Neurocognitive function as outcome and predictor for prefrontal transcranial direct current stimulation in major depressive disorder: an analysis from the DepressionDC trial.

Transcranial direct current stimulation (tDCS) of the prefrontal cortex might beneficially influence neurocognitive dysfunctions associated with major depressive disorder (MDD). However, previous studies of neurocognitive effects of tDCS have been inconclusive. In the current study, we analyzed longitudinal, neurocognitive data from 101 participants of a randomized controlled multicenter trial (DepressionDC), investigating the efficacy of bifrontal tDCS (2 mA, 30 min/d, for 6 weeks) in patients with MDD and insufficient response to selective serotonin reuptake inhibitors (SSRI). We assessed whether active tDCS compared to sham tDCS elicited beneficial effects across the domains of memory span, working memory, selective attention, sustained attention, executive process, and processing speed, assessed with a validated, digital test battery. Additionally, we explored whether baseline cognitive performance, as a proxy of fronto-parietal-network functioning, predicts the antidepressant effects of active tDCS versus sham tDCS. We found no statistically significant group differences in the change of neurocognitive performance between active and sham tDCS. Furthermore, baseline cognitive performance did not predict the clinical response to tDCS. Our findings indicate no advantage in neurocognition due to active tDCS in MDD. Additional research is required to systematically investigate the effects of tDCS protocols on neurocognitive performance in patients with MDD.

Subjective and objective measures of visual awareness converge.

Within consciousness research, the most appropriate assessment of visual awareness is matter of a controversial debate: Subjective measures rely on introspections of the observer related to perceptual experiences, whereas objective measures are based on performance of the observer to accurately detect or discriminate the stimulus in question across a series of trials. In the present study, we compared subjective and objective awareness measurements across different stimulus feature and contrast levels using a temporal two-alternative forced choice task. This task has the advantage to provide an objective psychophysical performance measurement, while minimizing biases from unconscious processing. Thresholds based on subjective ratings with the Perceptual Awareness Scale (PAS) and on performance accuracy were determined for detection (stimulus presence) and discrimination (letter case) tasks at high and low stimulus contrast. We found a comparable pattern of thresholds across tasks and contrasts for objective and subjective measurements of awareness. These findings suggest that objective performance measures based on accuracy and subjective ratings of the visual experience can provide similar information on the feature-content of a percept. The observed similarity of thresholds validates psychophysical and subjective approaches to awareness as providing converging and thus most likely veridical measures of awareness.

Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. METHODS: The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). FINDINGS: Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). INTERPRETATION: Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. FUNDING: German Federal Ministry of Education and Research.

The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment.

We assessed the structure-function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain (p < 0.001) or thalamus volumes (p < 0.001) than healthy volunteers. Healthy SAI responders (> 10% SAI) had more basal forebrain volume than non-responders (p = 0.004) or patients with MCI (p < 0.001). More basal forebrain volume was associated with stronger SAI in healthy volunteers (r = 0.33, p < 0.05) but not patients with MCI. There was no significant relationship between thalamus volumes and SAI. Basal forebrain volume is associated with cholinergic function (SAI) in healthy volunteers but not in MCI patients. The in-vivo investigation of the structure-function relationship could further our understanding of the human cholinergic system in patients with suspected or known cholinergic system degeneration.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D).

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Functional and structural impairment of transcallosal motor fibres in ALS: a study using transcranial magnetic stimulation, diffusion tensor imaging, and diffusion weighted spectroscopy.

Imaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is altered, since mirror movements seem to occur in ALS. Finally, reduced interhemispheric inhibition (IHI), studied by transcranial magnetic stimulation (TMS), has been reported. It is not known whether there is any association between these findings. Here, we studied the integrity of the CC in ALS on the morphological, the functional, the electrophysiological, and the clinical level. Twenty-seven right-handed ALS patients and 21 healthy right-handed controls were included. Mirror activity (MA) was quantified using surface EMG. Diffusion tensor imaging tractography was used to segment the CC and quantify fractional anisotropy (FA). We studied the diffusivity of the intra-axonal markers N-acetylaspartate+N-acetyl aspartyl glutamate D(tNAA) within the CC. IHI was studied as a marker of CC function using a double-pulse TMS protocol. ALS patients showed significantly decreased FA in the motor segment of the CC (p < 0.01), and IHI was significantly reduced compared to controls (p = 0.01). However, no differences were observed regarding D(tNAA) and MA. The morphological as well as the functional integrity of the CC are altered in ALS. IHI was reduced in ALS, associated with decreased FA in the motor CC. Patients did not exhibit increased MA. Also, no differences within the CC were observed using diffusion-weighted spectroscopy. IHI might serve as a marker of transcallosal pathway disruption in ALS, even before clinical deficits become apparent.

Ten minutes of transcranial static magnetic field stimulation does not reliably modulate motor cortex excitability.

Recently, modulatory effects of static magnetic field stimulation (tSMS) on excitability of the motor cortex have been reported. In our previous study we failed to replicate these results. It was suggested that the lack of modulatory effects was due to the use of an auditory oddball task in our study. Thus, we aimed to evaluate the role of an oddball task on the effects of tSMS on motor cortex excitability. In a within-subject-design we compared 10 minutes tSMS with and without oddball task. In one of the two sessions subjects had to solve an auditory oddball task during the exposure to the magnet, whereas there was no task during exposure in the other session. Motor cortex excitability was measured before and after tSMS. No modulation was observed in any condition. However, when data were pooled regarding the order of the sessions, a trend for an increase of excitability was observed in the first session compared to the second session. We now can rule out that the auditory oddball task destroys tSMS effects, as postulated. Our results rather suggest that fluctuations in the amplitudes of single pulse motor evoked potentials may possibly mask weak modulatory effects but may also lead to false positive results if the number of subjects in a study is too low. In addition, there might be a habituation effect to the whole procedure, resulting in less variability when subjects underwent the same experiment twice.

Evolution and Development at the Origin of a Phylum.

Quantifying morphological evolution is key to determining the patterns and processes underlying the origin of phyla. We constructed a hierarchical morphological character matrix to characterize the radiation and establishment of echinoderm body plans during the early Paleozoic. This showed that subphylum-level clades diverged gradually through the Cambrian, and the distinctiveness of the resulting body plans was amplified by the extinction of transitional forms and obscured by convergent evolution during the Ordovician. Higher-order characters that define these body plans were not fixed at the origin of the phylum, countering hypotheses regarding developmental processes governing the early evolution of animals. Instead, these burdened characters were flexible, enabling continued evolutionary innovation throughout the clades' history.

Vision modulation, plasticity and restoration using non-invasive brain stimulation - An IFCN-sponsored review.

The visual system has one of the most complex structures of all sensory systems and is perhaps the most important sense for everyday life. Its functional organization was extensively studied for decades in animal and humans, for example by correlating circumscribed anatomical lesions in patients with the resulting visual dysfunction. During the past two decades, significant achievements were accomplished in characterizing and modulating visual information processing using non-invasive stimulation techniques of the normal and damaged human eye and brain. Techniques include transcranial magnetic stimulation (TMS) and low intensity electric stimulation using either direct or alternating currents applied transcranially (tDCS or tACS) near or above the visual cortex, or alternating currents applied transorbitally (trACS). In the case of transorbital stimulation of the visual system the electrodes are attached near the eye, to the eyelids (transpalpebral electrical stimulation - TPES) or the cornea (tanscorneal electrical stimulation TcES). Here, we summarize the state-of-the-art of visual system magnetic and electric stimulation as a method to modulate normal vision, induce brain plasticity, and to restore visual functions in patients. We review this field's history, models of current flow paths in the eye and brain, neurophysiological principles (e.g. entrainment and after-effects), the effects on vision in normal subjects and the clinical impact on plasticity and vision restoration in patients with low vision, with a particular focus on "off-line" or "after-effects". With regard to the therapeutic possibilities, ACS was demonstrated to be effective in patients affected by glaucoma and optic neuropathy, while tDCS and random noise stimulation (tRNS) are most promising for the treatment of amblyopia, hemianopia and myopia. In addition, rTMS applied above the occipital area is a promising approach to treat migraine, neglect and hemianopia. Although the response to these treatment options is better than to sham stimulation in double blinded clinical studies, the clinical efficacy is still rather variable and a proportion of patients do not respond. It is therefore imperative to better understand the mechanisms of action to be able to optimize treatment protocols possibly through personalization of brain stimulation protocols. By identifying the current opportunities and challenges in the field, we hope to provide insights to help improve neuromodulation protocols to restore visual function in patients with visual system damage.

Relation of Promoter Methylation of the Oxytocin Gene to Stressful Life Events and Depression Severity.

Oxytocin (OT) is a neuropeptide associated with trauma, sociality, and depression. Despite the widely accepted assumption of OT playing a role in the etiology of mood and anxiety disorders, associations between stressful life events, depression, and epigenetic regulation of the gene coding for OT (OXT) have not yet been investigated. We therefore aimed to examine the interrelations of stressful life events, depression severity, and methylation of the promoter region of OXT in a sample of N = 146 inpatients suffering from major depression. We found significant negative associations of stressful life events with mean methylation status as well as with methylation status of single CpG sites in the promoter region of OXT. There was no association between depression severity and OXT methylation. However, there were significant sex differences in methylation status of OXT with women showing higher methylation rates than men, putatively suggesting that in depression OXT is less activated in females compared to males. These results speak against an association of OXT methylation and depression severity, but support the assumption of a dysregulation of the OT system due to life stress. Our findings further emphasize the importance of including sex as an important factor in the investigation of the interrelations between OXT, stress, and depression.

Changes in emotional processing following interoceptive network stimulation with rTMS.

Theories of emotion suggest a close relation of interoception and emotion. However, knowledge of underlying neuronal networks is still sparse. Repetitive transcranial magnetic stimulation (rTMS) is one neurostimulation method allowing causal conclusions between functions and brain regions via stimulation or inhibition of underlying brain structures. In this study, rTMS with a continuous theta burst stimulation (cTBS) protocol was used aiming for inhibition of important interoceptive network structures (frontotemporal insular network and right somatosensory cortices). Stimulation effects were investigated on interoceptive accuracy (IAc), emotional evaluation and neuronal correlates of emotional picture processing in 18 male participants. The main findings were an emotional flattening in subjective valences for affective stimuli after inhibition of the frontotemporal anterior insular network and of somatosensory cortices, being mirrored in visual evoked potentials as increased N2/decreased P3, indicating an initial orientation reaction followed by decreased attentional processing of positive stimuli. Moreover, cardiac and respiratory IAc were positively associated with P3 amplitudes and negatively related to positive valence ratings. Positive associations of decreases of cardiac/respiratory IAc with decreases of arousal ratings and decreases of P3 amplitudes for negative stimuli after inhibition of the frontotemporal insular network and after inhibition of somatosensory cortices allow the conclusion of a causal relationship between reduced activity in interoceptive network structures and blunted emotional processing of visual stimuli. Our results suggest that both arousal, and valence aspects of emotional processing are disturbed after inhibition of interoceptive network structures, confirming core assumptions of peripheral theories of emotions and models of interoceptive predictive coding.

The neural correlates of flow experience explored with transcranial direct current stimulation.

The experience of flow ensues when humans engage in a demanding task while task demands are balanced with the individual's level of skill or ability. Here, we further tested the hypothesis that the medial prefrontal cortex (MPFC) plays a causal role in mediating flow experience using transcranial direct current stimulation (tDCS) to interfere with MPFC's deactivation evoked by a flow paradigm and measured by magnetic resonance (MR)-based perfusion imaging. In a balanced, within-subjects repeated measure design, three treatments of tDCS (sham, anodal, cathodal) were applied in a sample of 22 healthy male participants. tDCS-modulatory effects on flow-specific regional cerebral blood flow (rCBF) and subjective flow experience significantly depended on participants' baseline level of flow experience during sham tDCS. Those participants with lower-flow experience during sham tDCS (LF) benefitted from tDCS, particularly from the anodal polarity, whereas both active treatments did not substantially affect subjects with relatively higher baseline flow experience (HF). Functionally, in LF subjects, relative deactivation of the right amygdala got more pronounced under anodal and cathodal tDCS, and changed inconsistently in HF subjects. Inter-individual regression analyses of rCBF data suggested that involvement of the subgenual anterior cingulate cortex appears crucial for affecting the response pattern in the right amygdala and can be modulated by tDCS. Present data support the notion that valuable insights into the neural mechanism of flow can be obtained using tDCS. However, a clearer understanding of tDCS' baseline dependency in terms of individual variations in brain connectivity states appears a necessary prerequisite to exploit this technique further.

Theta-burst modulation of mid-ventrolateral prefrontal cortex affects salience coding in the human ventral tegmental area.

In the context of hedonic (over-)eating the ventral tegmental area (VTA) as a core part of the dopaminergic reward system plays a central role in coding incentive salience of high-caloric food. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate whether transcranial magnetic theta-burst stimulation (TBS) over the right mid-ventrolateral prefrontal cortex (mid-VLPFC) can induce modulation of calorie-sensitive brain activation in the VTA. The prefrontal location for TBS had been predetermined by seed-based resting-state fMRI with a functionally defined portion of the VTA serving as seed region obtained from an independent second fMRI experiment. In a sample of 15 healthy male participants, modulation of calorie-sensitive VTA activation did not significantly differ between the two TBS protocols. Comparisons with baseline revealed that both TBS protocols significantly affected calorie-sensitive neural processing of the mid-VLPFC in a rather similar way. In the VTA significant modulation of calorie-sensitive activation was observed after continuous TBS, whereas the modulatory effect of intermittent TBS was less reliable but also associated with a decrease of activation for high-caloric food images. Neurostimulation of right mid-VLPFC is suggestive as a main entry point of downstream signal changes for high- and low-caloric food cues that could enforce a shift in valuating stimuli of initially different incentive salience.

1-Hz rTMS in the treatment of tinnitus: A sham-controlled, randomized multicenter trial.

BACKGROUND: Chronic tinnitus is a frequent, difficult to treat disease with high morbidity. OBJECTIVE: This multicenter randomized, sham-controlled trial investigated the efficacy and safety of 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal cortex in patients with chronic tinnitus. METHODS: Tinnitus patients were randomized to receive 10 sessions of either real or sham 1-Hz-rTMS (2000 stimuli, 110% motor threshold) to the left temporal cortex. The primary outcome was the change in the sum score of the tinnitus questionnaire (TQ) of Goebel and Hiller from baseline to end of treatment. RESULTS: A total of 163 patients were enrolled in the study (real rTMS: 75; sham rTMS: 78). At day 12, the baseline mean of 43.1 TQ points in 71 patients assigned to real rTMS changed by -0.5 points; it changed by 0.5 points from a baseline of 42.1 in 75 patients randomized to sham rTMS (adjusted mean difference between groups: -1.0; 95.19% confidence interval: -3.2 to 1.2; p = 0.36). All secondary outcome measures including measures of depression and quality of life showed no significant differences either (p > 0.11). The number of participants with side-effects or adverse events did not differ between groups. CONCLUSION: Real 1-Hz-rTMS over the left temporal cortex was well tolerated but not superior compared with sham rTMS in improving tinnitus severity. These findings are in contrast to results from studies with smaller sample sizes and put the efficacy of this rTMS protocol for treatment of chronic tinnitus into question. TRIAL REGISTRATION: Controlled Trials: http://www.isrctn.com/ISRCTN89848288.

Intact sensory-motor network structure and function in far from onset premanifest Huntington's disease.

Structural and functional changes attributable to the neurodegenerative process in Huntington's disease (HD) may be evident in HTT CAG repeat expansion carriers before the clinical manifestations of HD. It remains unclear, though, how far from motor onset a consistent signature of the neurodegenerative process in HD can be detected. Twelve far from onset preHD and 22 age-matched healthy control participants underwent volumetric structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and resting-state functional MRI (11 preHD, 22 controls) as well as electrophysiological measurements (12 preHD, 13 controls). There were no significant differences in white matter macro- and microstructure between far from onset preHD participants and controls. Functional connectivity in a basal ganglia-thalamic and motor networks, all measures of the motor efferent and sensory afferent pathways as well as sensory-motor integration were also similar in far from onset preHD and controls. With the methods used in far from onset preHD sensory-motor neural macro- or micro-structure and brain function were similar to healthy controls. This suggests that any observable structural and functional change in preHD nearer to onset, or in manifest HD, at least using comparable techniques such as in this study, most likely reflects an ongoing neurodegenerative process.

No modulatory effects by transcranial static magnetic field stimulation of human motor and somatosensory cortex.

BACKGROUND: Recently, it was reported that the application of a static magnetic field by placing a strong permanent magnet over the scalp for 10 min led to an inhibition of motor cortex excitability for at least 6 min after removing the magnet. When placing the magnet over the somatosensory cortex, a similar inhibitory after effect could be observed as well. OBJECTIVE: Our aim was to replicate the inhibitory effects of transcranial static magnetic field stimulation in the motor and somatosensory system. METHODS: The modulatory effect of static magnetic field stimulation was investigated in three experiments. In two experiments motor cortex excitability was measured before and after 10 or 15 min of magnet application, respectively. The second experiment included a sham condition and was designed in a double-blinded manner. In a third experiment, paired-pulse SSEPs were measured pre and four times post positioning the magnet over the somatosensory cortex for 10 min on both hemispheres, respectively. The SSEPs of the non stimulated hemisphere served as control condition. RESULTS: We did not observe any systematic effect of the static magnetic field neither on motor cortex excitability nor on SSEPs. Moreover, no SSEP paired-pulse suppression was found. CONCLUSION: We provide a detailed analysis of possible confounding factors and differences to previous studies on tSMS. After all, our results could not confirm the static magnetic field effect.