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1.  Assessment of Brainstem Function with Auricular Branch of Vagus Nerve Stimulation in Parkinson’s Disease 
PLoS ONE  2015;10(4):e0120786.
The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact.
To obtain neurophysiological evidence related to this pattern, we tested processing of afferent sensory information transmitted via the auricular branch of the vagus nerve (ABVN) which is known to be connected to autonomic regulation of cardiac rhythm.
In this cross-sectional observational study, we recorded (i) somatosensory evoked potentials (ABVN-SEP) and (ii) cutaneo-cardioautonomic response elicited by stimulation of the ABVN (modulation of heart-rate variability (HRV index; low frequency power, ln(LF), high frequency power, ln(HF); ln(LF/HF) ratio)) in 50 PD patients and 50 age and sex matched healthy controls. Additionally, auditory evoked potentials and trigeminal nerve SEP were assessed.
Neither ABVN-SEP nor any of the other functional brainstem parameters differed between patients and controls. Although HRV index was decreased in PD patients, modulation of ln(LF/HF) by ABVN-stimulation, likely indicating cardiac parasympathetic activation, did not differ between both groups.
Findings do not point to prominent dysfunction of processing afferent information from ABVN and its connected parasympathetic cardiac pathway in PD. They are consistent with the known pattern of degeneration of the vagal nuclei complex of the brainstem.
PMCID: PMC4388709  PMID: 25849807
2.  Instrument specific use-dependent plasticity shapes the anatomical properties of the corpus callosum: a comparison between musicians and non-musicians 
Long-term musical expertise has been shown to be associated with a number of functional and structural brain changes, making it an attractive model for investigating use-dependent plasticity in humans. Physiological interhemispheric inhibition (IHI) as examined by transcranial magnetic stimulation has been shown to be correlated with anatomical properties of the corpus callosum as indexed by fractional anisotropy (FA). However, whether or not IHI or the relationship between IHI and FA in the corpus callosum can be modified by different musical training regimes remains largely unknown. We investigated this question in musicians with different requirements for bimanual finger movements (piano and string players) and non-expert controls. IHI values were generally higher in musicians, but differed significantly from non-musicians only in string players. IHI was correlated with FA in the posterior midbody of the corpus callosum across all participants. Interestingly, subsequent analyses revealed that this relationship may indeed be modulated by different musical training regimes. Crucially, while string players had greater IHI than non-musicians and showed a positive structure-function relationship, the amount of IHI in pianists was comparable to that of non-musicians and there was no significant structure-function relationship. Our findings indicate instrument specific use-dependent plasticity in both functional (IHI) and structural (FA) connectivity of motor related brain regions in musicians.
PMCID: PMC4100438  PMID: 25076879
use-dependent plasticity; corpus callosum; musical training; pianists; string players; interhemispheric inhibition; fractional anisotropy; diffusion imaging
3.  Heritability of motor control and motor learning 
Physiological Reports  2013;1(7):e00188.
The aim of this study was to elucidate the relative contribution of genes and environment on individual differences in motor control and acquisition of a force control task, in view of recent association studies showing that several candidate polymorphisms may have an effect on them. Forty‐four healthy female twins performed brisk isometric abductions with their right thumb. Force was recorded by a transducer and fed back to the subject on a computer screen. The task was to place the tracing of the peak force in a force window defined between 30% and 40% of the subject's maximum force, as determined beforehand. The initial level of proficiency was defined as the number of attempts reaching the force window criterion within the first 100 trials. The difference between the number of successful trials within the last and the first 100 trials was taken as a measure of motor learning. For motor control, defined by the initial level of proficiency, the intrapair differences in monozygotic (MZ) and dizygotic (DZ) twins were 6.8 ± 7.8 and 13.8 ± 8.4, and the intrapair correlations 0.77 and 0.39, respectively. Heritability was estimated at 0.68. Likewise for motor learning intrapair differences in the increment of the number of successful trials in MZ and DZ twins were 5.4 ± 5.2 and 12.8 ± 7, and the intrapair correlations 0.58 and 0.19. Heritability reached 0.70. The present findings suggest that heredity accounts for a major part of existing differences in motor control and motor learning, but uncertainty remains which gene polymorphisms may be responsible.
Individual differences in motor control and learning are attributed to a great extent to genetic predisposition. However, uncertainty remains which gene polymorphism may be responsible.
PMCID: PMC3970744  PMID: 24744865
BDNF; dynamic motor training; force control; genetic variation
4.  Dysfunction of Autonomic Nervous System in Childhood Obesity: A Cross-Sectional Study 
PLoS ONE  2013;8(1):e54546.
To assess the distribution of autonomic nervous system (ANS) dysfunction in overweight and obese children.
Parasympathetic and sympathetic ANS function was assessed in children and adolescents with no evidence of impaired glucose metabolism by analysis of heart rate variability (low frequency power ln(LF), high frequency power, ln(HF); ln(LF/HF) ratio, ratio of longest RR interval during expiration to shortest interval during inspiration (E/I ratio), root mean square of successive differences (RMSSD); sympathetic skin response (SSR); and quantitative pupillography (pupil diameter in darkness, light reflex amplitude, latency, constriction velocity, re-dilation velocity). The relationship of each ANS variable to the standard deviation score of body mass index (BMI-SDS) was assessed in a linear model considering age, gender and pubertal stage as co-variates and employing an F-statistic to compare the fit of nested models. Group comparisons between normal weight and obese children as well as an analysis of dependence on insulin resistance (as indexed by the Homeostasis Model Assessment of Insulin Resistance, HOMA-IR) were performed for parameters shown to correlate with BMI-SDS. Statistical significance was set at 5%.
Measurements were performed in 149 individuals (mean age 12.0 y; 90 obese 45 boys; 59 normal weight, 34 boys). E/I ratio (p = 0.003), ln(HF) (p = 0.03), pupil diameter in darkness (p = 0.01) were negatively correlated with BMI-SDS, whereas ln(LF/HF) was positively correlated (p = 0.05). Early re-dilation velocity was in trend negatively correlated to BMI-SDS (p = 0.08). None of the parameters that depended significantly on BMI-SDS was found to be significantly correlated with HOMA-IR.
These findings demonstrate extended ANS dysfunction in obese children and adolescents, affecting several organ systems. Both parasympathetic activity and sympathetic activity are reduced. The conspicuous pattern of ANS dysfunction raises the possibility that obesity may give rise to dysfunction of the peripheral autonomic nerves resembling that observed in normal-weight diabetic children and adolescents.
PMCID: PMC3554723  PMID: 23358101
5.  Excitability decreasing central motor plasticity is retained in multiple sclerosis patients 
BMC Neurology  2012;12:92.
Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS.
We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window.
cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18%, p < 0.001). In contrast, post-cTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls.
Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.
PMCID: PMC3488470  PMID: 22974055
Multiple sclerosis; LTD; Motor plasticity; TMS; Motor cortex
6.  Paired Associative Stimulation of the Auditory System: A Proof-Of-Principle Study 
PLoS ONE  2011;6(11):e27088.
Paired associative stimulation (PAS) consisting of repeated application of transcranial magnetic stimulation (TMS) pulses and contingent exteroceptive stimuli has been shown to induce neuroplastic effects in the motor and somatosensory system. The objective was to investigate whether the auditory system can be modulated by PAS.
Acoustic stimuli (4 kHz) were paired with TMS of the auditory cortex with intervals of either 45 ms (PAS(45 ms)) or 10 ms (PAS(10 ms)). Two-hundred paired stimuli were applied at 0.1 Hz and effects were compared with low frequency repetitive TMS (rTMS) at 0.1 Hz (200 stimuli) and 1 Hz (1000 stimuli) in eleven healthy students. Auditory cortex excitability was measured before and after the interventions by long latency auditory evoked potentials (AEPs) for the tone (4 kHz) used in the pairing, and a control tone (1 kHz) in a within subjects design.
Amplitudes of the N1-P2 complex were reduced for the 4 kHz tone after both PAS(45 ms) and PAS(10 ms), but not after the 0.1 Hz and 1 Hz rTMS protocols with more pronounced effects for PAS(45 ms). Similar, but less pronounced effects were observed for the 1 kHz control tone.
These findings indicate that paired associative stimulation may induce tonotopically specific and also tone unspecific human auditory cortex plasticity.
PMCID: PMC3206892  PMID: 22073259
7.  Ventral Premotor Cortex May Be Required for Dynamic Changes in the Feeling of Limb Ownership: A Lesion Study 
The feeling of “body ownership” may be experimentally investigated by perceptual illusions. The “rubber hand illusion” (RHI) leads human subjects to experience an artificial hand as their own. According to functional imaging, the ventral premotor cortex (PMv) plays a key role in the integration of multisensory inputs allowing the “incorporation” of the rubber hand into body representation. However, causal structure–function relationships can only be obtained by lesion studies.
Here, we tested the RHI in 70 stroke patients and in 40 age-matched healthy controls. Additionally, asomatognosia, the unawareness of one’s own body parts, was assessed in a subgroup of 64 stroke patients. Ischemic lesions were delineated on diffusion-weighted magnetic resonance images and normalized. Right-hemispheric lesions were mirrored across the midline. Voxels that might be essential for RHI and/or somatognosia were defined by voxel-based lesion-symptom mapping. Probabilistic diffusion tractography was used to identify tracts passing through these voxels.
Contralesional rubber hand illusion failure (RHIF) was observed in 18 (26%) of 70 stroke patients, an additional ipsilesional RHIF in seven of these patients. RHIF-associated lesion voxels were located subcortically adjacent to the insula, basal ganglia, and within the periventricular white matter. Tractography revealed fiber tract connections of these voxels with premotor, parietal, and prefrontal cortex. Contralesional asomatognosia was found in 18 (28%) of 64 stroke patients. In contrast to RHIF, asomatognosia-associated lesion voxels showed no connection with PMv.
The results point to a role of PMv and its connections in mediating changes in the sense of limb ownership driven by multisensory stimulation.
PMCID: PMC3119817  PMID: 21451023
8.  Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease 
BMC Neurology  2011;11:88.
Studies in animals suggest that the noradrenergic system arising from the locus coeruleus (LC) and dopaminergic pathways mutually influence each other. Little is known however, about the functional state of the LC in patients with Parkinson disease (PD).
We retrospectively reviewed clinical and imaging data of 94 subjects with PD at an early clinical stage (Hoehn and Yahr stage 1-2) who underwent single photon computed tomography imaging with FP-CIT ([123I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane). FP-CIT binding values from the patients were compared with 15 healthy subjects: using both a voxel-based whole brain analysis and a volume of interest analysis of a priori defined brain regions.
Average FP-CIT binding in the putamen and caudate nucleus was significantly reduced in PD subjects (43% and 57% on average, respectively; p < 0.001). In contrast, subjects with PD showed an increased binding in the LC (166% on average; p < 0.001) in both analyses. LC-binding correlated negatively with striatal FP-CIT binding values (caudate: contralateral, ρ = -0.28, p < 0.01 and ipsilateral ρ = -0.26, p < 0.01; putamen: contralateral, ρ = -0.29, p < 0.01 and ipsilateral ρ = -0.29, p < 0.01).
These findings are consistent with an up-regulation of noradrenaline reuptake in the LC area of patients with early stage PD, compatible with enhanced noradrenaline release, and a compensating activity for degeneration of dopaminergic nigrostriatal projections.
PMCID: PMC3146819  PMID: 21777421
9.  Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder 
Structural abnormality of the substantia nigra can be detected by transcranial sonography in neuropsychiatric disorders such as Parkinson disease and restless legs syndrome. We investigated echogenicity of the substantia nigra as a potential structural marker for dysfunction of the nigrostriatal dopamine system in children with attention-deficit hyperactivity disorder (ADHD).
We used a blinded design and determined echogenicity of the substantia nigra by use of transcranial sonography in 22 children with ADHD and 22 healthy controls matched for age and sex.
The echogenic substantia nigra area was significantly larger in ADHD patients than in healthy controls (F1,42 = 9.298, p = 0.004, effect size = 0.92). We found no effects of age or sex.
Owing to a lack of dimensional assessment, we could not analyze the correlation between echogenicity and clinical symptoms.
Our results support the hypothesis that the nigrostriatal dopaminergic system is abnormal in children with ADHD.
PMCID: PMC2799505  PMID: 20040247
10.  Plasticity Resembling Spike-Timing Dependent Synaptic Plasticity: The Evidence in Human Cortex 
Spike-timing dependent plasticity (STDP) has been studied extensively in a variety of animal models during the past decade but whether it can be studied at the systems level of the human cortex has been a matter of debate. Only recently newly developed non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) have made it possible to induce and assess timing dependent plasticity in conscious human subjects. This review will present a critical synopsis of these experiments, which suggest that several of the principal characteristics and molecular mechanisms of TMS-induced plasticity correspond to those of STDP as studied at a cellular level. TMS combined with a second phasic stimulation modality can induce bidirectional long-lasting changes in the excitability of the stimulated cortex, whose polarity depends on the order of the associated stimulus-evoked events within a critical time window of tens of milliseconds. Pharmacological evidence suggests an NMDA receptor mediated form of synaptic plasticity. Studies in human motor cortex demonstrated that motor learning significantly modulates TMS-induced timing dependent plasticity, and, conversely, may be modulated bidirectionally by prior TMS-induced plasticity, providing circumstantial evidence that long-term potentiation-like mechanisms may be involved in motor learning. In summary, convergent evidence is being accumulated for the contention that it is now possible to induce STDP-like changes in the intact human central nervous system by means of TMS to study and interfere with synaptic plasticity in neural circuits in the context of behavior such as learning and memory.
PMCID: PMC3059695  PMID: 21423520
spike-timing dependent plasticity; long-term potentiation; long-term depression; paired associative stimulation; transcranial magnetic stimulation; human; cortex; translational neuroscience
11.  Lying obliquely—a clinical sign of cognitive impairment: cross sectional observational study 
Objective To determine if failure to spontaneously orient the body along the longitudinal axis of a hospital bed when asked to lie down is associated with cognitive impairment in older patients.
Design Cross sectional observational study.
Setting Neurology department of a university hospital in Germany.
Participants Convenience sample of 110 older (≥60 years) inpatients with neurological conditions and 23 staff neurologists.
Main outcome measures The main outcome measure was the association between the angle of the body axis and the results of three cognitive screening tests (mini-mental state examination, DemTect, and clock drawing test). Staff doctors were shown photographs of a model taken at a natural viewing able to determine their subjective perspective of what constitutes oblique.
Results 110 neurological inpatients (mean age 70.9 (SD 6.8) years) were included after exclusions. Evidence of cognitive impairment was found in 34, with scores indicating dementia in eight, according to the mini-mental state examination, and in 11 according to the DemTect. Across all patients, the mean angular deviation of the body axis from the longitudinal axis of the bed (range 0-23°) correlated linearly with the mini-mental state examination (r=−0.480), DemTect (r=−0.527), and the clock drawing test (r=−0.552) scores (P<0.001 for all), even after removing age as a covariate. Overall, 90% of staff neurologists considered a minimal body angle of 7° to be oblique. Angular deviation of at least 7° predicted cognitive impairment according to the three different tests, with specificities between 89% and 96% and sensitivities between 27% and 50%.
Conclusion Clinicians might suspect cognitive impairment in mobile older inpatients with neurological disorders who spontaneously position themselves obliquely when asked to lie on a bed.
PMCID: PMC2795135  PMID: 20015907
12.  Consensus: “Can tDCS and TMS enhance motor learning and memory formation?” 
Brain stimulation  2008;1(4):363-369.
Noninvasive brain stimulation has developed as a promising tool for cognitive neuroscientists. Transcranial magnetic (TMS) and direct current (tDCS) stimulation allow researchers to purposefully enhance or decrease excitability in focal areas of the brain. The purpose of this paper is to review information on the use of TMS and tDCS as research tools to facilitate motor memory formation, motor performance and motor learning in healthy volunteers. Studies implemented so far have mostly focused on the ability of TMS and tDCS to elicit relatively short lasting motor improvements and the mechanisms underlying these changes have been only partially investigated. Despite limitations including the scarcity of data, work that has been already accomplished raises the exciting hypothesis that currently available noninvasive transcranial stimulation techniques could modulate motor learning and memory formation in healthy humans and potentially in patients with neurological and psychiatric disorders.
PMCID: PMC2621080  PMID: 19802336

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