Comparing the after-effects of continuous theta burst stimulation and conventional 1 Hz rTMS on semantic processing.

Our aim was to evaluate continuous theta burst stimulation (cTBS) as a tool to induce temporary impairment (virtual lesion) in semantic processing. Four groups with 20 subjects each were stimulated. In the three experimental groups the stimulation site was the left superior temporal cortex. Stimulation was either 1Hz repetitive transcranial magnetic stimulation (rTMS) at 100% resting motor threshold (RMT) or cTBS, with intensities of 80% or 90% active motor threshold (AMT). The TMS-control group was stimulated at the right medial prefrontal cortex with 1 Hz rTMS. After stimulation subjects accomplished a lexical decision task with a duration of about 20 min. In an additional fifth group the lexical decision task was performed without TMS. Reaction times were not influenced by cTBS applied with 80% AMT, but prolonged for about 80 ms with 90% AMT compared to the no stimulation condition. An increase of 140 ms was found after 1 Hz rTMS. The effect lasted for the whole task, but declined from the first to the second half of the experiment. The direct comparison of cTBS and 1 Hz rTMS suggests that both stimulation patterns can induce virtual lesions in the left superior temporal cortex and impair semantic processing. We suppose that cTBS could replace 1 Hz rTMS in this field since the application is faster and it is more comfortable to the subjects.

Effect of 1 Hz repetitive transcranial magnetic stimulation over the auditory cortex on audiometry and otoacustic emissions.

Repetitive transcranial magnetic stimulation (rTMS) at low frequencies (≤1 Hz) delivered to the primary motor cortex for 15 min or longer has been shown to reduce motor cortex excitability. Over the visual cortex, 1 Hz rTMS led to increased phosphene thresholds and over the auditory cortex rTMS reduced auditory evoked potentials. rTMS above the auditory or temporo-parietal cortex has also been reported to reduce the severity of auditory hallucinations and the perception of tinnitus. However, possible unwanted effects on hearing function have not yet been investigated systematically. 12 right-handed normal hearing subjects (5 male, mean age 28.2 ± 4.3) received a single session of 18 min 1 Hz rTMS at 90% resting motor threshold intensity using an established coil positioning method targeting the Heschl's area of the left superior temporal gyrus. Standard pure tone audiometry and distortion-products otoacustic emissions (DPOAE) were performed before and immediately after stimulation. The main finding was that one session of 1 Hz rTMS over the temporal cortex modified neither the auditory threshold meaningfully nor the presence of DPOAE in healthy subjects. In conclusion, we found in this pilot approach no obvious indication for auditory dysfunctions due to direct electromagnetic stimulation of the superior temporal gyrus after one session of rTMS in healthy controls that may be interpreted as unwanted side effects. Nevertheless monitoring of auditory functions is strongly recommended in future clinical trials stimulating the auditory cortex, as this has not been done systematically in the past.

Transcranial magnetic stimulation in depression--lessons from the multicentre trials.

Looking at novelties and advances in medicine in particular in the treatment of major depressive disorder no principally new antidepressant treatment strategy has been established in clinical routine in the last fifty years. However, regarding the considerable issue of treatment resistance in depression, new therapeutic strategies are urgently required. In this context, repetitive transcranial magnetic stimulation above the dorsolateral prefrontal cortex has been proposed as a potential new treatment option for depression; furthermore, in October 2008 a first rTMS-device (NeuroStar TMS Therapy System) was approved by the FDA for the treatment of treatment resistant major refractory depression in adults. Yet, despite now nearly two decades of research in this field, no final answer concerning its validity for antidepressant treatment in the clinical practice is given. Numerous studies with small sample sizes and heterogeneous designs have been performed in this field yielding to different results. These were subjected to meta-analyses, assessing the antidepressant effect of rTMS, which are briefly summarized in this article. Further, multicentre-trials with larger numbers of patients were performed, which are presented and critically discussed here in more detail. This short review shall thus provide an overview of the current status of knowledge concerning rTMS in depression and it also provides some recommendations for future research in this field.

The value of neuronavigated rTMS for the treatment of depression.

Repetitive transcranial magnetic stimulation (rTMS) has been increasingly evaluated as a therapeutic tool for the treatment of depression, using various stimulation parameters and protocols. Heterogeneous results have been reported with regard to clinical outcome, at least partly due to the variety of procedures for coil placement above the desired site of stimulation. This article reviews the strategies for coil positioning in the treatment of depression. Considering preliminary clinical evidence, neuronavigated rTMS appears desirable to treat depression, compared to the standard targeting procedure (5cm anterior to the motor cortex). Coil positioning strategy might improve in the future by taking into consideration the individual abnormalities revealed by functional neuroimaging data.

Antidepressant effects of augmentative transcranial magnetic stimulation: randomised multicentre trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new treatment option for depression. Previous studies were performed with low sample sizes in single centres and reported heterogeneous results. AIMS: To investigate the efficacy of rTMS as augmentative treatment in depression. METHOD: In a randomised, double-blind, sham-controlled multicentre trial 127 patients with moderate to severe depressive episodes were randomly assigned to real or sham stimulation for 3 weeks in addition to simultaneously initiated antidepressant medication. RESULTS: We found no difference in the responder rates of the real and the sham treatment groups (31% in each) or in the decrease of the scores on the depression rating scales. CONCLUSIONS: The data do not support previous reports from smaller samples indicating an augmenting or accelerating antidepressant effect of rTMS. Further exploration of the possible efficacy of other stimulation protocols or within selected sub-populations of patients is necessary.

[A 3D FEM model for calculation of electromagnetic fields in transmagnetic stimulation]. / A 3D FEM model for calculation of electromagnetic fields in transcranial magnetic stimulation.

We developed a realistic finite elements method (FEM) model of the brain for the calculation of electromagnetic fields in transcranial magnetic stimulation (TMS). A focal butterfly stimulation coil was X-rayed, parameterized, and modeled. The magnetic field components of the TMS coil were calculated and compared for validation to pointwise measurements of the magnetic fields with a Hall sensor. We found a mean deviation of 7.4% at an axial distance of 20 mm to the coil. A 3D brain model with the biological tissues of white and gray matter, bone, and cerebrospinal fluid was developed. At a current sweep of 1000 A in 120 microseconds, the maximum induced current density in gray matter was 177 mA/m2 and the strongest electric field gradient covered an area of 40 mm x 53 mm.

The influence of current direction on phosphene thresholds evoked by transcranial magnetic stimulation.

OBJECTIVES: To quantify phosphene thresholds evoked by transcranial magnetic stimulation (TMS) in the occipital cortex as a function of induced current direction. METHODS: Phosphene thresholds were determined in 6 subjects. We compared two stimulator types (Medtronic-Dantec and Magstim) with monophasic pulses using the standard figure-of-eight coils and systematically varied hemisphere (left and right) and induced current direction (latero-medial and medio-lateral). Each measurement was made 3 times, with a new stimulation site chosen for each repetition. Only those stimulation sites were investigated where phosphenes were restricted to one visual hemifield. Coil positions were stereotactically registered. Functional magnetic resonance imaging (fMRI) of retinotopic areas was performed in 5 subjects to individually characterize the borders of visual areas; TMS stimulation sites were coregistered with respect to visual areas. RESULTS: Despite large interindividual variance we found a consistent pattern of phosphene thresholds. They were significantly lower if the direction of the induced current was oriented from lateral to medial in the occipital lobe rather than vice versa. No difference with respect to the hemisphere was found. Threshold values normalized to the square root of the stored energy in the stimulators were lower with the Medtronic-Dantec device than with the Magstim device. fMRI revealed that stimulation sites generating unilateral phosphenes were situated at V2 and V3. Variability of phosphene thresholds was low within a cortical patch of 2x2cm(2). Stimulation over V1 yields phosphenes in both visual fields. CONCLUSIONS: The excitability of visual cortical areas depends on the direction of the induced current with a preference for latero-medial currents. Although the coil positions used in this study were centered over visual areas V2 and V3, we cannot rule out the possibility that subcortical structures or V1 could actually be the main generator for phosphenes.

Motor thresholds in humans: a transcranial magnetic stimulation study comparing different pulse waveforms, current directions and stimulator types.

OBJECTIVES: To evaluate the stimulation effectiveness of different magnetic stimulator devices with respect to pulse waveform and current direction in the motor cortex. METHODS: In 8 normal subjects we determined motor thresholds of transcranial magnetic stimulation in a small hand muscle. We used focal figure-of-eight coils of 3 common stimulators (Dantec Magpro, Magstim 200 and Magstim Rapid) and systematically varied current direction (postero-anterior versus antero-posterior, perpendicular to the central sulcus) as well as pulse waveform (monophasic versus biphasic). The coil position was kept constant with a stereotactic positioning device. RESULTS: Motor thresholds varied consistently with changing stimulus parameters, despite substantial interindividual variability. By normalizing the values with respect to the square root of the energy of the capacitors in the different stimulators, we found a homogeneous pattern of threshold variations. The normalized Magstim threshold values were consistently higher than the normalized Dantec thresholds by a factor of 1.3. For both stimulator types the monophasic pulse was more effective if the current passed the motor cortex in a postero-anterior direction rather than antero-posterior. In contrast, the biphasic pulse was weaker with the first upstroke in the postero-anterior direction. We calculated mean factors for transforming the intensity values of a particular configuration into that of another configuration by normalizing the different threshold values of each individual subject to his lowest threshold value. CONCLUSIONS: Our transformation factors allow us to compare stimulation intensities from studies using different devices and pulse forms. The effectiveness of stimulation as a function of waveform and current direction follows the same pattern as in a peripheral nerve preparation (J Physiol (Lond) 513 (1998) 571).

Visual attention and metacontrast modify latency to perception in opposite directions.

In human observers, cue-induced visual attention ('bottom-up' transient focal attention) shortens the latency of perception. Metacontrast reduces the intensity of perception and can even obliterate it. We show that a close relationship exists between both, but that their effects are reversed: cue-induced visual attention not only shortens latency but also intensifies perception, and metacontrast not only lowers intensity of perception but also prolongs latency. A common neurophysiological mechanism for both is possible. Indirect evidence suggests that this could be a subthreshold modulation of neuronal thresholds by de- and hyperpolarization.

Cortical visual processing is temporally dispersed by luminance in human subjects.

Increasing the intensity of a stimulus such as luminance results in faster processing of the signal and therefore decreases simple motor reaction time (RT). We studied the latencies of visual evoked potentials (VEPs, N80, P100, N130) and RTs in eight subjects to flashing spots of light while varying the luminance of the spots from 1 to 1000 cd/m2. The data show that processing time as a function of intensity is modified not only at the retina but also at later processing sites. This indicates a temporal dispersion of the visual signal over the whole processing stream from visual input all the way to motor output.

Phosphenes and transient scotomas induced by magnetic stimulation of the occipital lobe: their topographic relationship.

Transcranial magnetic stimulation (TMS) of the visual cortex is known to induce phosphenes and is able to suppress visual perception. To address the topographic relationship of phosphenes and transient scotomas, the visual field of 10 normal subjects was investigated using a perimetric approach. The central visual field (diameter: 20 degrees) was tested at 32 sites. Perceptual thresholds were determined by presenting 1 ms test spots flashed with varying intensity in random order. TMS was applied with a focal figure-of-eight coil placed over the inion. All subjects perceived phosphenes, mostly restricted to one of the lower quadrants within the visual field. In 13 out of 15 investigations, a magnetic stimulus triggered 100 ms after the visual target resulted in a relative scotoma with threshold changes of 8 dB or more. In 9 of 13 investigations, scotomas coincided spatially with sketches of phosphenes made by subjects in a separate test. Scotomas covered only a small percentage of the total visual field, which may explain the failure of previous studies to find perceptual suppression with the focal coil. The present result demonstrates that phosphenes evoked during TMS can serve as a guide for optimal visual stimulus alignment in neuropsychological experiments.

The Fröhlich effect: a consequence of the interaction of visual focal attention and metacontrast.

Usually we assume that the central nervous system preserves temporal sequences. Here we show that moving objects--in the context of behaviour often dangerous ones--are seen with a shorter latency than stationary (flashed) objects. In addition moving objects are deblurred. Two mechanisms contribute to this functional specialisation: cue-induced visual focal attention and metacontrast. Under unnatural conditions these mechanisms lead to an optical illusion first described by Fröhlich [Fröhlich, F. W. (1923). Uber die Messung der Empfindungszeit. Zeitschrift für Sinnesphysiologie, 54, 58-78].

Are recognition deficits following occipital lobe TMS explained by raised detection thresholds?

It is known that transcranial magnetic stimulation (TMS) administered over the occipital pole suppresses recognition of visual objects. Our aim was to ascertain whether this suppression can be interpreted as a change in visual contrast threshold. Four subjects detected the orientation of an U-shaped hook flashed for 21 ms. Under control conditions, mean contrast threshold was found at 0.88 log units Weber contrast. Thresholds were raised if TMS was applied 40-200 ms after the visual stimulus. Maximum elevation was 1.67 log units under TMS at 120 ms stimulus onset asynchrony. This phenomenon can be interpreted as a reduction in signal-to-noise ratio of the visual stimuli by TMS, which can be compensated for by increasing the contrast of the stimuli.

Repetition blindness in schizophrenic patients.

Repetition blindness is the failure to report the detection of repeated items in rapid visually presented lists. It can be explained in terms of either a processing limitation or an active inhibitory process. In two studies conducted in either English or German language we set out to induce repetition blindness under various conditions in a total of 47 control subjects and 30 schizophrenic patients. The patients displayed the phenomenon to at least the same degree as normal control subjects. These results render unlikely accounts of repetition blindness which involve processes known to be dysfunctional in schizophrenic patients. Moreover, the study provides an example of how the performance of schizophrenic patients can constrain theories of normal cognition.

[Functional magnetic resonance tomography in psychopathological research]. / Funktionelle Magnetresonanztomographie in der psychopathologischen Forschung.

Mental disorders are characterised by psychopathological symptoms which correspond to functional brain states. Functional magnetic resonance imaging (fMRI) is used for the non-invasive study of cerebral activation patterns in man. First of all, the neurobiological principles and presuppositions of the method are outlined. Results from the Heidelberg imaging lab on several simple sensorimotor tasks as well as higher cognitive functions, such as working and semantic memory, are then presented. Thereafter, results from preliminary fMRI studies of psychopathological symptoms are discussed, with emphasis on hallucinations, psychomotoric phenomena, emotions, as well as obsessions and compulsions. Functional MRI is limited by the physics underlying the method, as well as by practical constraints regarding its use in conjunction with mentally ill patients. Within this framework, the problems of signal-to-noise ratio, data analysis strategies, motion correction, and neurovascular coupling are considered. Because of the rapid development of the field of fMRI, maps of higher cognitive functions and their respective pathology seem to be coming within easy reach.

Functional magnetic resonance imaging of category-specific cortical activation: evidence for semantic maps.

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of cortical activity during a picture naming task. Subjects (n=12) had to covertly name either animals or furniture items. Functional scanning was performed using a conventional 1.5-Tesla whole-body MRI system. Images obtained during naming the two categories were compared using a non-parametric test. The study revealed evidence for domain-specific lexical regions in left middle, right middle and inferior frontal areas, as well as in superior and middle temporal areas. The results corroborate neuropsychological data and demonstrate directly and non-invasively in human volunteers that semantic representations in frontal and temporal areas are, to some degree, localized and possibly implemented as multiple maps. A completely distributed storage of semantic information is rendered unlikely.

[Frontal-subcortical neuronal circuits]. / Frontal-subkortikale neuronale Schaltkreise.

Recent findings on frontal and subcortical circuitry provide an uniform and integral view of numerous neurological and psychiatric disorders. Frontal cortical areas, the basal ganglia and the thalamus are linked in parallel circuits, which can be related to specific mental and motor functions and pathologies. In particular, five such circuits can be distinguished: (1) motor, (2) oculomotor, (3) dorsolateral-pre-frontal, (4) lateral orbitofrontal, and (5) mediofrontal limbic. The anatomy of these circuits as well as the involved neurotransmitters provide a comprehensive framework for understanding the symptoms of neurological diseases such as frontal lobe infarctions, Parkinson's, Huntington's, and Binswanger's disease, as well as psychiatric diseases such as schizophrenic, affective, and obsessive-compulsive disorder.

Functional MR imaging of the prefrontal cortex: specific activation in a working memory task.

Functional magnetic resonance imaging was used to identify cortical regions activated by a working memory task involving letter detection. Twenty four normal subjects were scanned with a conventional 1.5-T magnet while performing one of two tasks: In the activation task, subjects responded by pressing a button whenever any presented letter was the same as the second last in the sequence. In the control condition, subjects had to respond to a single predefined letter without memory update requirements. The activation task and the control condition were identical with regard to perceptual input and motor output. They were different only regarding the task demand. Movement artifacts were minimized in a two way strategy and eight subjects were excluded from further analysis. Functional MR data from the remaining 16 subjects were analyzed on the basis of anatomical regions-of-interest which were manually defined in each subject. The engagement of working memory produced significant activation in the dorsolateral prefrontal cortex (Brodmann's areas 9, 10, 46, and 47) in both hemispheres. Results demonstrate the applicability of the paradigm within a clinical MRI setup and corroborate previous findings of non-lateralized dorsolateral prefrontal activation during continuous context updating and active maintenance.

Dopaminergic modulation of semantic network activation.

In order to examine the effect of dopamine on semantic processing, we performed a double-blind, placebo-controlled study. Healthy volunteers (n = 31) were tested in a lexical decision paradigm after ingestion of either L-dopa 100 mg with benserazide 25 mg or placebo. While direct semantic priming was influenced only marginally by L-dopa, the indirect priming effects was reduced significantly. These data support the hypothesis that dopamine increases the signal-to-noise ratio in semantic networks by reducing the spread of semantic processing, thereby leading to a focussing of activation.

Functional MR imaging of semantic information processing and learning-related effects using psychometrically controlled stimulation paradigms.

Functional magnetic resonance imaging (fMRI), in conjunction with carefully designed, psychometrically optimized stimulation procedures, was used to investigate the relation between brain activation and the processing of word associations. A semantic discrimination task of word-pair similarity was performed by normal subjects (n = 17) within a clinical 1.5-Tesla whole-body MRI system. A color similarity task of psychometrically equivalent difficulty, as indicated by behavioral data acquired online during fMRI, served as active control condition. Comparisons between tasks dramatically improved results compared to comparisons between task and resting condition. The language paradigm selectively activated left frontal and left fronto-temporal areas. Cortical activation during the semantic task decreased significantly over three runs of the same word list and was paralleled by decreased reaction times. No such changes were observed in the active control condition indicating selective learning of the language task only. When combined with psychological activation schemes and the acquisition of behavioral data, fMRI represents a powerful tool for the study of brain-behavior interaction.