Showing papers by "Gereon R. Fink published in 2014"

Dorsal and Ventral Attention Systems Distinct Neural Circuits but Collaborative Roles

Abstract: The idea of two separate attention networks in the human brain for the voluntary deployment of attention and the reorientation to unexpected events, respectively, has inspired an enormous amount of research over the past years. In this review, we will reconcile these theoretical ideas on the dorsal and ventral attentional system with recent empirical findings from human neuroimaging experiments and studies in stroke patients. We will highlight how novel methods-such as the analysis of effective connectivity or the combination of neurostimulation with functional magnetic resonance imaging-have contributed to our understanding of the functionality and interaction of the two systems. We conclude that neither of the two networks controls attentional processes in isolation and that the flexible interaction between both systems enables the dynamic control of attention in relation to top-down goals and bottom-up sensory stimulation. We discuss which brain regions potentially govern this interaction according to current task demands.

Connectivity-based approaches in stroke and recovery of function

Abstract: Summary After focal damage, cerebral networks reorganise their structural and functional anatomy to compensate for both the lesion itself and remote effects. Novel developments in the analysis of functional neuroimaging data enable us to assess in vivo the specific contributions of individual brain areas to recovery of function and the effect of treatment on cortical reorganisation. Connectivity analyses can be used to investigate the effect of stroke on cerebral networks, and help us to understand why some patients make a better recovery than others. This systems-level view also provides insights into how neuromodulatory interventions might target pathological network configurations associated with incomplete recovery. In the future, such analyses of connectivity could help to optimise treatment regimens based on the individual network pathology underlying a particular neurological deficit, thereby opening the way for stratification of patients based on the possible response to an intervention.

Dose-dependent effects of theta burst rTMS on cortical excitability and resting-state connectivity of the human motor system.

Abstract: Theta burst stimulation (TBS), a specific protocol of repetitive transcranial magnetic stimulation (rTMS), induces changes in cortical excitability that last beyond stimulation. TBS-induced aftereffects, however, vary between subjects, and the mechanisms underlying these aftereffects to date remain poorly understood. Therefore, the purpose of this study was to investigate whether increasing the number of pulses of intermittent TBS (iTBS) (1) increases cortical excitability as measured by motor-evoked potentials (MEPs) and (2) alters functional connectivity measured using resting-state fMRI, in a dose-dependent manner. Sixteen healthy, human subjects received three serially applied iTBS blocks of 600 pulses over the primary motor cortex (M1 stimulation) and the parieto-occipital vertex (sham stimulation) to test for dose-dependent iTBS effects on cortical excitability and functional connectivity (four sessions in total). iTBS over M1 increased MEP amplitudes compared with sham stimulation after each stimulation block. Although the increase in MEP amplitudes did not differ between the first and second block of M1 stimulation, we observed a significant increase after three blocks (1800 pulses). Furthermore, iTBS enhanced resting-state functional connectivity between the stimulated M1 and premotor regions in both hemispheres. Functional connectivity between M1 and ipsilateral dorsal premotor cortex further increased dose-dependently after 1800 pulses of iTBS over M1. However, no correlation between changes in MEP amplitudes and functional connectivity was detected. In summary, our data show that increasing the number of iTBS stimulation blocks results in dose-dependent effects at the local level (cortical excitability) as well as at a systems level (functional connectivity) with a dose-dependent enhancement of dorsal premotor cortex-M1 connectivity.

Comparison of 18F-FET PET and Perfusion-Weighted MR Imaging: A PET/MR Imaging Hybrid Study in Patients with Brain Tumors

Abstract: PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) provides important diagnostic information in addition to that from conventional MR imaging on tumor extent and activity of cerebral gliomas. Recent studies suggest that perfusion-weighted MR imaging (PWI), especially maps of regional cerebral blood volume (rCBV), may provide similar diagnostic information. In this study, we directly compared 18F-FET PET and PWI in patients with brain tumors. Methods: Fifty-six patients with gliomas were investigated using static 18F-FET PET and PWI. For comparison, 8 patients with meningiomas were included. We generated a set of tumor and reference volumes of interest (VOIs) based on morphologic MR imaging and transferred these VOIs to the corresponding 18F-FET PET scans and PWI maps. From these VOIs, tumor-to-brain ratios (TBR) were calculated, and normalized histograms were generated for 18F-FET PET and rCBV maps. Furthermore, in rCBV maps and in 18F-FET PET scans, tumor volumes, their spatial congruence, and the distance between the local hot spots were assessed. Results: For patients with glioma, TBR was significantly higher in 18F-FET PET than in rCBV maps (TBR, 2.28 ± 0.99 vs. 1.62 ± 1.13; P

Network Connectivity and Individual Responses to Brain Stimulation in the Human Motor System

Abstract: The mechanisms driving cortical plasticity in response to brain stimulation are still incompletely understood. We here explored whether neural activity and connectivity in the motor system relate to the magnitude of cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Twelve right-handed volunteers underwent functional magnetic resonance imaging during rest and while performing a simple hand motor task. Resting-state functional connectivity, task-induced activation, and task-related effective connectivity were assessed for a network of key motor areas. We then investigated the effects of intermittent theta-burst stimulation (iTBS) on motor-evoked potentials (MEP) for up to 25 min after stimulation over left primary motor cortex (M1) or parieto-occipital vertex (for control). ITBS-induced increases in MEP amplitudes correlated negatively with movement-related fMRI activity in left M1. Control iTBS had no effect on M1 excitability. Subjects with better response to M1-iTBS featured stronger preinterventional effective connectivity between left premotor areas and left M1. In contrast, resting-state connectivity did not predict iTBS aftereffects. Plasticity-related changes in M1 following brain stimulation seem to depend not only on local factors but also on interconnected brain regions. Predominantly activity-dependent properties of the cortical motor system are indicative of excitability changes following induction of cortical plasticity with rTMS.

Individualized current-shaping reduces DBS-induced dysarthria in patients with essential tremor

Abstract: Objective: To investigate in patients with essential tremor (ET) treated with thalamic/subthalamic deep brain stimulation (DBS) whether stimulation-induced dysarthria (SID) can be diminished by individualized current-shaping with interleaving stimulation (cs-ILS) while maintaining tremor suppression (TS). Methods: Of 26 patients screened, 10 reported SID and were invited for testing. TS was assessed by the Tremor Rating Scale and kinematic analysis of postural and action tremor. SID was assessed by phonetic and logopedic means. Additionally, patients rated their dysarthria on a visual analog scale. Results: In 6 of the 10 patients with ET, DBS-ON (relative to DBS-OFF) led to SID while tremor was successfully reduced. When comparing individualized cs-ILS with a non–current-shaped interleaving stimulation (ILS) in these patients, there was no difference in TS while 4 of the 6 patients showed subjective improvement of speech during cs-ILS. Phonetic analysis (ILS vs cs-ILS) revealed that during cs-ILS there was a reduction of voicing during the production of voiceless stop consonants and also a trend toward an improvement in oral diadochokinetic rate, reflecting less dysarthria. Logopedic rating showed a trend toward deterioration in the diadochokinesis task when comparing ON with OFF but no difference between ILS and cs-ILS. Conclusion: This is a proof-of-principle evaluation of current-shaping in patients with ET treated with thalamic/subthalamic DBS and experiencing SID. Data suggest a benefit on SID from individual shaping of current spread while TS is preserved. Classification of evidence: This study provides Class IV evidence that in patients with ET treated with DBS with SID, individualized cs-ILS reduces dysarthria while maintaining tremor control. Neurology® 2014;82:614–619

Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo

Abstract: Aromatic (ar-) turmerone is a major bioactive compound of the herb Curcuma longa. It has been suggested that ar-turmerone inhibits microglia activation, a property that may be useful in treating neurodegenerative disease. Furthermore, the effects of ar-turmerone on neural stem cells (NSCs) remain to be investigated. We exposed primary fetal rat NSCs to various concentrations of ar-turmerone. Thereafter, cell proliferation and differentiation potential were assessed. In vivo, naive rats were treated with a single intracerebroventricular (i.c.v.) injection of ar-turmerone. Proliferative activity of endogenous NSCs was assessed in vivo, by using noninvasive positron emission tomography (PET) imaging and the tracer [18F]-fluoro-L-thymidine ([18F]FLT), as well as ex vivo. In vitro, ar-turmerone increased dose-dependently the number of cultured NSCs, because of an increase in NSC proliferation (P < 0.01). Proliferation data were supported by qPCR-data for Ki-67 mRNA. In vitro as well as in vivo, ar-turmerone promoted neuronal differentiation of NSCs. In vivo, after i.c.v. injection of ar-turmerone, proliferating NSCs were mobilized from the subventricular zone (SVZ) and the hippocampus of adult rats, as demonstrated by both [18F]FLT-PET and histology (P < 0.05). Both in vitro and in vivo data suggest that ar-turmerone induces NSC proliferation. Ar-turmerone thus constitutes a promising candidate to support regeneration in neurologic disease.

Gait and upper limb variability in Parkinson’s disease patients with and without freezing of gait

Abstract: Patients with Parkinson’s disease (PD) and freezing of gait (FOG) (freezers) demonstrate high gait variability. The objective of this study was to determine whether freezers display a higher variability of upper limb movements and elucidate if these changes correlate with gait. We were the first group to compare directly objectively measured gait and upper limb movement variability of freezers between freezing episodes. Patients with objectively verified FOG (n = 11) and PD patients without FOG (non-freezers) (n = 11) in a non-randomized medication condition (OFF/ON) were analyzed. Uncued antiphasic finger tapping and forearm diadochokinetic movements were analyzed via three-dimensional ultrasound kinematic measurements. Gait variability of straight gait was assessed using ground reaction forces. Freezers had shorter stride length (p = 0.004) and higher stride length variability (p = 0.005) in the medication OFF condition. Movement variability was not different during finger tapping or diadochokinesia between the groups. There was a trend towards more freezing of the upper limb during finger tapping for the freezers (p = 0.07). Variability in stride length generation and stride timing was not associated with variability of upper limb movement in freezers. Our findings demonstrate that: (1) freezers have a higher spatial gait variability between freezing episodes; (2) freezing-like episodes of the upper limb occur in PD patients, and tend to be more pronounced among freezers than non-freezers for finger tapping; (3) spatial and temporal upper extremity variability is equally affected in freezers and non-freezers in an uncued task. Upper limb freezing is not correlated to lower limb freezing, implicating a different pathophysiology.

Neural response to social rejection in children with early separation experiences.

Abstract: Objective Nonhuman and human studies have documented the adverse effects of early life stress (ELS) on emotion regulation and underlying neural circuitry. Less is known about how these experiences shape social processes and neural circuitry. In this study, we thus investigated how ELS affects children's perception of, and neural response to, negative social experiences in a social exclusion paradigm (Cyberball). Method Twenty-five foster or adopted children with ELS (age 10.6 ± 1.8 years, 13 male and 12 female) and 26 matched nonseparated controls (age 10.38 ± 1.7 years, 12 male and 14 female) took part in a Cyberball paradigm during functional magnetic resonance imaging (fMRI). Results During peer rejection, children with ELS reported significantly more feelings of exclusion and frustration than nonseparated controls. On the neural level, children with ELS showed reduced activation in the dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (dlPFC), and reduced connectivity between dlPFC-dACC, areas previously implicated in affect regulation. Conversely, children with ELS showed increased neural activation in brain regions involved in memory, arousal, and threat-related processing (middle temporal gyrus, thalamus, ventral tegmental area) relative to controls during social exclusion. The number of separation experiences before entering the permanent family predicted reductions in fronto-cingulate recruitment. The relationship between early separations and self-reported exclusion was mediated by dlPFC activity. Conclusion The findings suggest that ELS leads to alterations in neural circuitry implicated in the regulation of socioemotional processes. This neural signature may underlie foster children's differential reactivity to rejection in everyday life and could increase risk for developing affective disorders.

Age dependent changes in the neural substrates of empathy in Autism Spectrum Disorder

Abstract: In typical development, empathic abilities continue to refine during adolescence and early adulthood. Children and adolescents with autism spectrum disorders (ASD) show deficits in empathy, whereas adults with ASD may have developed compensatory strategies. We aimed at comparing developmental trajectories in the neural mechanisms underlying empathy in individuals with ASD and typically developing control (TDC) subjects. Using an explicit empathizing paradigm and functional magnetic resonance imaging, 27 participants with ASD and 27 TDC aged 12–31 years were investigated. Participants were asked to empathize with emotional faces and to either infer the face’s emotional state (other-task) or to judge their own emotional response (self-task). Differential age-dependent changes were evident during the self-task in the right dorsolateral prefrontal cortex, right medial prefrontal cortex, right inferior parietal cortex, right anterior insula and occipital cortex. Age-dependent decreases in neural activation in TDC were paralleled by either increasing or unchanged age-dependent activation in ASD. These data suggest ASD-associated deviations in the developmental trajectories of self-related processing during empathizing. In TDC, age-dependent modulations of brain areas may reflect the ‘fine-tuning’ of cortical networks by reduction of task-unspecific brain activity. Increased age-related activation in individuals with ASD may indicate the development of compensatory mechanisms.

Deep brain stimulation in the ventrolateral thalamus/subthalamic area in dystonia with head tremor.

Abstract: Background Pallidal deep brain stimulation (GPi-DBS) effectively ameliorates idiopathic dystonia, although approximately 15% of patients respond insufficiently. Although various thalamic and subthalamic targets have been suggested for dystonic tremor, no systematic studies have been published on thalamic DBS in dystonic tremor. We assessed the effect of thalamic/subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind design. Methods Dystonic head tremor and dystonia before and 3 months after surgery were quantified via blinded video-ratings using the Fahn-Tolosa-Marin-Tremor-Scale and the Burke-Fahn-Marsden-Dystonia-Rating-Scale in seven patients with idiopathic cervical or segmental dystonia, dystonic head tremor, and bilateral Th-DBS. Pain, side effects, adverse events, and stimulation parameters were assessed. Results Th-DBS improved dystonic tremor and dystonia (P < 0.05; 57.1% and 70.4%, respectively). Head tremor amplitude and pain were also improved (P < 0.05; 77.5% and 90.0%, respectively). Side effects included dysarthria, gait disturbance, slowness of movement, and weight gain. Conclusion Dystonic head tremor and dystonia can be improved with Th-DBS. © 2014 International Parkinson and Movement Disorder Society

Masking produces compression of space and time in the absence of eye movements.

Abstract: Whenever the visual stream is abruptly disturbed by eye movements, blinks, masks, or flashes of light, the visual system needs to retrieve the new locations of current targets and to reconstruct the timing of events to straddle the interruption. This process may introduce position and timing errors. We here report that very similar errors are seen in human subjects across three different paradigms when disturbances are caused by either eye movements, as is well known, or, as we now show, masking. We suggest that the characteristic effects of eye movements on position and time, spatial and temporal compression and saccadic suppression of displacement, are consequences of the interruption and the subsequent reconnection and are seen also when visual input is masked without any eye movements. Our data show that compression and suppression effects are not solely a product of ocular motor activity but instead can be properties of a correspondence process that links the targets of interest across interruptions in visual input, no matter what their source.

Corneal confocal microscopy detects small fiber damage in chronic inflammatory demyelinating polyneuropathy (CIDP).

Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune-mediated peripheral neuropathy with multifocal involvement. Reliable biomarkers for diagnosis, disease progression, and treatment response remain to be developed. We assessed the utility of corneal confocal microscopy (CCM) as a diagnostic marker for CIDP in 16 patients. CCM parameters including corneal nerve fiber density (NFD), nerve fiber length, number of main nerve trunks, number of nerve branches, nerve tortuosity, and dendritic cell density (DCD) were compared to those from 15 healthy controls and correlated with clinical and electrophysiological findings. CIDP patients had a significantly lower corneal NFD compared to healthy controls. The total nerve fiber length and the number of nerve branches were significantly decreased, whereas nerve tortuosity was increased in patients with CIDP. There was no positive correlation between corneal NFD and clinical or electrophysiological assessments. The average DCD was not significantly different in CIDP patients and controls. CCM measures suggest damage to small sensory afferents in the cornea in CIDP patients. Further studies are needed to compare different neuropathic conditions and to explore longitudinal changes of CCM parameters.

Posterior reversible encephalopathy syndrome and stroke after intravenous immunoglobulin treatment in Miller-Fisher syndrome/Bickerstaff brain stem encephalitis overlap syndrome.

Abstract: The association of a posterior reversible encephalopathy syndrome (PRES) without arterial hypertension with autoimmune-mediated inflammatory neuropathies such as Guillain–Barre syndrome (GBS) is a rare and poorly understood phenomenon. To date, PRES has been described as initial manifestation, coincidental finding, or adverse event subsequent to immunomodulatory treatment with intravenous immunoglobulin (IVIG) in cases of axonal and demyelinating GBS as well as in Miller–Fisher syndrome (MFS). We here report a case of MFS/Bickerstaff brain stem encephalitis (BBE)–overlap syndrome and nonhypertensive PRES that occurred in close temporal association with IVIG treatment and caused stroke. Immunoadsorption ameliorated the disease course. Our case supports the notion that in severe cases, immunoadsorption should be considered as first-line therapy instead of IVIG for rapid removal of IgG and thus to hasten recovery and improve functional outcome.

The effects of 1 Hz rTMS preconditioned by tDCS on gait kinematics in Parkinson’s disease

Abstract: Hypokinetic gait is a common and very disabling symptom of Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) over the motor cortex has been used with variable effectiveness to treat hypokinesia in PD. Preconditioning rTMS by transcranial direct current stimulation (tDCS) may enhance its effectiveness to treat hypokinetic gait in PD. Three-dimensional kinematic gait analysis was performed (1) prior to, (2) immediately after and (3) 30 min after low-frequency rTMS (1 Hz, 900 pulses, 80% of resting motor threshold) over M1 contralateral to the more affected body side preconditioned by (1) cathodal, (2) anodal or (3) sham tDCS (amperage: 1 mA, duration: 10 min) in ten subjects with PD (7 females, mean age 63 ± 9 years) and ten healthy subjects (four females, mean age 50 ± 11 years). The effects of tDCS-preconditioned rTMS on gait kinematics were assessed by the following parameters: number of steps, step length, stride length, double support time, cadence, swing and stance phases. Our data suggest a bilateral improvement of hypokinetic gait in PD after 1 Hz rTMS over M1 of the more affected body side preceded by anodal tDCS. In contrast, 1 Hz rTMS alone (preceded by sham tDCS) and 1 Hz rTMS preceded by cathodal tDCS were ineffective to improve gait kinematics in PD. In healthy subjects, gait kinematics was unaffected by either intervention. Preconditioning motor cortex rTMS by tDCS is a promising approach to treat hypokinetic gait in PD.

Young adults with dyskinetic cerebral palsy improve subjectively on pallidal stimulation, but not in formal dystonia, gait, speech and swallowing testing.

Abstract: Background: Pharmacological treatment of dyskinetic cerebral palsy (CP) is often ineffective. Data about outcome of deep brain stimulation (DBS) in these patients

Dissociating animacy processing in high-functioning autism: Neural correlates of stimulus properties and subjective ratings

Abstract: When movements indicate meaningful actions, even nonbiological objects induce the impression of “having a mind” or animacy. This basic social ability was investigated in adults with high-functioning autism (HFA, n = 13, and matched controls, n = 13) by systematically varying motion properties of simple geometric shapes. Critically, trial-by-trial variations of (1) motion complexity of stimuli, and of (2) participants’ individual animacy ratings were separately correlated with neural activity to dissociate cognitive strategies relying more closely on stimulus analysis vs. subjective experience. Increasing motion complexity did not yield any significant group differences, and in both groups, it correlated with neural activity in regions involved in perceptual and evaluative processing, including the ventral medial prefrontal cortex (mPFC), superior temporal gyrus (STG) and posterior cingulate cortex (PCC). In contrast, although there were no significant behavioral differences between the groups, increasing ...

The moon illusion and size-distance scaling-evidence for shared neural patterns

Abstract: A moon near to the horizon is perceived larger than a moon at the zenith, although-obviously-the moon does not change its size. In this study, the neural mechanisms underlying the "moon illusion" were investigated using a virtual 3-D environment and fMRI. Illusory perception of an increased moon size was associated with increased neural activity in ventral visual pathway areas including the lingual and fusiform gyri. The functional role of these areas was further explored in a second experiment. Left V3v was found to be involved in integrating retinal size and distance information, thus indicating that the brain regions that dynamically integrate retinal size and distance play a key role in generating the moon illusion.

The synthetic NCAM mimetic peptide FGL mobilizes neural stem cells in vitro and in vivo

Abstract: The neural cell adhesion molecule (NCAM) plays a role in neurite outgrowth, synaptogenesis, and neuronal differentiation. The NCAM mimetic peptide FG Loop (FGL) promotes neuronal survival in vitro and enhances spatial learning and memory in rats. We here investigated the effects of FGL on neural stem cells (NSC) in vitro and in vivo. In vitro, cell proliferation of primary NSC was assessed after exposure to various concentrations of NCAM or FGL. The differentiation potential of NCAM- or FGL-treated cells was assessed immunocytochemically. To investigate its influence on endogenous NSC in vivo, FGL was injected subcutaneously into adult rats. The effects on NSC mobilization were studied both via non-invasive positron emission tomography (PET) imaging using the tracer [18F]-fluoro-l-thymidine ([18F]FLT), as well as with immunohistochemistry. Only FGL significantly enhanced NSC proliferation in vitro, with a maximal effect at 10 μg/ml. During differentiation, NCAM promoted neurogenesis, while FGL induced an oligodendroglial phenotype; astrocytic differentiation was neither affected by NCAM or FGL. Those differential effects of NCAM and FGL on differentiation were mediated through different receptors. After FGL-injection in vivo, proliferative activity of NSC in the subventricular zone (SVZ) was increased (compared to placebo-treated animals). Moreover, non-invasive imaging of cell proliferation using [18F]FLT-PET supported an FGL-induced mobilization of NSC from both the SVZ and the hippocampus. We conclude that FGL robustly induces NSC mobilization in vitro and in vivo, and supports oligodendroglial differentiation. This capacity renders FGL a promising agent to facilitate remyelinization, which may eventually make FGL a drug candidate for demyelinating neurological disorders.

Dysautonomia in Narcolepsy: Evidence by Questionnaire Assessment

Abstract: Background and Purpose Excessive daytime sleepiness and sudden sleep attacks are the main features of narcolepsy, but rapid-eye-movement sleep behavior disorder (RBD), hyposmia, and depression can also occur. The latter symptoms are nonmotor features in idiopathic Parkinson's disease (IPD). In the present study, IPD-proven diagnostic tools were tested to determine whether they are also applicable in the assessment of narcolepsy.

Klinische Neuropsychologie ist keine psychologische Psychotherapie

Abstract: Die Neuropsychologie hat als wissenschaftliches Fach und als klinische Anwendungsdisziplin in den letzten Jahrzehnten einen auserordentlichen Aufschwung genommen und sich von einer randst ndigen Subdisziplin in Medizin und Psychologie zu einem eigenst ndigen Fach emanzipiert. In den letzten Jahren wurde die klinische Neuropsychologie sukzessive als Therapieverfahren anerkannt und in die Strukturen der ambulanten Gesundheitsversorgung integriert.Wir sehen jedoch die vonVerbandsfunktion ren der Psychologen, u.a. aus der Gesellschaft f r Neuropsychologie (GNP), favorisierte sozialrechtliche Eingliederung der klinischen Neuropsychologie in die psychologische Psychotherapie sachlich und fachlich als falsch an und bef rchten, dass die durch diese Einordnung unter die Psychotherapie bedingten inhaltlichen und formalen Implikationen mittelfristig zu einer Gef hrdung des Patientenwohls f hren werden.