Daniel Zeller

Depression of Human Corticospinal Excitability Induced by Magnetic Theta-burst Stimulation: Evidence of Rapid Polarity-Reversing Metaplasticity

Metaplasticity refers to the activity-dependent modification of the ability of synapses to undergo subsequent potentiation or depression, and is thought to maintain homeostasis of cortical excitability. Continuous magnetic theta-burst stimulation (cTBS; 50 Hz-bursts of 3 subthreshold magnetic stimuli repeated at 5 Hz) is a novel repetitive magnetic stimulation protocol used to model changes of synaptic efficacy in human motor cortex. Here we examined the influence of prior activity on the effects induced by cTBS. Without prior voluntary motor activation, application of cTBS for a duration of 20 s (cTBS300) facilitated subsequently evoked motor potentials (MEP) recorded from APB muscle. In contrast, MEP-size was depressed, when cTBS300 was preceded by voluntary activity of sufficient duration. Remarkably, even without prior voluntary activation, depression of MEP-size was induced when cTBS was extended over 40 s. These findings provide in vivo evidence for extremely rapid metaplasticity reversing potentiation of corticospinal excitability to depression. Polarity-reversing metaplasticity adds considerable complexity to the brains response toward new experiences. Conditional dependence of cTBS-induced depression of corticospinal excitability on prior neuronal activation suggests that the TBS-model of synaptic plasticity may be closer to synaptic mechanisms than previously thought.

Small fibre pathology in patients with fibromyalgia syndrome

Fibromyalgia syndrome is a clinically well-characterized chronic pain condition of high socio-economic impact. Although the pathophysiology is still unclear, there is increasing evidence for nervous system dysfunction in patients with fibromyalgia syndrome. In this case-control study we investigated function and morphology of small nerve fibres in 25 patients with fibromyalgia syndrome. Patients underwent comprehensive neurological and neurophysiological assessment. We examined small fibre function by quantitative sensory testing and pain-related evoked potentials, and quantified intraepidermal nerve fibre density and regenerating intraepidermal nerve fibres in skin punch biopsies of the lower leg and upper thigh. The results were compared with data from 10 patients with monopolar depression without pain and with healthy control subjects matched for age and gender. Neurological and standard neurophysiological examination was normal in all patients, excluding large fibre polyneuropathy. Patients with fibromyalgia syndrome had increased scores in neuropathic pain questionnaires compared with patients with depression and with control subjects (P < 0.001 each). Compared with control subjects, patients with fibromyalgia syndrome but not patients with depression had impaired small fibre function with increased cold and warm detection thresholds in quantitative sensory testing (P < 0.001). Investigation of pain-related evoked potentials revealed increased N1 latencies upon stimulation at the feet (P < 0.001) and reduced amplitudes of pain-related evoked potentials upon stimulation of face, hands and feet (P < 0.001) in patients with fibromyalgia syndrome compared to patients with depression and to control subjects, indicating abnormalities of small fibres or their central afferents. In skin biopsies total (P < 0.001) and regenerating intraepidermal nerve fibres (P < 0.01) at the lower leg and upper thigh were reduced in patients with fibromyalgia syndrome compared with control subjects. Accordingly, a reduction in dermal unmyelinated nerve fibre bundles was found in skin samples of patients with fibromyalgia syndrome compared with patients with depression and with healthy control subjects, whereas myelinated nerve fibres were spared. All three methods used support the concept of impaired small fibre function in patients with fibromyalgia syndrome, pointing towards a neuropathic nature of pain in fibromyalgia syndrome.

Timing-dependent plasticity in human primary somatosensory cortex

Animal experiments suggest that cortical sensory representations may be remodelled as a consequence of changing synaptic efficacy by timing‐dependent associative neuronal activity. Here we describe a timing‐based associative form of plasticity in human somatosensory cortex. Paired associative stimulation (PAS) was performed by combining repetitive median nerve stimulation with transcranial magnetic stimulation (TMS) over the contralateral postcentral region. PAS increased exclusively the amplitude of the P25 component of the median nerve‐evoked somatosensory‐evoked potential (MN‐SSEP), which is probably generated in the superficial cortical layers of area 3b. SSEP components reflecting neuronal activity in deeper cortical layers (N20 component) or subcortical regions (P14 component) remained constant. PAS‐induced enhancement of P25 amplitude displayed topographical specificity both for the recording (MN‐SSEP versus tibial nerve‐SSEP) and the stimulation (magnetic stimulation targeting somatosensory versus motor cortex) arrangements. Modulation of P25 amplitude was confined to a narrow range of interstimulus intervals (ISIs) between the MN pulse and the TMS pulse, and the sign of the modulation changed with ISIs differing by only 15 ms. The function describing the ISI dependence of PAS effects on somatosensory cortex resembled one previously observed in motor cortex, shifted by ∼7 ms. The findings suggest a simple model of modulation of excitability in human primary somatosensory cortex, possibly by mechanisms related to the spike‐timing‐dependent plasticity of neuronal synapses located in upper cortical layers.

Theta-burst stimulation: Remote physiological and local behavioral after-effects

Theta-burst stimulation (TBS), a novel repetitive transcranial magnetic stimulation (TMS) protocol, is capable of suppressing the amplitude of contralateral motor-evoked potentials (MEP) for several minutes after the end of a conditioning train over the motor cortex. It remains unknown whether TBS leads to effects on motor cortical excitability when applied to contralateral brain sites distant but connected to motor cortex and whether TBS triggers measurable changes in force control. Subjects received bursts (50 Hz) of three subthreshold magnetic stimuli repeated at 5 Hz for 20 s (TBS-300) or 40 s (TBS-600) over the hand area of the left motor cortex (M1(LEFT)). With TBS-300, conditioning of right motor cortex (M1(RIGHT)), right dorsal premotor cortex (PMd(RIGHT)), and a mid-occipital (MO) region also were tested. Corticospinal excitability was probed by evoking MEPs in abductor pollicis brevis (APB) muscle by single suprathreshold stimuli over M1(LEFT) or M1(RIGHT) before and after TBS. Force level control was assessed in an isometric right thumb abduction task. With TBS-600, the time course of physiological and behavioral changes was monitored. TBS over either of the motor cortices reduced the amplitude of MEP in the contralateral APB and increased it in the ipsilateral APB. In contrast, conditioning TBS over PMd(RIGHT) or MO did not modify MEP size. Post-TBS right thumb force level control was impaired, with contralateral M1(LEFT) stimulation only, for a duration of at least 5 min. TBS may induce remote physiological effects and reveals local functional properties of the underlying brain region.

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 ones 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.

LTP-like changes induced by paired associative stimulation of the primary somatosensory cortex in humans : source analysis and associated changes in behaviour

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long‐term potentiation‐like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN‐SSEP) recordings and two‐point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near‐synchronously to an afferent signal containing mechanoreceptive information, MN‐SSEP changes (significant at 21–31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS‐induced MN‐SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near‐synchronous afferent signal contained predominantly proprioceptive information, PAS‐induced MN‐SSEP changes (20–29 ms) were shifted medially, and tactile performance remained stable. With near‐synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN‐SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS‐evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing‐dependent and qualitatively congruent behavioural changes.

Rapid-onset central motor plasticity in multiple sclerosis.

Objective: To study rapid-onset central motor plasticity, and its relationship to motor impairment and CNS injury in patients with multiple sclerosis (MS). Methods: In this cross-sectional observational study, motor plasticity was examined neurophysiologically and behaviorally in 22 patients with moderately severe (median Expanded Disability Status Scale score 2.5 [0–6]) stable MS and matched healthy controls. First, plasticity was assessed using paired associative stimulation (PAS), a protocol modeling long-term synaptic potentiation in human cortex. PAS combines repetitive electric nerve stimulation with transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Second, motor learning was tested by a force production task. Motor impairment was assessed by functional tests. CNS injury was evaluated by obtaining normalized N-acetyl-aspartate (NAA/Cr) spectra using magnetic resonance spectroscopy and by the corticomuscular latency (CML) to the abductor pollicis brevis muscle as tested by TMS. Results: Patients with MS performed worse than controls in functional motor tests, CMLs were prolonged, and NAA/Cr was decreased. PAS-induced enhancement of corticospinal excitability and training-induced increments of motor performance were comparable between patients with MS and controls. Neither PAS-induced plasticity nor motor learning performance correlated with motor impairment or measures of CNS injury. Patients with high CNS injury and good motor performance did not differ significantly from those with high CNS injury and poor motor performance with respect to PAS-induced plasticity and motor learning success. Conclusions: Despite motor impairment and CNS injury in patients with multiple sclerosis (MS), rapid-onset motor plasticity is comparable to that in healthy subjects. Compensation of MS-related CNS injury is unlikely to be constrained by insufficient rapid-onset neuroplasticity.

Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case–control study

BackgroundFabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP).MethodsIn this case–control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function.ResultsAll Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients.ConclusionSmall fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.

Reduced early visual emotion discrimination as an index of diminished emotion processing in Parkinson's disease? - Evidence from event-related brain potentials.

Although Parkinsons disease (PD) is defined by its motor symptoms, it is now well recognized that cognitive and affective domains, such as recognition of emotion from facial expressions, may also be impaired. To examine brain mechanisms involved in processing of emotion recognition from facial expressions, we obtained affective ratings and visual event-related potentials (ERPs) in response to facial expressions from 18 PD patients under dopamine-replacement therapy, and 17 healthy age- and sex-matched controls. In control subjects, the early posterior negativity (EPN) of the ERP, which is thought to reflect early perceptual emotion discrimination, was larger in response to emotional compared to neutral facial expressions. In contrast, this emotional modulation of the EPN was absent in PD patients indicating impaired early emotion discrimination. Behaviorally, PD patients showed no impairments in emotion recognition as measured by affective ratings. These findings suggest that facial emotion processing may be disrupted at an early stage of visual neural processing in PD. Absence of behavioral impairment may point to compensatory strategies of emotion recognition in medicated PD patients. Further research should clarify these dissociations between behavioral and neurophysiological levels of emotion processing in PD.

Sensory processing and the rubber hand illusion-an evoked potentials study

The rubber hand illusion (RHI) paradigm—in which illusory bodily ownership is induced by synchronous tactile stimulation of a participants (hidden) hand and a (visible) surrogate—allows one to investigate how the brain resolves conflicting multisensory evidence during perceptual inference. To identify the functional anatomy of the RHI, we used multichannel EEG, acquired under three conditions of tactile stimulation. Evoked potentials were averaged from EEG signals registered to the timing of brushstrokes to the participants hand. The participants hand was stroked either in the absence of an artificial hand (REAL) or synchronously with an artificial hand, which either lay in an anatomically plausible (CONGRUENT) or impossible (INCONGRUENT) position. The illusion was reliably elicited in the CONGRUENT condition. For right-hand stimulation, significant differences between conditions emerged at the sensor level around 55 msec after the brushstroke at left frontal and right parietal electrodes. Response amplitudes were smaller for illusory (CONGRUENT) compared with nonillusory (INCONGRUENT and REAL) conditions in the contralateral perirolandic region (pre- and postcentral gyri), superior and inferior parietal lobule, whereas veridical perception of the artificial hand (INCONGRUENT) amplified responses at a scalp region overlying the contralateral postcentral gyrus and inferior parietal lobule compared with the remaining two conditions. Left-hand stimulation produced similar contralateral patterns. These results are consistent with predictive coding models of multisensory integration and may reflect the attenuation of somatosensory precision that is required to resolve perceptual hypotheses about conflicting multisensory input.