Neuroanatomical Predictors of Transcranial Direct Current Stimulation (tDCS)-Induced Modifications in Neurocognitive Task Performance in Typically Developing Individuals.

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique gaining more attention in neurodevelopmental disorders (NDDs). Due to the phenotypic heterogeneity of NDDs, tDCS is unlikely to be equally effective in all individuals. The present study aimed to establish neuroanatomical markers in typically developing (TD) individuals that may be used for the prediction of individual responses to tDCS. Fifty-seven male and female children received 2 mA anodal and sham tDCS, targeting the left dorsolateral prefrontal cortex (DLPFCleft), right inferior frontal gyrus, and bilateral temporoparietal junction. Response to tDCS was assessed based on task performance differences between anodal and sham tDCS in different neurocognitive tasks (N-back, flanker, Mooney faces detection, attentional emotional recognition task). Measures of cortical thickness (CT) and surface area (SA) were derived from 3 Tesla structural MRI scans. Associations between neuroanatomy and task performance were assessed using general linear models (GLM). Machine learning (ML) algorithms were employed to predict responses to tDCS. Vertex-wise estimates of SA were more closely linked to differences in task performance than measures of CT. Across ML algorithms, highest accuracies were observed for the prediction of N-back task performance differences following stimulation of the DLPFCleft, where 65% of behavioral variance was explained by variability in SA. Lower accuracies were observed for all other tasks and stimulated regions. This suggests that it may be possible to predict individual responses to tDCS for some behavioral measures and target regions. In the future, these models might be extended to predict treatment outcome in individuals with NDDs.

Stratification of responses to tDCS intervention in a healthy pediatric population based on resting-state EEG profiles.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique with a wide variety of clinical and research applications. As increasingly acknowledged, its effectiveness is subject dependent, which may lead to time consuming and cost ineffective treatment development phases. We propose the combination of electroencephalography (EEG) and unsupervised learning for the stratification and prediction of individual responses to tDCS. A randomized, sham-controlled, double-blind crossover study design was conducted within a clinical trial for the development of pediatric treatments based on tDCS. The tDCS stimulation (sham and active) was applied either in the left dorsolateral prefrontal cortex or in the right inferior frontal gyrus. Following the stimulation session, participants performed 3 cognitive tasks to assess the response to the intervention: the Flanker Task, N-Back Task and Continuous Performance Test (CPT). We used data from 56 healthy children and adolescents to implement an unsupervised clustering approach that stratify participants based on their resting-state EEG spectral features before the tDCS intervention. We then applied a correlational analysis to characterize the clusters of EEG profiles in terms of participant's difference in the behavioral outcome (accuracy and response time) of the cognitive tasks when performed after a tDCS-sham or a tDCS-active session. Better behavioral performance following the active tDCS session compared to the sham tDCS session is considered a positive intervention response, whilst the reverse is considered a negative one. Optimal results in terms of validity measures was obtained for 4 clusters. These results show that specific EEG-based digital phenotypes can be associated to particular responses. While one cluster presents neurotypical EEG activity, the remaining clusters present non-typical EEG characteristics, which seem to be associated with a positive response. Findings suggest that unsupervised machine learning can be successfully used to stratify and eventually predict responses of individuals to a tDCS treatment.

Cytokine alterations in CSF and serum samples of patients with a first episode of schizophrenia: results and methodological considerations.

We determined cytokine levels in paired serum/CSF samples from first-episode schizophrenia (FES) participants (n = 20) and controls (n = 21) using a 13-plex immunoassay. Applying strictly-determined detection limits, 12 cytokines were found in serum and two in CSF. Higher serum MCP-1 levels (p = 0.007) were present in FES versus controls, which correlated with serum IgG (R = - 0.750; p = 0.013). Finally, IL-18 levels correlated with body weight in FES (R = 0.691; p = 0.041). This study demonstrates potential limitations in the sensitivity of multiplex cytokine assays for CSF studies in mental disorders and suggests that some published studies in this area should be re-evaluated.

Neural Mechanisms Underlying the Effects of Novel Sounds on Task Performance in Children With and Without ADHD.

Distractibility is one of the key features of attention deficit hyperactivity disorder (ADHD) and has been associated with alterations in the neural orienting and alerting networks. Task-irrelevant stimuli are thus expected to have detrimental effects on the performance of patients with ADHD. However, task-irrelevant presentation of novel sounds seems to have the opposite effect and improve subsequent attentional performance particularly in patients with ADHD. Here, we aimed to understand the neural modulations of the attention networks underlying these improvements. Fifty boys (25 with ADHD) participated in a functional magnetic resonance imaging (fMRI) study in which unique (novel) or repeatedly presented (familiar) sounds were placed before a visual flanker task in 2/3 of the trials. We found that presenting any sound improved task performance in all participants, but the underlying neural mechanisms differed for the type of sound. Familiar sounds led to a stronger increase in activity in the left posterior insula in patients with ADHD compared to typically developing peers. Novel sounds led to activations of the fronto-temporoparietal ventral attention network, likewise in ADHD and TD. These changes in signaling by novelty in the right inferior frontal gyrus were directly related to improved response speed showing that neural orienting network activity following novel sounds facilitated subsequent attentional performance. This mechanism of behavioral enhancement by short distractions could potentially be useful for cognitive trainings or homework situations.

Multichannel anodal tDCS over the left dorsolateral prefrontal cortex in a paediatric population.

Methodological studies investigating transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) in paediatric populations are limited. Therefore, we investigated in a paediatric population whether stimulation success of multichannel tDCS over the lDLPFC depends on concurrent task performance and individual head anatomy. In a randomised, sham-controlled, double-blind crossover study 22 healthy participants (10-17 years) received 2 mA multichannel anodal tDCS (atDCS) over the lDLPFC with and without a 2-back working memory (WM) task. After stimulation, the 2-back task and a Flanker task were performed. Resting state and task-related EEG were recorded. In 16 participants we calculated the individual electric field (E-field) distribution. Performance and neurophysiological activity in the 2-back task were not affected by atDCS. atDCS reduced reaction times in the Flanker task, independent of whether atDCS had been combined with the 2-back task. Flanker task related beta oscillation increased following stimulation without 2-back task performance. atDCS effects were not correlated with the E-field. We found no effect of multichannel atDCS over the lDLPFC on WM in children/adolescents but a transfer effect on interference control. While this effect on behaviour was independent of concurrent task performance, neurophysiological activity might be more sensitive to cognitive activation during stimulation. However, our results are limited by the small sample size, the lack of an active control group and variations in WM performance.

Effects of a five-day HD-tDCS application to the right IFG depend on current intensity: A study in children and adolescents with ADHD.

Impaired executive functions in ADHD are associated with hypoactivity of the right inferior frontal gyrus (IFG). This region was targeted via repetitive applications of anodal, high-definition transcranial direct current simulation (HD-tDCS) on five consecutive days in 33 ADHD patients (10-17years) and in a healthy control group (n=13, only sham). Patients received either sham (n=13) or verum tDCS with 0.5mA (n=9) or 0.25mA (n=11) depending on individual cutaneous sensitivity. During stimulation, participants performed a combined working memory and response inhibition paradigm (n-back/nogo). At baseline, post, and a 4-month follow up, electroencephalography was recorded during this task. Moreover, interference control (flanker task) and spatial working memory (spanboard task) were assessed to explore possible transfer effects. Omission errors and reaction time variability in all tasks served as measures of attention. In the 0.25mA group increased nogo commission errors indicated a detrimental tDCS effect on response inhibition. After the 5-day stimulation, attentional improvements in the 0.5mA group were indicated by reduced omission errors and reaction time variability. Variability improvements were still evident at follow up. In all groups, nogo P3 amplitudes were reduced post-stimulation, but in the 0.5mA group this reduction was smaller than in the 0.25mA group. Results of the current study suggest distinct effects of tDCS with different current intensities demonstrating the importance of a deeper understanding on the impact of stimulation parameters and repeated tDCS applications to develop effective tDCS-based therapy approaches in ADHD.

Transcranial direct-current stimulation and pediatric attention deficit hyperactivity disorder (ADHD)-Findings from an interview ethics study with children, adolescents, and their parents.

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a brain stimulation technique for an alternative or complementary treatment for various neurological disorders, including pediatric ADHD. However, little is known about the experiences of participants undergoing tDCS treatments in clinical trials. Exploration of their views on the matter is an important contribution to the societal debate on ethical issues of tDCS, allowing for a responsible translation into clinical practice and timely identification of potential challenges. METHODS: in-depth interviews study with children with ADHD undertaking tDCS and their parents (n=32). RESULTS: Children reported overall good experiences with the stimulation, although they found participation in the clinical study very tiring and time consuming. Their responses to the actual effects of the stimulation were mixed. Parents were very keen for their children to participate in the study as they saw it as a promising and safe alternative to medication. Even though many of them understood the techniques, they often did not see the link between the (current) lack of side effects and an absence of longitudinal studies. Unlike children, interviewed parents were cautious about using tDCS for non-medical/enhancement purposes. DISCUSSION: There is a need for more transparent information about the state of the art of tDCS, its function and what it actually might be able to offer. It is especially important in order to prevent unrealistic hopes and to make sure that future pediatric patients and their carers are more aware of the potential side-effects and long-term effects of tDCS.

Transcranial direct current stimulation in attention-deficit/hyperactivity disorder: A meta-analysis of clinical efficacy outcomes.

BACKGROUND: Evidence for the application of transcranial direct current stimulation (tDCS) in the clinical care of attention-deficit/hyperactivity disorder (ADHD) is limited. Therefore, we aimed to summarize study results using meta-analyses of measures of the cardinal symptoms of ADHD. METHODS: We conducted a systematic literature search (PubMed/pubpsych/PsychInfo/WOS) until 01/05/2020 for randomized controlled trials (RCTs) evaluating tDCS vs. control condition in patients with ADHD. A random effects meta-analysis of symptom-related outcomes was performed separately for data on the immediate effect and follow-up. Subgroup- and metaregression analyses for patient characteristics and tDCS parameters were included. RESULTS: Meta-analyzing 13 studies (n=308, age=23.7±13.3), including 20 study arms, tDCS had an immediate effect on overall symptom severity, inattention, and impulsivity, but not on hyperactivity. Results were significant in children and adolescents (8 studies, n=133, age=12.4±3.0). Follow-up data (3 days-4 weeks after stimulation) suggested an ongoing beneficial effect regarding overall symptom severity and a delayed effect on hyperactivity. DISCUSSION: TDCS seems to be a promising method to treat clinical symptoms in ADHD with long-lasting effects. Still, more research considering the individual neuropsychological and anatomical dispositions of the subjects is needed to optimize tDCS protocols and efficacy. Safety issues of tDCS treatment in children and adolescents are addressed.

Exploration of a novel virtual environment improves memory consolidation in ADHD.

Experimental evidence in rodents and humans suggests that long-term memory consolidation can be enhanced by the exploration of a novel environment presented during a vulnerable early phase of consolidation. This memory enhancing effect (behavioral tagging) is caused by dopaminergic and noradrenergic neuromodulation of hippocampal plasticity processes. In translation from animal to human research, we investigated whether behavioral tagging with novelty can be used to tackle memory problems observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). 34 patients with ADHD and 34 typically developing participants (age 9-15 years) explored either a previously familiarized or a novel virtual environment 45 min after they had learned a list of 20 words. Participants took a free recall test both immediately after learning the word list and after 24 h. Patients who explored a familiar environment showed significantly impaired memory consolidation compared to typically developing peers. Exploration of a novel environment led to significantly better memory consolidation in children and adolescents with ADHD. However, we did not observe a beneficial effect of novel environment exploration in typically developing participants. Our data rather suggested that increased exploration of a novel environment as well as higher feelings of virtual immersion compromised memory performance in typically developing children and adolescents, which was not the case for patients with ADHD. We propose that behavioral tagging with novel virtual environments is a promising candidate to overcome ADHD related memory problems. Moreover, the discrepancy between children and adolescents with and without ADHD suggests that behavioral tagging might only be able to improve memory consolidation for weakly encoded information.

Individual Baseline Performance and Electrode Montage Impact on the Effects of Anodal tDCS Over the Left Dorsolateral Prefrontal Cortex.

Anodal transcranial direct current stimulation (tDCS), applied over the left dorsolateral prefrontal cortex (lDLPFC), can produce significant effects on working memory (WM) performance and associated neurophysiological activity. However, results from previous studies are inconsistent and occasionally contradictory. This inconsistency may be attributed to methodological and individual differences during experiments. This study therefore investigated two hypotheses: (1) A multichannel-optimized montage was expected to be more effective than a classical bipolar montage, because of increased focality. (2) The subjects were expected to benefit differently from the stimulation depending on their initial task performance. In a sham-controlled crossover study, 24 healthy participants received bipolar, multichannel, and sham stimulation for 20 min in randomized order, targeting the lDLPFC while performing a 2-back WM task. After stimulation, electroencephalography (EEG) was recorded at rest and during 2-back and nontarget continuous performance task (CPT) performance. Bipolar and multichannel stimulations were both well tolerated and effectively blinded. We found no effect of stimulation on behavioral performance or neuronal oscillations comparing the classical bipolar or multichannel montage with sham stimulation. We did, however, find an interaction between stimulation and initial task performance. For multichannel stimulation, initially low-performing participants tended to improve their WM performance while initially high-performing participants tended to worsen their performance compared to sham stimulation. Both tDCS montages induced changes in neural oscillatory power, which correlated with baseline performance. The worse the participants' initial WM performance was, the more task-related theta power was induced by multichannel and bipolar stimulation. The same effect was observed for alpha power in the nontarget task following multichannel stimulation. Notably, we were not able to show a superiority of multichannel stimulation compared to bipolar stimulation. Still, comparing both montages with sham stimulation, multichannel stimulation led to stronger effects than bipolar stimulation. The current study highlights the importance of investigating different parameters with potential influence on tDCS effects in combination. Our results demonstrate how individual differences in cognitive performance and electrode montages influence effects of tDCS on neuropsychological performance. These findings support the idea of an individualized and optimized stimulation setting, potentially leading to increased tDCS effects.

Economical Assessment of Working Memory and Response Inhibition in ADHD Using a Combined n-back/Nogo Paradigm: An ERP Study.

The development of cognitive interventions in attention-deficit/hyperactivity disorder (ADHD) often requires the assessment of multiple cognitive functions. However, experimental settings consisting of various tasks are particularly strenuous for patients and can thus result in poor data quality. For the economical assessment of working memory and response inhibition, this study aims to validate a combined n-back/nogo paradigm by comparing it to single task versions and to demonstrate its applicability for ADHD research. Twenty-five healthy individuals and 34 ADHD patients between 9 and 16 years participated in this event-related potential (ERP) study. Healthy controls underwent single task versions of a 2-back working memory task and a go/nogo response inhibition task as well as the introduced combined 2-back/nogo task. This combined task demonstrated a comparable ERP structure for working memory and response inhibition aspects as single task versions. Behaviorally, higher working memory performance during the combined paradigm indicated lower task difficulty, while high correlations between combined and single task versions still indicated valid working memory measures. For response inhibition performance, different task versions resulted in similar outcomes. The application of the combined n-back/nogo paradigm in ADHD patients revealed the expected working memory and response inhibition deficits, increased omission errors, reaction times, and standard deviation of reaction time, as well as diminished n-back P3 and nogo P3 amplitudes. We conclude that the combined n-back/nogo task is an effective paradigm for the economical assessment of working memory and response inhibition deficits in ADHD on a behavioral and neurophysiological level.