Uwe Herwig

Transcranial magnetic stimulation in therapy studies : Examination of the reliability of standard coil positioning by neuronavigation

Transcranial magnetic stimulation is investigated as a new tool in the therapy of depression and other psychiatric disorders. In almost all studies, the dorsolateral prefrontal cortex (DLPFC) has been selected as the target site for stimulation. Usually this region was determined by identifying the patients motor cortex, and from there the coil was placed 5 cm rostrally. The aim of our study was to test the reliability of this standard procedure. A neuronavigational system was used to relate the final coil position after applying the standard procedure to the individual cortical anatomy. In 7 of 22 subjects, the Brodman area 9 of the DLPFC was targeted correctly in this manner. In 15 subjects, the center of the coil was found to be located more dorsally (e.g., above the premotor cortex). The current method for locating the DLPFC is not precise anatomically and may be improved by navigating procedures taking individual anatomy into account.

The navigation of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a new method for investigating cortical information processing and for investigating therapeutic applications in psychiatry and neurology. A common problem of most studies in this field regards the localization of the magnetic coil with respect to the cortex. This article reviews the currently used methods and proposes a neuronavigational approach. The method of neuronavigated TMS is described and discussed in detail. It is used to guide the magnetic coil on an individual basis to a structurally or functionally predetermined cortical area while monitoring the location of the coil in relation to the subjects head in real time. Possible applications of TMS in combination with functional neuroimaging in clinical research within a cognitive neuroscience framework are discussed. Future applications of TMS should take individual anatomy into account, and neuronavigation provides the means to do so.

Add-on rTMS for treatment of depression: a pilot study using stereotaxic coil-navigation according to PET data

OBJECTIVEnRepetitive transcranial magnetic stimulation (rTMS) is regarded as a potentially new tool to treat depression. In a double-blind, randomized, sham-controlled pilot study we investigated the efficacy of neuronavigated rTMS, guided according to the prefrontal metabolic state determined by positron emission tomography (PET).nnnMETHODSn25 patients with major depression were included. Prior to rTMS, PET scans were obtained. For the real stimulation condition, the dorsolateral prefrontal cortex (DLPFC) with lower metabolic activity compared to the contralateral hemisphere was selected, if detected by prior PET. Stimulation parameters were 15 Hz, 110% motor threshold (MT), 3000 stimuli/day, for 10 days. A neuronavigational system was used to place the magnetic coil above each individuals selected cortical region (real condition: DLPFC, sham: midline parieto-occipital, intensity 90% of MT). RTMS was administered add-on to medication. Depression-related symptoms were rated with Becks, Hamiltons (HAM-D), and Montgomery-Asbergs (MADRS) depression rating scales.nnnRESULTSnReal stimulation improved depression according to HAM-D and MADRS moderately but significantly better compared to sham at the end of the stimulation sessions. In the real condition, four out of 13 patients responded with a mean improvement in HAM-D and/or MADRS of at least 50%, whereas none responded to sham. Antidepressant effects of stimulation of the relatively hypometabolic DLPFC were comparable to stimulation in absence of metabolic differences.nnnCONCLUSIONSnA moderate improvement of depressive symptoms after rTMS was observed. Our preliminary data show that stimulation of prefrontal hypometabolism may not be advantageous to stimulation irrespective of the metabolic state.

Spatial congruence of neuronavigated transcranial magnetic stimulation and functional neuroimaging.

OBJECTIVESnTranscranial magnetic stimulation (TMS) is progressively gaining relevance as a tool in cognitive neuroscience and clinical research. However, most studies in this field do not consider individual anatomy. Neuronavigational devices allow to guide the coil to a specific cortical area, predetermined by functional magnetic resonance imaging (fMRI). Therefore, it is crucial to know whether the area of a certain function as identified by fMRI corresponds to the area where the TMS should be placed in order to influence this function.nnnMETHODSnWe investigated the spatial relation between the cortical area activated by a motor task in fMRI and the area of magnetically evoked motor potentials (MEP) in 8 subjects, using a spacing of 5x5 mm. A neuronavigational system was adapted for coil positioning and for the registration of the stimulation coordinates.nnnRESULTSnA spatial divergence of the centers of gravity from fMRI and MEP was found with a mean distance of about 10 mm, with the MEP centers being, by a mean derivation of 7.5 mm, consistently anterior to the center of fMRI activation. However, regarding MEP areas and fMRI activities, a large overlap was found for stimulation intensities of both 110 and 120% motor threshold.nnnCONCLUSIONSnThe combination of fMRI and neuronavigated TMS is useful for non-invasive investigation of individual cortical functions predetermined by fMRI. Whereas both are spatially by and large congruent, discrepencies in the exact spatial relation between MEP and fMRI areas should be considered and further studied.

Accuracy of stereotaxic positioning of transcranial magnetic stimulation

Summary:In cognitive neuroscience, optically tracked frameless stereotaxic navigation has been successfully used to precisely guide transcranial magnetic stimulation (TMS) to desired cortical areas for brain-mapping purposes. Thereby, potential sources of imprecision are the fixation of a reference frame to the head of the subject and the referencing procedure according to certain landmarks (LM). The aim of our study was to evaluate the accuracy of frameless stereotaxic coil positioning in a standard experimental setting. A parameter for accuracy is the reproducibility of LM coordinates. In order to test the stability of the referencing for stereotaxic positioning within a single TMS session (within-session stability), the coordinates of six predefined facial LM in nine subjects were recorded first after the initial registration and second after a 20 minutes TMS session. The two sets of coordinates were then compared. The reliability of the positioning coordinates between different TMS sessions (inter-session repeatability) was addressed by registering the subjects LM coordinates in two independent TMS sessions. The variance of the recorded coordinates was analyzed. Altogether, LM were registered 1728 times (192 measures per subject). Within-session stability: The mean Euclidean distance (MED) between the LM position coordinates before and after a TMS session was 1.6 mm, when pooling over all LM. Inter-session repeatability: The MED between the LM positions recorded after the reference procedures of two different sessions showed an average deviation of 2.5 mm. In conclusion, optically tracked frameless stereotaxic coil positioning is from the technical viewpoint of high stability and repeatability. It is therefore a precise method for TMS brain mapping studies or for repeated TMS treatments, with the need of topographically exact stimulation.

Intracortical excitability is modulated by a norepinephrine-reuptake inhibitor as measured with paired-pulse transcranial magnetic stimulation

AbstractnObjective. Paired-pulse transcranial magnetic stimulation (ppTMS) of the motor cortex can be used to measure intracortical inhibition and facilitation of evoked motor potentials dependent on different interstimulus intervals (ISI). The reuptake-inhibition of norepinephrine, known as an excitatory neuromodulator and neurotransmitter, was postulated to enhance cortical excitability through increased facilitation and reduced inhibition as measured with ppTMS.nMethods. Eight healthy subjects were examined with ppTMS at ISIs of 2, 3, 4, 5, 6, 7, 8, 10, 15 and 20xa0ms before and approximately 1.5xa0h after ingestion of 8xa0mg reboxetine. The group effects at the different ISIs pre/post reboxetine intake were analysed.nResults. Post-reboxetine ppTMS showed an enhanced intracortical facilitation effect at ISIs of 8, 10, 15 and 20xa0ms. A decreased inhibition was found at an ISI of 3xa0ms.nConclusions. Reboxetine-induced higher postsynaptic norepinephrine level enhances intracortical excitability as measured with ppTMS. This finding provides new perspectives for evaluating neurophysiological properties of antidepressive medication and for investigating the pathophysiology of depression.

Side Effects of Transcranial Magnetic Stimulation Biased Task Performance in a Cognitive Neuroscience Study

Summary:Transcranial magnetic stimulation (TMS) is increasingly used as a research tool for functional brain mapping in cognitive neuroscience. Despite being mostly tolerable, side effects of TMS could influence task performance in behavioural TMS studies. In order to test this issue, healthy subjects assessed the discomfort caused by the stimulation during a verbal working memory task. We investigated the relation between subjective disturbance and task performance. Subjects were stimulated during the delay period of a delayed-match-to-sample task above cortical areas that had been identified before to be involved in working memory. Task performance and subjective disturbance due to side effects were monitored. The subjects’ grade of discomfort correlated with the error rates: the higher the discomfort, the more errors were made. Conclusively, TMS side effects may bias task performance in cognitive neuroscience studies and may thereby lead to misinterpretation of results. We emphasize the importance of controlling side effects of the stimulation as a source of biasing effects in TMS studies.

Increased cortical thickness in a frontoparietal network in social anxiety disorder.

Social anxiety disorder (SAD) is the second leading anxiety disorder. On the functional neurobiological level, specific brain regions involved in the processing of anxiety‐laden stimuli and in emotion regulation have been shown to be hyperactive and hyper‐responsive in SAD such as amygdala, insula and orbito‐ and prefrontal cortex. On the level of brain structure, prior studies on anatomical differences in SAD resulted in mixed and partially contradictory findings. Based on previous functional and anatomical models of SAD, this study examined cortical thickness in structural magnetic resonance imaging data of 46 patients with SAD without comorbidities (except for depressed episode in one patient) compared with 46 matched healthy controls in a region of interest‐analysis and in whole‐brain. In a theory‐driven ROI‐analysis, cortical thickness was increased in SAD in left insula, right anterior cingulate and right temporal pole. Furthermore, the whole‐brain analysis revealed increased thickness in right dorsolateral prefrontal and right parietal cortex. This study detected no regions of decreased cortical thickness or brain volume in SAD. From the perspective of brain networks, these findings are in line with prior functional differences in salience networks and frontoparietal networks associated with executive‐controlling and attentional functions. Hum Brain Mapp 35:2966–2977, 2014.

General emotion processing in social anxiety disorder: Neural issues of cognitive control

Anxiety disorders are characterized by deficient emotion regulation prior to and in anxiety-evoking situations. Patients with social anxiety disorder (SAD) have increased brain activation also during the anticipation and perception of non-specific emotional stimuli pointing to biased general emotion processing. In the current study we addressed the neural correlates of emotion regulation by cognitive control during the anticipation and perception of non-specific emotional stimuli in patients with SAD. Thirty-two patients with SAD underwent functional magnetic resonance imaging during the announced anticipation and perception of emotional stimuli. Half of them were trained and instructed to apply reality-checking as a control strategy, the others anticipated and perceived the stimuli. Reality checking significantly (p<0.01) reduced activity in insular, amygdalar and medial thalamic areas during the anticipation and perception of negative emotional stimuli. The medial prefrontal cortex was comparably active in both groups (p>0.50). The results suggest that cognitive control in patients with SAD influences emotion processing structures, supporting the usefulness of emotion regulation training in the psychotherapy of SAD. In contrast to studies in healthy subjects, cognitive control was not associated with increased activation of prefrontal regions in SAD. This points to possibly disturbed general emotion regulating circuits in SAD.

Altered emotion processing circuits during the anticipation of emotional stimuli in women with borderline personality disorder.

Borderline personality disorder (BPD) is associated with disturbed emotion processing, typically encompassing intense and fast emotional reactions toward affective stimuli. In this study, we were interested in whether emotional dysregulation in BPD occurs not only during the perception of emotional stimuli, but also during the anticipation of upcoming emotional pictures in the absence of concrete stimuli. Eighteen female patients with a diagnosis of BPD and 18 healthy control subjects anticipated cued visual stimuli with prior known emotional valence or prior unknown emotional content during functional magnetic resonance imaging. Brain activity during the anticipation of emotional stimuli was compared between both groups. When anticipating negative pictures, BPD patients demonstrated less signal change in the left dorsal anterior cingulate cortex (dACC) and left middle cingulate cortex (MCC), and enhanced activations in the left pregenual ACC, left posterior cingulate cortex (PCC) as well as in left visual cortical areas including the lingual gyrus. During the anticipation of ambiguously announced stimuli, brain activity in BPD was also reduced in the left MCC extending into the medial and bilateral dorsolateral prefrontal cortex. Results point out that deficient recruitment of brain areas related to cognitive–emotional interaction already during the anticipation phase may add to emotional dysregulation in BPD. Stronger activation of the PCC could correspond to an increased autobiographical reference in BPD. Moreover, increased preparatory visual activity during negative anticipation may contribute to hypersensitivity toward emotional cues in this disorder.