[The application of rTMS in OCD in the Netherlands and Belgium: consensus statement]. / De toepassing van rTMS bij dwangstoornissen in Nederland en België: consensusverklaring.

BACKGROUND: Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS), is increasingly used in the treatment of neurological diseases and psychiatric disorders. Where rTMS is already an accepted treatment option for depression, in the Netherlands/Belgium, no consensus exist on the application of rTMS for (obsessive-compulsive disorder (OCD). People with OCD who do not respond enough to exposure therapy and serotonergic antidepressants are in great need for treatment alternatives. AIM: Consensus statement on the application of rTMS as treatment for OCD METHOD: Evaluation of the current literature on the efficacy of rTMS for OCD, mainly based on recent meta-analysis, by a broad group of experts in the field of rTMS, OCD and treatment guidelines. RESULTS: rTMS is a potentially effective treatment for OCD with a medium effect size (g ≈ 0,5). Based on the current literature it is not yet clear which rTMS protocol is the most effective. CONCLUSION: based on the evidence for rTMS in OCD, and the non-invasive nature of the treatment modality, rTMS can considered in cases with OCD who do not respond enough to exposure therapy and serotonergic antidepressants, prior to the start of more invasive treatment alternatives, such as deep brain stimulation or lesion surgery.

The behavioral component of sexual inhibition and its relation with testosterone levels: An fMRI study in transgender and cisgender individuals.

Many transgender individuals report having difficulties with initiating and seeking sexual contacts. Relatively to cisgender individuals, transgender individuals are more likely to avoid sexual activity, indicating that the groups might differ in the neural underpinnings of the behavioral component of sexual inhibition. In this fMRI study, transgender (n = 33) and cisgender (n = 34) participants performed an Approach Avoidance Task (AAT) assessing sexual inhibition. We found that over the entire sample, the task elicited brain activation commonly associated with general and sexual inhibition, for instance in the bilateral insula, right inferior parietal lobule, and right inferior and middle frontal gyri. Upon investigating group differences between transgender and cisgender participants, we mainly found similarities in neural activation during the task. However, there were group differences in regions involved in decision making processes (left middle temporal gyrus) and sexual response inhibition (right anterior cingulate cortex and left inferior parietal lobule). In order to investigate whether these group differences were modulated by testosterone levels, we performed ROI-analyses assessing the relationship between testosterone and neural activation during the AAT (controlling for sex assigned at birth), but no correlations were found. On the whole brain level, however, we found that testosterone correlated positively with cerebral activation in the right claustrum (a region associated with sexual arousal) during the approach of sexual stimuli in the transgender group. Overall, these findings indicate that transgender and cisgender individuals mostly show similarities in their neural response to a sexual Approach-Avoidance task, and that testosterone levels are unlikely to play an important role.

[Neural networks and clinical efficacy of transcranial brain stimulation in psychiatry]. / Neurale netwerken en klinische effecti­vi­teit van transcraniële hersenstimulatie in de psychiatrie.

BACKGROUND: Non-invasive forms of brain stimulation, including transcranial magnetic stimulation and direct current stimulation, are increasingly being considered by clinicians as a somatic treatment option for psychiatric disorders. AIM: Review article on the history, efficacy transcranial brain stimulation in psychiatric disorders and the role of neural networks for improving clinical efficacy. METHOD: Review of scientific literature. RESULTS: Transcranial magnetic stimulation has been proven effective for the treatment of depression, but treatment efficacy varies widely for other psychiatric disorders. Transcranial direct current stimulation is still at an experimental stage, but results suggest that using weak currents can have positive effects. Neuroscience research provides tools for improving therapeutic outcomes based on neural network approaches. CONCLUSION: Transcranial brain stimulation grafted on network information appears to be a promising approach for enhancing therapeutic outcome in psychiatric disorders.

Frequency-specific transcranial neuromodulation of alpha power alters visuospatial attention performance.

Transcranial alternating current stimulation (tACS) at 10 Hz has been shown to modulate spatial attention. However, the frequency-specificity and the oscillatory changes underlying this tACS effect are still largely unclear. Here, we applied high-definition tACS at individual alpha frequency (IAF), two control frequencies (IAF+/-2Hz) and sham to the left posterior parietal cortex and measured its effects on visuospatial attention performance and offline alpha power (using electroencephalography, EEG). We revealed a behavioural and electrophysiological stimulation effect relative to sham for IAF but not control frequency stimulation conditions: there was a leftward lateralization of alpha power for IAF tACS, which differed from sham for the first out of three minutes following tACS. At a high value of this EEG effect (moderation effect), we observed a leftward attention bias relative to sham. This effect was task-specific, i.e., it could be found in an endogenous attention but not in a detection task. Only in the IAF tACS condition, we also found a correlation between the magnitude of the alpha lateralization and the attentional bias effect. Our results support a functional role of alpha oscillations in visuospatial attention and the potential of tACS to modulate it. The frequency-specificity of the effects suggests that an individualization of the stimulation frequency is necessary in heterogeneous target groups with a large variation in IAF.

[Consensus statement on the application of rTMS in depression in the Netherlands and Belgium]. / Consensusverklaring voor de toepassing van rTMS bij depressie in Nederland en België.

BACKGROUND: Since 2017, repetitive transcranial magnetic stimulation (rTMS) has become eligible for reimbursement for the treatment of therapy-resistant depression in the Dutch healthcare system.
AIM: To initiate a guideline in the Netherlands and Belgium for the safe and effective application of rTMS for the treatment of depression.
METHOD: Based on literature review, existing guidelines and consensus among Dutch rTMS experts, recommendations were developed regarding the implementation of rTMS as a treatment of depression. All available evidence was weighed and discussed among all co-authors and recommendations were reached by consensus among the group.
RESULTS: rTMS targeting the dorsolateral prefrontal cortex (DLPFC) should be seen as a first choice in the treatment of depression using high-frequency rTMS (left) or, as an alternative, low-frequency rTMS (right). Stimulation protocols should use more than 1000 pulses per session for an average of 20-30 sessions, offered in 2-5 sessions per week. Contraindications for rTMS include epilepsy, intracranial presence of (magnetisable) metals, pacemaker and cochlear implant.
CONCLUSION: rTMS, performed by competent professionals is an effective and safe treatment for depression.

[Brain stimulation: the most direct form of neurostimulation]. / Hersenstimulatie: de meest directe vorm van neuromodulatie.

BACKGROUND: Brain stimulation is the most direct form of neuromodulation. Direct brain stimulation is an older procedure that has taken various forms, but 'non-invasive brain stimulation' is a more recent development. AIM: To provide an overview of the current arsenal of non-invasive brain stimulation techniques. METHOD: We discuss the underlying principles, the pros and cons, and the applicability of non-invasive brain stimulation in experimental research and treatment of neuropsychiatric disorders. RESULTS: Non-invasive brain stimulation is a direct form of neuromodulation, which is not invasive, harmful or painful. Its effects are in principle temporary, which makes the technique suitable for experimental research. At the same time, temporary effects can have lasting clinical consequences, if they target neuroplasticity to aid rehabilitation or alleviate symptoms. CONCLUSION: Whereas the value of non-invasive brain stimulation for research purposes is undisputed, its efficacy and value as a treatment for neuropsychiatric disorders are still being debated. Nevertheless, the accumulated evidence about the clinical efficacy of the treatment for certain disorders is sufficiently compelling to start thinking about European regulations and standard medical insurance coverage.

Seeing in the dark: Phosphene thresholds with eyes open versus closed in the absence of visual inputs.

BACKGROUND: Voluntarily opening or closing our eyes results in fundamentally different input patterns and expectancies. Yet it remains unclear how our brains and visual systems adapt to these ocular states. OBJECTIVE/HYPOTHESIS: We here used transcranial magnetic stimulation (TMS) to probe the excitability of the human visual system with eyes open or closed, in the complete absence of visual inputs. METHODS: Combining Bayesian staircase procedures with computer control of TMS pulse intensity allowed interleaved determination of phosphene thresholds (PT) in both conditions. We measured parieto-occipital EEG baseline activity in several stages to track oscillatory power in the alpha (8-12 Hz) frequency-band, which has previously been shown to be inversely related to phosphene perception. RESULTS: Since closing the eyes generally increases alpha power, one might have expected a decrease in excitability (higher PT). While we confirmed a rise in alpha power with eyes closed, visual excitability was actually increased (PT was lower) with eyes closed. CONCLUSIONS: This suggests that, aside from oscillatory alpha power, additional neuronal mechanisms influence the excitability of early visual cortex. One of these may involve a more internally oriented mode of brain operation, engaged by closing the eyes. In this state, visual cortex may be more susceptible to top-down inputs, to facilitate for example multisensory integration or imagery/working memory, although alternative explanations remain possible.

A 7T fMRI study investigating the influence of oscillatory phase on syllable representations.

Stimulus categorization is influenced by oscillations in the brain. For example, we have shown that ongoing oscillatory phase biases identification of an ambiguous syllable that can either be perceived as /da/ or /ga/. This suggests that phase is a cue for the brain to determine syllable identity and this cue could be an element of the representation of these syllables. If so, brain activation patterns for /da/ should be more unique when the syllable is presented at the /da/ biasing (i.e. its "preferred") phase. To test this hypothesis we presented non-ambiguous /da/ and /ga/ syllables at either their preferred or non-preferred phase (using sensory entrainment) while measuring 7T fMRI. Using multivariate pattern analysis in auditory regions we show that syllable decoding performance is higher when syllables are presented at their preferred compared to their non-preferred phase. These results suggest that phase information increases the distinctiveness of /da/ and /ga/ brain activation patterns.

Allocentric coding in ventral and dorsal routes during real-time reaching: Evidence from imaging-guided multi-site brain stimulation.

Recent evidence has revealed an advantage for movements to last target positions in a structured visual display, suggesting a mediating role of allocentric, in addition to egocentric, information in goal-directed reaching. This notion is accommodated by the recently updated perception-action model (Milner and Goodale, 2008), which postulates functional roles of ventral and dorsal neural areas in allocentric coding. In the present study, we used imaging-guided multi-site continuous theta burst stimulation (cTBS) over regions of the ventral and dorsal processing streams to unravel their functional contribution on visually guided reaching in two display conditions: the "egocentric" condition where the target appeared in an empty display and the "allocentric" condition where the target appeared in a structured display with placeholders marking possible target locations. Cortical sites for cTBS were identified individually for each participant via coregistration with magnetic resonance scans. Results indicated that cTBS in the egocentric condition did not affect movement time, but cTBS in the allocentric condition modulated movement time contingent on stimulation site and target position. In particular, cTBS over the lateral occipital cortex (part of the ventral stream) and over the angular gyrus (part of the dorsal stream) eliminated the last-target advantage by slowing down reaching to the salient last target position. cTBS over the superior parietal occipital cortex did not affect the last-target advantage. These outcomes provide the first causal evidence for allocentric coding in ventral and dorsal routes during real-time reaching, thereby supporting the updated perception-action model.

Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation.

Since its introduction in the 1980s, Transcranial Magnetic Stimulation (TMS) has proven to be a versatile method to non-invasively study human brain function by reversibly altering ongoing neural processing. In addition, TMS has been explored as a therapeutic intervention in a number of neurological and neuropsychiatric conditions. However, our understanding of TMS-induced changes in neural activity patterns is still rather limited, particularly when it comes to changes in neural network dynamics beyond the cortical site directly targeted by TMS. In order to monitor both its local and remote neurophysiological effects, TMS has been combined with complementary neuroimaging methods that allow additional insights into how observed TMS effects at the behavioral level can be interpreted by taking into account the full scale of its impact throughout the brain. The current review provides a comprehensive overview of the existing multimodal TMS literature, covering studies in which TMS was combined with one of the three main neuroimaging modalities, namely Electroencephalography, Positron Emission Tomography, and functional Magnetic Resonance Imaging. Besides constituting a reflection of the status quo in this exciting multidisciplinary research field, this review additionally reveals both convergent and divergent observations across modalities that await corroboration or resolution, thereby further guiding ongoing basic research and providing useful constraints to optimize future clinical applications.

Null results in TMS: from absence of evidence to evidence of absence.

It is always difficult to interpret null results. But as a research method, transcranial magnetic stimulation (TMS) has so many degrees of freedom that null results are often dismissed as meaningless. We feel that this may be unnecessary, if not counterproductive. Null results seem to inherently fulfill an important role in brain mapping. In fact, without null results, neuroimaging as an enterprise would not make sense. We argue that null results are similarly important in TMS research. By itself, neuroimaging research leaves room for doubt concerning whether or not an activated region is actually necessary for intact task performance. Interference methods such as TMS can therefore complement brain research by testing the functional relevance of that region. However, if then only positive TMS results are taken seriously, the brain interference paradigm seems less informative than promised. But how can null results inform us if they only constitute absence of evidence? We suggest that three main arguments contravene interpretation of null results in TMS. These we call the localization argument, the neural efficacy argument, and the power argument. We proceed to discuss in turn how, and under which conditions, each of these arguments may be nuanced. These considerations lead us to value null results along a gradient of meaningfulness, rather than a dichotomy. This perspective may open up a new range of TMS applications, where research questions about the lack of functional relevance of a particular brain region become valid. In this context we make specific recommendations on experimentation and interpretation. We propose that it is often not only meaningful to interpret null results, but also useful to make such findings available to the community, especially now that improved methods and an expanded knowledge base make null results more interpretable than they have been in the past.

The dynamics of interhemispheric compensatory processes in mental imagery.

The capacity to generate and analyze mental visual images is essential for many cognitive abilities. We combined triple-pulse transcranial magnetic stimulation (tpTMS) and repetitive TMS (rTMS) to determine which distinct aspect of mental imagery is carried out by the left and right parietal lobe and to reveal interhemispheric compensatory interactions. The left parietal lobe was predominant in generating mental images, whereas the right parietal lobe was specialized in the spatial comparison of the imagined content. Furthermore, in case of an rTMS-induced left parietal lesion, the right parietal cortex could immediately compensate such a left parietal disruption by taking over the specific function of the left hemisphere.

Functional imaging of visuospatial processing in Alzheimer's disease.

Alzheimer's disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.

The experimental combination of rTMS and fMRI reveals the functional relevance of parietal cortex for visuospatial functions.

We combined repetitive transcranial magnetic stimulation (rTMS) and functional magnetic resonance imaging (fMRI) to investigate the functional relevance of parietal cortex activation during the performance of visuospatial tasks. fMRI provides information about local transient changes in neuronal activation during behavioural or cognitive tasks. Information on the functional relevance of this activation was obtained by using rTMS to induce temporary regional deactivations. We thereby turned the physiological parameter of brain activity into an independent variable controlled and manipulated by the experimenter and investigated its effect on the performance of the cognitive tasks within a controlled experimental design. We investigated cognitive tasks that were performed on the same visual material but differed in the demand on visuospatial functions. For the visuospatial tasks we found a selective enhancement of fMRI signal in the superior parietal lobule (SPL) and a selective impairment of performance after rTMS to this region in comparison to a control group. We could thus show that the parietal cortex is functionally important for the execution of spatial judgements on visually presented material and that TMS as an experimental tool has the potential to interfere with higher cognitive functions such as visuospatial information processing.