Carlos Schönfeldt-Lecuona

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

Using the International 10-20 EEG system for positioning of transcranial magnetic stimulation

Background: The International 10-20 system for EEG electrode placement is increasingly applied for the positioning of transcranial magnetic stimulation (TMS) in cognitive neuroscience and in psychiatric treatment studies. The crucial issue in TMS studies remains the reliable positioning of the coil above the skull for targeting a desired cortex region. In order to asses the precision of the 10-20 system for this purpose, we tested its projections onto the underlying cortex by using neuronavigation. Methods: In 21 subjects, the 10-20 positions F3, F4, T3, TP3, and P3, as determined by a 10-20 positioning cap, were targeted stereotactically. The corresponding individual anatomical sites were identified in the Talairach atlas. Results: The main targeted regions were: for F3 Brodmann areas (BA) 8/9 within the dorsolateral prefrontal cortex, for T3 BA 22/42 on the superior temporal gyrus, for TP3 BA 40/39 in the area of the supramarginal and angular gyrus, and for P3 BA 7/40 on the inferior parietal lobe. However, in about 10% of the measurements adjacent and possibly functionally distinct BAs were reached. The ranges were mainly below 20 mm. Conclusion: Using the 10-20 system for TMS positioning is applicable at low cost and may reach desired cortex regions reliably on a larger scale level. For finer grained positioning, possible interindividual differences, and therefore the application of neuroimaging based methods, are to be considered.

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.

Regional Brain Activation Changes and Abnormal Functional Connectivity of the Ventrolateral Prefrontal Cortex During Working Memory Processing in Adults With Attention-Deficit/ Hyperactivity Disorder

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009.

Mechanisms and Applications of Theta-burst rTMS on the Human Motor Cortex

Theta-burst Stimulation (TBS) is a novel form of repetitive transcranial magnetic stimulation (rTMS). Applied over the primary motor cortex it has been successfully used to induce changes in cortical excitability. The advantage of this stimulation paradigm is that it is able to induce strong and long lasting effects using a lower stimulation intensity and a shorter time of stimulation compared to conventional rTMS protocols. Since its first description, TBS has been used in both basic and clinical research in the last years and more recently it has been expanded to other domains than the motor system. Its capacity to induce synaptic plasticity could lead to therapeutic implications for neuropsychiatric disorders. The neurobiological mechanisms of TBS are not fully understood at present; they may involve long-term potentiation (LTP)- and depression (LTD)-like processes, as well as inhibitory mechanisms modulated by GABAergic activity. This article highlights current hypotheses regarding the mechanisms of action of TBS and some central factors which may influence cortical responses to TBS. Furthermore, previous and ongoing research performed in the field of TBS on the motor cortex is summarized.

Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease

In clinically presymptomatic individuals with the Huntingtons disease (HD) gene mutation, functional neuroimaging data have suggested a dysfunction of multiple cortical and subcortical regions including the prefrontal and parietal cortex, as well as the striatum. Although it has been hypothesized that these activation differences most likely reflect aberrant corticostriatal circuits, the functional coupling of neural networks associated with cognitive performance has not been investigated so far. In this study, we used functional magnetic resonance imaging (fMRI) and multivariate analytic techniques to investigate memory-related patterns of functional connectivity in healthy controls (n=16) and pre-HD individuals (n=16). Independent component analyses (ICA) revealed distinct bilateral frontostriatal and frontoparietal networks that were activated during a verbal working memory paradigm in both healthy controls and pre-HD subjects. Compared with healthy controls, pre-HD individuals exhibited lower functional connectivity in left lateral prefrontal and parietal regions as well as in the bilateral putamen. Functional connectivity indices in the left putamen were negatively correlated with the CAG repeat size and the UHDRS behavioral score, and positively correlated with the predicted years to manifest symptom onset. The connectivity of the right putamen was negatively correlated with the UHDRS motor score. In pre-HD individuals, these results suggest an early frontostriatal and frontoparietal deficit of dissociable functional networks associated with executive processing.

Cortical dysfunction in patients with Huntington's disease during working memory performance

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntingtons disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event‐related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy‐related activation confounds. Voxel‐based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso‐ and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM‐related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy. Hum Brain Mapp, 2009.

Spatial congruence of neuronavigated transcranial magnetic stimulation and functional neuroimaging.

OBJECTIVES Transcranial 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. METHODS We 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. RESULTS A 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. CONCLUSIONS The 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.

Altered frontostriatal coupling in pre-manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose:  Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals.