors based on two overcrowded alkenes with a notable absence of a stereogenic center show potential to function as novel mechanical systems in the development of more advanced nanomachines offering controlled motion over surfaces. Elucidation of the key parameters and limitations of these third-generation motors is essential for the design of optimized molecular machines based on light-driven rotary motion. Herein we demonstrate the thermal and photochemical rotational behavior of a series of third-generation light-driven molecular motors. The steric hindrance of the core unit exerted upon the rotors proved pivotal in controlling the speed of rotation, where a smaller size results in lower barriers. The presence of a pseudo-asymmetric carbon center provides the motor with unidirectionality. Tuning of the steric effects of the substituents at the bridgehead allows for the precise control of the direction of disrotary motion, illustrated by the design of two motors which show opposite rotation with respect to a methyl substituent. A third-generation molecular motor with the potential to be the fastest based on overcrowded alkenes to date was used to visualize the equal rate of rotation of both its rotor units. The autonomous rotational behavior perfectly followed the predicted model, setting the stage for more advanced motors for functional dynamic systems.

Magnetic resonance-transcranial ultrasound fusion imaging: A novel tool for brain electrode location.

BACKGROUND: A combination of preoperative magnetic resonance imaging (MRI) with real-time transcranial ultrasound, known as fusion imaging, may improve postoperative control of deep brain stimulation (DBS) electrode location. Fusion imaging, however, employs a weak magnetic field for tracking the position of the ultrasound transducer and the patient's head. Here we assessed its feasibility, safety, and clinical relevance in patients with DBS. METHODS: Eighteen imaging sessions were conducted in 15 patients (7 women; aged 52.4 ± 14.4 y) with DBS of subthalamic nucleus (n = 6), globus pallidus interna (n = 5), ventro-intermediate (n = 3), or anterior (n = 1) thalamic nucleus and clinically suspected lead displacement. Minimum distance between DBS generator and magnetic field transmitter was kept at 65 cm. The pre-implantation MRI dataset was loaded into the ultrasound system for the fusion imaging examination. The DBS lead position was rated using validated criteria. Generator DBS parameters and neurological state of patients were monitored. RESULTS: Magnetic resonance-ultrasound fusion imaging and volume navigation were feasible in all cases and provided with real-time imaging capabilities of DBS lead and its location within the superimposed magnetic resonance images. Of 35 assessed lead locations, 30 were rated optimal, three suboptimal, and two displaced. In two cases, electrodes were re-implanted after confirming their inappropriate location on computed tomography (CT) scan. No influence of fusion imaging on clinical state of patients, or on DBS implantable pulse generator function, was found. CONCLUSIONS: Magnetic resonance-ultrasound real-time fusion imaging of DBS electrodes is safe with distinct precautions and improves assessment of electrode location. It may lower the need for repeated CT or MRI scans in DBS patients.

Value of combined midbrain sonography, olfactory and motor function assessment in the differential diagnosis of early Parkinson's disease.

OBJECTIVE: Characteristic features of Parkinson's disease (PD) are asymmetric parkinsonian motor signs, hyposmia and substantia nigra (SN) hyperechogenicity on transcranial ultrasound. However, each of these features has limited diagnostic value as they may be present, albeit less frequently, in other parkinsonian disorders. Here, the diagnostic sensitivity and specificity of combined assessment of these three features are evaluated. METHODS: 632 patients with parkinsonism (PD, vascular parkinsonism, atypical parkinsonian syndromes, essential tremor and major depressive disorder with motor slowing) were assessed on the Unified Parkinson's disease Rating Scale for motor asymmetry (right-left score difference ≥2), the 12 item Sniffin' Sticks test (SS-12) and transcranial ultrasound. The derivation (validation) cohort consisted of 517 (115) subjects (193 (35) women; age 65.4±9.6 (62.3±10.3) years) of whom 385 (68) had PD and 132 (47) non-PD parkinsonism; another 21 (6) subjects were not included due to missing transcranial insonability. Of the validation cohort, all patients had a disease duration ≤2 years and observers were blind to diagnoses. RESULTS: The optimum cut-off values for discrimination of PD were SS-12 score <8 (hyposmia) and SN echogenic size ≥0.24 cm(2) (SN hyperechogenicity). Sensitivity, specificity and positive predictive values for the diagnosis of PD were as follows, for the derivation cohort: motor asymmetry 88%, 54% and 85%; hyposmia 75%, 70% and 88%; SN hyperechogenicity 90%, 63% and 88%; two features present 96%, 72% and 91%; three features present 57%, 94% and 97%; and for the validation cohort: two features present 91%, 77% and 85%; three features present 49%, 98% and 97%. CONCLUSION: The combined assessment of motor asymmetry, hyposmia and SN hyperechogenicity improves diagnostic specificity and allows early diagnosis of PD.

Substantia nigra echogenicity in Parkinson's disease: relation to serum iron and C-reactive protein.

In Parkinson's disease (PD), substantia nigra hyperechogenicity (SN-h) has been related to both, local iron accumulation and microglia activation. We analysed its relationship in PD patients with serum iron (n = 31) and C-reactive protein (CRP; n = 193). SN-h correlated with lower CRP and iron levels. Also, patients with a first-degree relative with PD had lower iron levels. Microglia activation, if reflected by SN-h, may be therefore unrelated to serum CRP. Findings support the idea that SN-h indicates inherited alteration of iron metabolism.

Mirror movements in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor syndrome with clinical evidence of upper and lower motor neuron dysfunction. Mirror movements (MM) in ALS have been reported and attributed to a disturbed transcallosal inhibition (TI). Hence, occurrence of MM in ALS might be explained by involvement of transcallosal projecting fibre tracts into the degenerative process of the motor system. Twenty-six consecutive ALS patients were studied by clinical investigation of MM and by transcranial magnetic stimulation testing of TI using evaluation of the ipsilateral silent period. MM were observed in 39% of ALS patients. There was a significant correlation between the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and occurrence of MM (correlation coefficient -0.315; p = 0.044). In conclusion, all MM patients had pathological TI at least in one hemisphere, which indicates involvement of transcallosally projecting output neurons in ALS patients, which in turn may be an early feature of the disease process with the potential of a diagnostic biomarker.

Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17.

Spinocerebellar ataxia (SCA17) is a rare genetic disorder characterized by a variety of neuropsychiatric symptoms. Recently, using magnetic resonance imaging (MRI) voxel-based morphometry (VBM), several specific functional-structural correlations comprising differential degeneration related to motor and psychiatric symptoms were reported in patients with SCA17. To investigate gray matter volume (GMV) changes over time and its association to clinical neuropsychiatric symptomatology, nine SCA17 mutation carriers and nine matched healthy individuals underwent a detailed neuropsychiatric clinical examination and a high-resolution T1-weighted volume MRI scan, both at baseline and follow-up after 18 months. Follow-up images revealed a progressive GMV reduction in specific degeneration patterns. In contrast to healthy controls, SCA17 patients showed a greater atrophy not only in cerebellar regions but also in cortical structures such as the limbic system (parahippocampus, cingulate) and parietal precuneus. Clinically, progression of motor symptoms was more pronounced than that of psychiatric symptoms. Correlation with the clinical motor scores revealed a progressive reduction of GMV in cerebellar and cerebral motor networks, whereas correlation with psychiatric scores displayed a more widespread GMV impairment in frontal, limbic, parietal, and also cerebellar structures. Interestingly, changes in global functioning were correlated with bilateral atrophy within the para-/hippocampus. While there was a good temporal association between worsening of motor symptoms and progression in cerebral and cortical neurodegeneration, the progression in psychiatric related neurodegeneration seemed to be more widespread and complex, showing progressive atrophy that preceded the further development of clinical psychiatric symptoms.

Pallidal deep-brain stimulation in primary generalized or segmental dystonia.

BACKGROUND: Neurostimulation of the internal globus pallidus has been shown to be effective in reducing symptoms of primary dystonia. We compared this surgical treatment with sham stimulation in a randomized, controlled clinical trial. METHODS: Forty patients with primary segmental or generalized dystonia received an implanted device for deep-brain stimulation and were randomly assigned to receive either neurostimulation or sham stimulation for 3 months. The primary end point was the change from baseline to 3 months in the severity of symptoms, according to the movement subscore on the Burke-Fahn-Marsden Dystonia Rating Scale (range, 0 to 120, with higher scores indicating greater impairment). Two investigators who were unaware of treatment status assessed the severity of dystonia by reviewing videotaped sessions. Subsequently, all patients received open-label neurostimulation; blinded assessment was repeated after 6 months of active treatment. RESULTS: Three months after randomization, the change from baseline in the mean (+/-SD) movement score was significantly greater in the neurostimulation group (-15.8+/-14.1 points) than in the sham-stimulation group (-1.4+/-3.8 points, P<0.001). During the open-label extension period, this improvement was sustained among patients originally assigned to the neurostimulation group, and patients in the sham-stimulation group had a similar benefit when they switched to active treatment. The combined analysis of the entire cohort after 6 months of neurostimulation revealed substantial improvement in all movement symptoms (except speech and swallowing), the level of disability, and quality of life, as compared with baseline scores. A total of 22 adverse events occurred in 19 patients, including 4 infections at the stimulator site and 1 lead dislodgment. The most frequent adverse event was dysarthria. CONCLUSIONS: Bilateral pallidal neurostimulation for 3 months was more effective than sham stimulation in patients with primary generalized or segmental dystonia. (ClinicalTrials.gov number, NCT00142259 [ClinicalTrials.gov].).

Deep brain stimulation in dystonia: sonographic monitoring of electrode placement into the globus pallidus internus.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment in primary dystonia. Its success depends on the implantation accuracy of the DBS electrode into the targeted GPi. Discrepancies of up to 4 mm between the initial target, selected on preoperative MRI, and the final DBS lead location are caused mainly by caudal brain shift that occurs once the cranium is open. Nowadays, transcranial sonography (TCS) can display echogenic deep brain structures with higher image resolution compared to MRI under clinical conditions. Here, we demonstrate for the first time the use of a contemporary clinical high-end TCS system for intraoperative monitoring of DBS electrode position. Herewith, a high-resolution real-time imaging of closely located microelectrodes and of the DBS lead through the intact skull is feasible. Simultaneous color-coded sonographic imaging of arteries near the anatomical target allows further intraoperative refinement of DBS lead positioning, simultaneously preventing hemorrhages.

Pallidal deep brain stimulation improves quality of life in segmental and generalized dystonia: results from a prospective, randomized sham-controlled trial.

As part of the first randomized, sham-stimulation controlled trial on deep brain stimulation (DBS) in primary segmental or generalized dystonia, health-related quality of life (HRQoL) was assessed by SF-36. After the 3-month sham-controlled phase, significant HRQoL improvement occurred only in the active-stimulation group. The open-label extension phase resulted in a significant improvement in all SF-36 domains following 6 months of neurostimulation. These results demonstrate a favorable impact of DBS on HRQoL in primary dystonia.

Restoration of disturbed intracortical motor inhibition and facilitation in attention deficit hyperactivity disorder children by methylphenidate.

BACKGROUND: Previous investigations using transcranial magnetic stimulation (TMS) have shown that neural inhibitory motor circuits are disturbed in ADHD children. We sought to investigate the influence of methylphenidate (MPH) on inhibitory and facilitatory motor circuits of ADHD children with TMS paired pulse protocols using surplus long interval inter-stimulus intervals (ISI) not investigated so far. METHODS: Motorcortical modulation was tested with TMS paired pulse protocols employing ISI of 3, 13, 50, 100, 200, and 300 msec in 18 ADHD children before and on treatment with MPH. Clinical improvement by MPH was measured by the Conners score. RESULTS: Analysis of variance (ANOVA) revealed a significant three-way interaction "Group x Amplitude x ISI," p = .001. Subsequent two-factorial ANOVAs and t-tests showed group specific differences of motor evoked potential (MEP) amplitudes for inhibitory ISIs of 3 and 100 msec, and for facilitatory ISIs of 13 and 50 msec. Compared to controls, an adjustment of these parameters by MPH could be shown. On MPH, a significant bivariate correlation was found between the Conners score reduction and averaged MEP amplitude changes only for inhibitory ISIs (3 and 100 msec). CONCLUSIONS: In ADHD children, MPH modulates disturbed facilitatory and inhibitory motor circuits, which for the latter is associated with clinical improvement.

Transcranial brain sonography findings in discriminating between parkinsonism and idiopathic Parkinson disease.

BACKGROUND: In several pilot studies, transcranial brain sonography findings of substantia nigra and lenticular nucleus discriminated between idiopathic Parkinson disease (PD) and atypical parkinsonian disorders. OBJECTIVE: To study the use of transcranial brain sonography in excluding the diagnosis of idiopathic PD in patients with sporadic parkinsonism. DESIGN AND SETTING: All patients with parkinsonism admitted to our movement disorder clinic from January 1, 2003, through December 31, 2005, who fulfilled clinical diagnostic criteria for definite PD, probable parkinsonian variant of multiple-system atrophy (MSA-P), or probable progressive supranuclear palsy (PSP) were prospectively studied with transcranial brain sonography by an investigator blinded to clinical diagnoses. Patients Eligible patients included 138 with sporadic idiopathic PD (82 men and 56 women; mean +/- SD age, 67.1 +/- 9.8 years; mean +/- SD disease duration, 7.5 +/- 6.3 years; mean +/- SD motor score on the Unified Parkinson Disease Rating Scale, 32.6 +/- 18.1), 21 with MSA-P (10 men and 11 women; mean +/- SD age, 65.4 +/- 9.5 years; mean +/- SD duration of disease, 3.1 +/- 2.0 years; mean +/- SD motor score, 33.5 +/- 16.1), and 22 with PSP (13 men and 9 women; mean +/- SD age, 71.2 +/- 5.5 years; mean +/- SD duration of disease, 3.4 +/- 2.4 years; mean +/- SD motor score, 46.2 +/- 18.9). In 7 patients, transcranial brain sonography was not possible owing to insufficient temporal acoustic bone windows. MAIN OUTCOME MEASURES: Sensitivity, specificity, and predictive value of transcranial brain sonography in indicating an atypical parkinsonian syndrome rather than idiopathic PD in patients with sporadic parkinsonism. RESULTS: Normal echogenic substantia nigra indicated MSA-P rather than PD (sensitivity, 90%; specificity, 98%; positive predictive value, 86%), whereas third-ventricle dilatation of more than 10 mm in combination with lenticular nucleus hyperechogenicity indicated PSP rather than PD (sensitivity, 84%; specificity, 98%; positive predictive value, 89%). Normal echogenic substantia nigra combined with lenticular nucleus hyperechogenicity indicated MSA-P or PSP (sensitivity, 59%; specificity, 100%; positive predictive value, 100%). In parkinsonism with age at onset younger than 60 years, normal echogenic substantia nigra alone indicated MSA-P or PSP (sensitivity, 75%; specificity, 100%; positive predictive value, 100%). CONCLUSIONS: Distinct transcranial brain sonography findings can exclude the diagnosis of PD in patients with sporadic parkinsonism. Sonographic discrimination of atypical parkinsonian syndromes from PD is clearer in patients with onset of parkinsonism at younger than 60 years.

The two sides of associative plasticity in writer's cramp.

Neuronal plasticity is to be kept within operational limits to serve its purpose as a safe memory system that shapes and focuses sensory and motor representations. Temporal and spatial properties of motor cortical plasticity were assessed in patients with writer's cramp using a model of long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy. Paired associative stimulation (PAS) combined repetitive electric stimulation of the median or ulnar nerve (MN or UN) with subsequent transcranial magnetic stimulation of the contralateral dominant motor cortex at 21.5 ms (MN-PAS21.5; UN-PAS21.5) or 10 ms (MN-PAS10). Motor-evoked potentials were recorded from abductor pollicis brevis (APB) muscle and abductor digiti minimi (ADM) muscles in 10 patients with writer's cramp and 10 matched healthy control subjects. Following MN-PAS21.5 or UN-PAS21.5 in non-dystonic subjects, motor responses increased if the afferent PAS-component came from a homologous peripheral region and remained stable with a non-homologous input. In contrast, following either MN-PAS21.5 or UN-PAS21.5, both APB- and ADM-amplitudes increased in patients. Compared with controls, this increase started earlier, its magnitude was larger and its duration longer. Following MN-PAS10 in controls, APB-amplitudes decreased, while ADM-amplitudes increased. In writer's cramp, the decrease of APB-amplitudes started earlier and lasted longer. Of note, ADM-amplitudes were decreased, too. LTP-like as well as LTD-like plasticity is abnormal with respect to both gain and spatial organization. These findings may help to develop a pathophysiological model explaining core features of focal dystonia.

[Diagnosis and treatment of tremor in Parkinson's disease and essential tremor]. / Benigner Tremor oder Morbus Parkinson? Die Abgrenzung ist für die Therapie entscheidend.

For patients presenting predominantly or purely with tremor, the correct diagnosis of tremor-dominant Parkinson's disease (PD) versus essential tremor (ET) is very important for prognosis and effective therapy. ET tremor is usually characterized by symmetric bilateral postural and kinetic tremor, which may respond to low alcohol consumption. Many patients have a family history of ET tremors. Medical treatment with primidone or beta-blockers effectively controls ET tremor, but in many cases no treatment is needed at all. The typical tremor form of PD is an asymmetric rest tremor, which is treated with dopaminergic agents such as levodopa. Differential diagnosis of ET and PD may be difficult in a subset of PD patients who present with additional postural and kinetic tremor and in a minority of ET patients who show a clear asymmetry of their postural and kinetic tremor. In some patients with ET, the tremor can later become severe and even require treatment with deep brain stimulation.

Causes of failure of pallidal deep brain stimulation in cases with pre-operative diagnosis of isolated dystonia.

INTRODUCTION: Pallidal deep brain stimulation (GPi-DBS) is an effective therapy for isolated dystonia, but 10-20% of patients show improvement below 25-30%. We here investigated causes of insufficient response to GPi-DBS in isolated dystonia in a cross-sectional study. METHODS: Patients with isolated dystonia at time of surgery, and <30% improvement on the Burke-Fahn-Marsden dystonia-rating-scale (BFMDRS) after ≥6 months of continuous GPi-DBS were videotaped ON and OFF stimulation, and history, preoperative videos, brain MRI, medical records, stimulation settings, stimulation system integrity, lead location, and genetic information were obtained and reviewed by an expert panel. RESULTS: 22 patients from 11 centres were included (8 men, 14 women; 9 generalized, 9 segmental, 3 focal, 1 bibrachial dystonia; mean (range): age 48.7 (25-72) years, disease duration 22.0 (2-40) years, DBS duration 45.5 (6-131) months). Mean BFMDRS-score was 31.7 (4-93) preoperatively and 32.3 (5-101) postoperatively. Half of the patients (n = 11) had poor lead positioning alone or in combination with other problems (combined with: other disease n = 6, functional dystonia n = 1, other problems n = 2). Other problems were disease other than isolated inherited or idiopathic dystonia (n = 5), fixed deformities (n = 2), functional dystonia (n = 3), and other causes (n = 1). Excluding patients with poor lead location from further analysis, non-isolated dystonia accounted for 45.5%, functional dystonia for 27.3%, and fixed deformities for 18.2%. In patients with true isolated dystonia, lead location was the most frequent problem. CONCLUSION: After exclusion of lead placement and stimulation programming issues, non-isolated dystonia, functional dystonia and fixed deformities account for the majority of GPi-DBS failures in dystonia.

Sonographic discrimination of dementia with Lewy bodies and Parkinson's disease with dementia.

OBJECTIVE: To study the use of transcranial sonography (TCS) in discriminating between patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). METHODS: Fourteen patients with DLB, 31 with PDD and 73 with PD without dementia (PDnD) were studied with TCS. RESULTS: All assessable patients with DLB, 97% with PDD, and 94% with PDnD showed at least unilateral hyperechogenicity of substantia nigra (SN). However, bilateral marked SN hyperechogenicity was present in 80% of DLB patients but only in one third of PDD and PDnD patients, and was associated with younger age at disease onset in PD but not in DLB. An asymmetry index > or = 1.15 of bilateral SN echogenic sizes, estimated by division of larger size by smaller size, was found in 69% of PDD patients but only 20% of DLB patients. Combination of SN echogenic sizes, asymmetry indices and onset age discriminated PDD from DLB with a sensitivity of 96%, a specificity of 80% and a positive predictive value of 93%. TCS of brainstem raphe, thalami, lenticular nuclei, caudate nuclei and ventricle widths did not discriminate between DLB and PDD. Compared with PDnD patients, DLB and PDD patients exhibited significantly larger widths of third ventricle and of frontal horns. In PDD patients, scores on the Unified Parkinson's Disease Rating Scale correlated with widths of third ventricle and of frontal horns. CONCLUSIONS: SN hyperechogenicity is typical for PDD and DLB. However, size, asymmetry and relation of SN hyperechogenicity to age at disease onset discriminate PDD from DLB.

An algorithm for calculating exam quality as a basis for performance-based allocation of funds at medical schools.

OBJECTIVE: The amendment of the Medical Licensing Act (ÄAppO) in Germany in 2002 led to the introduction of graded assessments in the clinical part of medical studies. This, in turn, lent new weight to the importance of written tests, even though the minimum requirements for exam quality are sometimes difficult to reach. Introducing exam quality as a criterion for the award of performance-based allocation of funds is expected to steer the attention of faculty members towards more quality and perpetuate higher standards. However, at present there is a lack of suitable algorithms for calculating exam quality. METHODS: In the spring of 2014, the students' dean commissioned the "core group" for curricular improvement at the University Medical Center in Rostock to revise the criteria for the allocation of performance-based funds for teaching. In a first approach, we developed an algorithm that was based on the results of the most common type of exam in medical education, multiple choice tests. It included item difficulty and discrimination, reliability as well as the distribution of grades achieved. RESULTS: This algorithm quantitatively describes exam quality of multiple choice exams. However, it can also be applied to exams involving short assay questions and the OSCE. It thus allows for the quantitation of exam quality in the various subjects and - in analogy to impact factors and third party grants - a ranking among faculty. CONCLUSION: Our algorithm can be applied to all test formats in which item difficulty, the discriminatory power of the individual items, reliability of the exam and the distribution of grades are measured. Even though the content validity of an exam is not considered here, we believe that our algorithm is suitable as a general basis for performance-based allocation of funds.

The role of mutations in COL6A3 in isolated dystonia.

Specific mutations in COL6A3 have recently been reported as the cause of isolated recessive dystonia, which is a rare movement disorder. In all patients, at least one mutation was located in Exons 41 and 42. In an attempt to replicate these findings, we assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. We identified nine heterozygous carriers of rare variants including five different missense mutations and an extremely rare synonymous variant. In these nine patients, we sequenced the remaining 41 coding exons of COL6A3 to test for a second mutation in the compound heterozygous state. In only one of them, a second rare variant was identified (Thr732Met + Pro3082Arg). Of note, this patient had been diagnosed with Parkinson´s disease (with dystonic posturing) due to homozygous PINK1 mutations. The COL6A3 mutations clearly did not segregate with the disease in the four affected siblings of this family. Further, there was no indication for a disease-modifying effect of the COL6A3 mutations since disease severity or age at onset did not correlate with the number of COL6A3 mutated alleles in this family. In conjunction with the relatively high frequency of homozygous carriers of reported mutations in publically available databases, our data call a causal role for variants in COL6A3 in isolated dystonia into question.