Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review.

Despite the numerous pharmacological interventions targeting dementia, no disease-modifying therapy is available, and the prognosis remains unfavorable. A promising perspective involves tackling high-frequency gamma-band (> 30 Hz) oscillations involved in hippocampal-mediated memory processes, which are impaired from the early stages of typical Alzheimer's Disease (AD). Particularly, the positive effects of gamma-band entrainment on mouse models of AD have prompted researchers to translate such findings into humans using transcranial alternating current stimulation (tACS), a methodology that allows the entrainment of endogenous cortical oscillations in a frequency-specific manner. This systematic review examines the state-of-the-art on the use of gamma-tACS in Mild Cognitive Impairment (MCI) and dementia patients to shed light on its feasibility, therapeutic impact, and clinical effectiveness. A systematic search from two databases yielded 499 records resulting in 10 included studies and a total of 273 patients. The results were arranged in single-session and multi-session protocols. Most of the studies demonstrated cognitive improvement following gamma-tACS, and some studies showed promising effects of gamma-tACS on neuropathological markers, suggesting the feasibility of gamma-tACS in these patients anyhow far from the strong evidence available for mouse models. Nonetheless, the small number of studies and their wide variability in terms of aims, parameters, and measures, make it difficult to draw firm conclusions. We discuss results and methodological limitations of the studies, proposing possible solutions and future avenues to improve research on the effects of gamma-tACS on dementia.

The Interaction of the Dorsolateral and Ventromedial Prefrontal Cortex During Mind Wandering.

BACKGROUND AND AIMS: Mind wandering refers to spontaneously occurring, often disruptive thoughts during an ongoing task or resting state. The ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are two main cortical areas which are involved in this process. This study aimed to explore the interaction of these areas during mind wandering by enhancing specific oscillatory activity of these areas via transcranial alternating current stimulation (tACS) in the theta frequency range. MATERIAL AND METHODS: Eighteen healthy adults participated in a randomized, single-blinded, crossover study. tACS (1.5 mA, 6 Hz) was applied in five sessions with one week interval via (1) two channels with synchronized stimulation over the left dlPFC and right vmPFC, (2) the same electrode placement with anti-phase stimulation, (3) stimulation over the left dlPFC only, (4) stimulation over right vmPFC only, and (5) sham stimulation. The return electrodes were placed over the contralateral shoulder in all conditions. The sustained attention to response task (SART) with embedded probes about task-unrelated-thoughts and awareness of these thoughts was performed during intervention. RESULTS: Stimulation did not alter SART performance. Right vmPFC stimulation decreased mind wandering and increased awareness of mind wandering. Left dlPFC stimulation and desynchronized stimulation over the dlPFC and vmPFC increased mind wandering compared to the sham stimulation condition. Synchronized stimulation had no effect on mind wandering, but increased awareness of mind wandering. CONCLUSION: The results suggest that regional entrainment of the vmPFC decreases mind wandering and increases awareness of mind wandering, whereas regional entrainment of the dlPFC increases mind wandering, but decreases awareness. Under desynchronized stimulation of both areas, the propensity of mind wandering was increased, whereas synchronized stimulation increased the awareness of mind wandering. These results suggest a role of the dlPFC in initiation of mind wandering, whereas the vmPFC downregulates mind wandering, and might exert this function by counteracting respective dlPFC effects via theta oscillations.

NMDA receptor-related mechanisms of dopaminergic modulation of tDCS-induced neuroplasticity.

Dopamine is a key neuromodulator of neuroplasticity and an important neuronal substrate of learning, and memory formation, which critically involves glutamatergic N-methyl-D-aspartate (NMDA) receptors. Dopamine modulates NMDA receptor activity via dopamine D1 and D2 receptor subtypes. It is hypothesized that dopamine focuses on long-term potentiation (LTP)-like plasticity, i.e. reduces diffuse widespread but enhances locally restricted plasticity via a D2 receptor-dependent NMDA receptor activity reduction. Here, we explored NMDA receptor-dependent mechanisms underlying dopaminergic modulation of LTP-like plasticity induced by transcranial direct current stimulation (tDCS). Eleven healthy, right-handed volunteers received anodal tDCS (1 mA, 13 min) over the left motor cortex combined with dopaminergic agents (the D2 receptor agonist bromocriptine, levodopa for general dopamine enhancement, or placebo) and the partial NMDA receptor agonist D-cycloserine (dosages of 50, 100, and 200 mg, or placebo). Cortical excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potentials. We found that LTP-like plasticity was abolished or converted into LTD-like plasticity via dopaminergic activation, but reestablished under medium-dose D-cycloserine. These results suggest that diffuse LTP-like plasticity is counteracted upon via D2 receptor-dependent reduction of NMDA receptor activity.

Consolidation of motor sequence learning eliminates susceptibility of SMAproper to TMS: a combined rTMS and cTBS study.

Earlier research suggested that after 210 practice trials, the supplementary motor area (SMA) is involved in executing all responses of familiar 6-key sequences in a discrete sequence production (DSP) task (Verwey, Lammens, and van Honk, 2002). This was indicated by slowing of each response 20 and 25 min after the SMA had been stimulated for 20 min using repetitive transcranial magnetic stimulation (rTMS). The present study used a similar approach to assess the effects of TMS to the more posterior SMAproper at the end of practice and also 24 h later. As expected stimulation of SMAproper with 20 min of 1 Hz rTMS and 40 s of continuous theta burst stimulation (cTBS) immediately after practice slowed sequence execution relative to a sham TMS condition, but stimulation on the day following practice did not cause slowing. This indicates that offline consolidation makes learning robust against stimulation of SMAproper. Execution of all responses in the sequence was disrupted 0, 20, and 40 min after rTMS, but after cTBS, this occurred only after 40 min. The results suggest that it is implicit sequence knowledge that is processed by the SMAproper and that consolidates.

Efficacy of transcranial Direct Current Stimulation (tDCS) combined with intensive speech therapy for language production in monozygotic twins with corpus callosum dysgenesis (CCD): A sham-controlled single subject study.

The purpose of this single subject study was to investigate whether transcranial direct current stimulation (tDCS) applied to both hemispheres combined with speech therapy can improve language learning in a pair of 5-year-old twins with corpus callosum dysgenesis (CCD). The treatment protocol included anodal tDCS with simultaneous speech therapy in one of the participants (T.D.), and sham-tDCS with the same montage, and stimulation regime concomitant with speech therapy for the other twin (A.D.). Our findings show that T.D. improved in language production when treated with speech therapy in combination with tDCS. A.D. showed evidence for a relatively minor behavioral benefit from speech therapy.

Phase synchronized 6 Hz transcranial electric and magnetic stimulation boosts frontal theta activity and enhances working memory.

Network-level synchronization of theta oscillations in the cerebral cortex is linked to many vital cognitive functions across daily life, such as executive functions or regulation of arousal and consciousness. However, while neuroimaging has uncovered the ubiquitous functional relevance of theta rhythms in cognition, there remains a limited set of techniques for externally enhancing and stabilizing theta in the human brain non-invasively. Here, we developed and employed a new phase-synchronized low-intensity electric and magnetic stimulation technique to induce and stabilize narrowband 6-Hz theta oscillations in a group of healthy human adult participants, and then demonstrated how this technique also enhances cognitive processing by assaying working memory. Our findings demonstrate a technological advancement of brain stimulation methods, while also validating the causal link between theta activity and concurrent cognitive behavior, which may ultimately help to not only explain mechanisms, but offer perspectives for restoring deficient theta-band network activity observed in neuropsychiatric diseases.

Timing matters: Transcranial direct current stimulation after extinction learning impairs subsequent fear extinction retention.

BACKGROUND: Transcranial direct current stimulation (tDCS) has previously been shown to improve fear extinction learning and retention when administered prior to or during extinction learning. This study investigates whether tDCS immediately following extinction learning improves efficacy of extinction memory retention. METHODS: 30 participants completed a 2-day fear learning and extinction paradigm, where they acquired fear of a stimulus conditioned to an aversive electric shock on day 1. Extinction learning occurred on day 1, with tDCS or sham tDCS administered immediately following the learning phase. Participants returned for a second day test of extinction memory recall. Skin conductance was measured as the primary outcome. RESULTS/CONCLUSIONS: Participants in the tDCS group showed impaired fear extinction retention on day 2, marked by significant generalisation of fear to the safety stimulus. This contrasts with earlier studies showing improved extinction retention when stimulation occurred during encoding of extinction learning, compared to immediate consolidation as in our study. These findings may have important implications for the use of tDCS during exposure therapy for anxiety and trauma disorders.

Dosage-Dependent Impact of Acute Serotonin Enhancement on Transcranial Direct Current Stimulation Effects.

BACKGROUND: The serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals. METHODS: Twelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation. RESULTS: Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60-120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated. CONCLUSIONS: Acute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.

Noradrenergic Enhancement of Motor Learning, Attention, and Working Memory in Humans.

BACKGROUND: Noradrenaline has an important role as a neuromodulator of the central nervous system. Noradrenergic enhancement was recently shown to enhance glutamate-dependent cortical facilitation and long term potentiation-like plasticity. As cortical excitability and plasticity are closely linked to various cognitive processes, here we aimed to explore whether these alterations are associated with respective cognitive performance changes. Specifically, we assessed the impact of noradrenergic enhancement on motor learning (serial reaction time task), attentional processes (Stroop interference task), and working memory performance (n-back letter task). METHODS: The study was conducted in a cross-over design. Twenty-five healthy humans performed the respective cognitive tasks after a single dose of the noradrenaline reuptake inhibitor reboxetine or placebo administration. RESULTS: The results show that motor learning, attentional processes, and working memory performance in healthy participants were improved by reboxetine application compared with placebo. CONCLUSIONS: The results of the present study thus suggest that noradrenergic enhancement can improve memory formation and executive functions in healthy humans. The respective changes are in line with related effects of noradrenaline on cortical excitability and plasticity.

Prevention of schizophrenia deficits via non-invasive adolescent frontal cortex stimulation in rats.

Schizophrenia is a severe neurodevelopmental psychiatric affliction manifested behaviorally at late adolescence/early adulthood. Current treatments comprise antipsychotics which act solely symptomatic, are limited in their effectiveness and often associated with side-effects. We here report that application of non-invasive transcranial direct current stimulation (tDCS) during adolescence, prior to schizophrenia-relevant behavioral manifestation, prevents the development of positive symptoms and related neurobiological alterations in the maternal immune stimulation (MIS) model of schizophrenia.

Nonlinear Effects of Dopamine D1 Receptor Activation on Visuomotor Coordination Task Performance.

Dopamine plays an important role in the modulation of neuroplasticity, which serves as the physiological basis of cognition. The physiological effects of dopamine depend on receptor subtypes, and the D1 receptor is critically involved in learning and memory formation. Evidence from both animal and human studies shows a dose-dependent impact of D1 activity on performance. However, the direct association between physiology and behavior in humans remains unclear. In this study, four groups of healthy participants were recruited, and each group received placebo or medication inducing a low, medium, or high amount of D1 activation via the combination of levodopa and a D2 antagonist. After medication, fMRI was conducted during a visuomotor learning task. The behavioral results revealed an inverted U-shaped effect of D1 activation on task performance, where medium-dose D1 activation led to superior learning effects, as compared to placebo as well as low- and high-dose groups. A respective dose-dependent D1 modulation was also observed for cortical activity revealed by fMRI. Further analysis demonstrated a positive correlation between task performance and cortical activation at the left primary motor cortex. Our results indicate a nonlinear curve of D1 modulation on motor learning in humans and the respective physiological correlates in corresponding brain areas.

Contribution to the ongoing discussion on fluoride toxicity.

Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.

Effect of combined yoga and transcranial direct current stimulation intervention on working memory and mindfulness.

Transcranial direct stimulation, a non-invasive neurostimulation technique for modulating cortical excitability, and yoga have both respectively been shown to positively affect cognition. While preliminary research has shown that combined transcranial direct stimulation and meditation may have synergistic effects on mood and cognition, this was the first study to explore the combination of transcranial direct stimulation and yoga. Twenty-two healthy volunteers with a regular yoga practice were randomized to receive either active transcranial direct stimulation (anodal left, cathodal right dorsolateral prefrontal cortex) followed by yoga intervention or sham transcranial direct stimulation followed by yoga intervention a double-blind, cross-over design over two separate intervention days. Outcome measures included working memory performance, measured with the n-back task and mindfulness state, measured with the Toronto Mindfulness Scale, and were conducted offline, with pre-post assessments. Twenty participants completed both days of the intervention. Active transcranial direct stimulation did not have a significant effect on working memory or levels of mindfulness. There was a significant placebo effect, with better performance on day 1 of the intervention, irrespective of whether participants received active or sham transcranial direct stimulation. There was no significant difference between active versus sham transcranial direct stimulation concerning working memory performance and mindfulness, which may be accounted by the small sample size, the transient nature of the intervention, the fact that yoga and transcranial direct stimulation concerning were not conducted simultaneously, and the specific site of stimulation.

Offline Bi-Frontal Anodal Transcranial Direct Current Stimulation Decreases Total Sleep Time Without Disturbing Overnight Memory Consolidation.

OBJECTIVES: A proposed replay of memory traces between the hippocampus and frontal cortical brain areas during sleep is of high relevance for overnight memory consolidation. Recently, we demonstrated that bi-frontal anodal transcranial direct current stimulation (tDCS) prior to sleep increases waking EEG gamma power and decreases total sleep time during the night. It is unclear whether this effect on cortical excitability has an influence on overnight memory consolidation. We hypothesized that bi-frontal evening tDCS interferes with overnight memory consolidation with a polarity specific impairment following anodal tDCS. MATERIALS AND METHODS: Nineteen healthy participants underwent a within-subject, repeated-measures protocol in the sleep laboratory with bi-frontal tDCS applied prior to sleep according to the experimental protocol (anodal, cathodal, sham stimulation). Memory tasks for declarative and procedural memory were assessed prior to tDCS and on the following morning. RESULTS: No deterioration of overnight memory consolidation following evening offline bi-frontal tDCS could be detected. CONCLUSION(S): The application of tDCS can be considered safe regarding overnight memory consolidation and represents a promising treatment approach in conditions of decreased vigilance and arousal.

Probing the relevance of repeated cathodal transcranial direct current stimulation over the primary motor cortex for prolongation of after-effects.

KEY POINTS: To explore the capability of cathodal transcranial direct current stimulation (tDCS) to induce late-phase long-term depression (LTD) via repeated stimulation. Conventional (1 mA for 15 min) and intensified (3 mA for 20 min) protocols with short (20 min) and long (24 h) intervals were tested. Late-phase plasticity was not induced by a single repetition of stimulation. Repetition reduced the efficacy of stimulation protocols with higher intensities. ABSTRACT: Transcranial direct current stimulation (tDCS) has shown promising results in pilot studies as a therapeutic intervention in disorders of the central nervous system, but more sustained effects are required for clinical application. To address this issue, one possible solution is the use of repeated stimulation protocols. Previous studies indicated the possibility of extending the after-effects of single intervention cathodal tDCS by repeating the tDCS, with relatively short intervals between repetitions being most effective. In this study, we thus investigated the effects of repeated stimulation protocols at short and long intervals, for a conventional tDCS protocol (1 mA for 15 min) and a newly developed optimized protocol (3 mA for 20 min). In 16 healthy participants, we compared single interventions of conventional and optimized protocols, repeated application of these protocols at intervals of 20 min and 24 h, and a sham tDCS session. tDCS-induced neuroplastic after-effects were then monitored with transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) until the following evening after stimulation. The results revealed that the duration of the after-effects of repeated conventional and optimized protocols with short intervals remained nearly unchanged compared to the respective single intervention protocols. For the long-interval (24 h) protocol, stimulation with the conventional protocol did not significantly alter respective after-effects, while it reduced the efficacy of the optimized protocol, compared with respective single interventions. Thus late-phase plasticity could not be induced by a single repetition of stimulation in this study, but repetition reduced the efficacy of stimulation protocols with higher intensities. This study provides further insights into the dependency of tDCS-induced neuroplasticity on stimulation parameters, and therefore delivers crucial information for future tDCS applications.

Current intensity- and polarity-specific online and aftereffects of transcranial direct current stimulation: An fMRI study.

Transcranial direct current stimulation (tDCS) induces polarity- and dose-dependent neuroplastic aftereffects on cortical excitability and cortical activity, as demonstrated by transcranial magnetic stimulation (TMS) and functional imaging (fMRI) studies. However, lacking systematic comparative studies between stimulation-induced changes in cortical excitability obtained from TMS, and cortical neurovascular activity obtained from fMRI, prevent the extrapolation of respective physiological and mechanistic bases. We investigated polarity- and intensity-dependent effects of tDCS on cerebral blood flow (CBF) using resting-state arterial spin labeling (ASL-MRI), and compared the respective changes to TMS-induced cortical excitability (amplitudes of motor evoked potentials, MEP) in separate sessions within the same subjects (n = 29). Fifteen minutes of sham, 0.5, 1.0, 1.5, and 2.0-mA anodal or cathodal tDCS was applied over the left primary motor cortex (M1) in a randomized repeated-measure design. Time-course changes were measured before, during and intermittently up to 120-min after stimulation. ROI analyses indicated linear intensity- and polarity-dependent tDCS after-effects: all anodal-M1 intensities increased CBF under the M1 electrode, with 2.0-mA increasing CBF the greatest (15.3%) compared to sham, while all cathodal-M1 intensities decreased left M1 CBF from baseline, with 2.0-mA decreasing the greatest (-9.3%) from sham after 120-min. The spatial distribution of perfusion changes correlated with the predicted electric field, as simulated with finite element modeling. Moreover, tDCS-induced excitability changes correlated more strongly with perfusion changes in the left sensorimotor region compared to the targeted hand-knob region. Our findings reveal lasting tDCS-induced alterations in cerebral perfusion, which are dose-dependent with tDCS parameters, but only partially account for excitability changes.

Enhancing spatial reasoning by anodal transcranial direct current stimulation over the right posterior parietal cortex.

Spatial reasoning is essential for an agent's navigation and the cognitive processing of abstract arrangements. Meta-analyses of neuroimaging data reveal that both the right posterior parietal cortex and left dorsolateral prefrontal cortex (PPC and DLPFC, respectively) show increased activation during spatial relational reasoning. To investigate whether participants' reasoning performance can be modified and potentially enhanced, anodal transcranial direct current stimulation (tDCS) was applied over either region. 51 healthy adult participants solved spatial reasoning problems after the application of either anodal tDCS over the right PPC, the left DLPFC or a sham stimulation. We expect anodal stimulation to enhance cortical excitability which would be reflected by enhanced reasoning performance in participants receiving stimulation. The results demonstrate that anodal stimulation applied over the right PPC enhances participants' performance in indeterminate reasoning problems, compared to sham and anodal stimulation over the left DLPFC. This finding is highly relevant for clarifying the cognitive mechanisms of relational reasoning and for clinical applications, e.g., enhancing or restoring higher cognitive functions for spatial representation and reasoning.

ADHD subtype-specific cognitive correlates and association with self-esteem: a quantitative difference.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a major neurodevelopmental disorder with heterogeneous symptoms, subtypes, and cognitive deficits. Cognitive deficits are central to ADHD pathophysiology and one potential source of heterogeneity in ADHD. Subtype-specific cognitive correlates are not, however, well-studied. We explored cognitive correlates of ADHD subtypes based on the Wechsler Intelligence Scale for Children (WISC-IV) scores. We also assessed subtype-specific self-esteem rating in ADHD subtypes and explored its association with cognitive correlates. METHODS: One hundred thirty-nine children with ADHD (80.6% boy, 19.4% girl) were categorized into the predominantly "hyperactive (ADHD-H)", "inattentive (ADHD-I)" and "combined (ADHD-C)" subtype based on their symptoms and scores on the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL) and Conners Parent-Rating Scale (CPRS-RS). They were then individually administrated the WISC-IV and completed a self-esteem inventory. Group differences in the WISC-IV indices and their predictability in discriminating ADHD subtypes were analyzed. RESULTS: We found a quantitative differentiation of cognitive abilities among ADHD subtypes with "working memory" as the most compromised cognitive domain. ADHD-I had the poorest cognitive profile while ADHD-H scored highest in all cognitive domains. Importantly, cognitive abilities were negatively correlated with inattention and positively correlated with hyperactive symptoms. Moreover, self-esteem ratings were positively correlated with the cognitive domains and were rated differently based on the subtypes. ADHD-H, with the highest cognitive strength, reported the highest level of self-esteem among all subtypes. CONCLUSIONS: ADHD subtype-specific symptoms, cognitive deficits, and self-esteem problems should be considered for precise diagnosis and effective and personalized treatment in ADHD in light of further supporting evidence and assessments. Cognitive interventions might be more compatible with and effective in inattentive and combined subtypes of ADHD. Working memory improving-based interventions can benefit all ADHD subtypes. A supportive educational system in school and providing adjunct supportive interventions should be considered for children with ADHD as well.

Efficacy and clinical predictors of response to rTMS treatment in pharmacoresistant obsessive-compulsive disorder (OCD): a retrospective study.

BACKGROUND: Application of repetitive transcranial magnetic stimulation (rTMS) for treating obsessive-compulsive disorder (OCD) has been promising and approved by the Food and Drug Administration in 2018, but effects differ between patients. Knowledge about clinical predictors of rTMS response may help to increase clinical efficacy but is not available so far. METHODS: In a retrospective study, we investigated the efficacy of rTMS over the dorsolateral prefrontal cortex (DLPFC) or supplementary motor area (SMA) in 65 pharmaco-resistant OCD outpatients recruited for rTMS treatment from July 2015 to May 2017. Patients received either SMA rTMS (n = 38) or bilateral DLPFC rTMS (n = 27) in case of reporting higher affective and depressive symptoms in addition to the primary OCD symptoms. OCD symptoms and depression/anxiety states were measured at baseline (before the 1st session) and after the 20th session of rTMS. Additionally, we performed a binary logistic regression analysis on the demographic and clinical variables based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) 3-factor and 2-factor models and individual items to investigate potential predictors of rTMS response. RESULTS: Patients' scores in Y-BOCS and Beck anxiety/depression inventories were significantly decreased following rTMS treatment. 46.2% of all patients responded to rTMS, based on the criterion of at least a 30% reduction in Y-BOCS scores. There was no significant difference between response rates of patients in DLPFC and SMA groups. No significant demographic predictors of rTMS efficacy were identified. The factors "obsession severity", "resistance" and "disturbance" and the "interference due to obsessions" and "resistance against compulsions" items of the Y-BOCS significantly predicted response to rTMS. CONCLUSIONS: In patients with less intrusive/interfering thoughts, and low scores in the "obsession severity", "disturbance", and "resistance" factors, rTMS might have superior effects. Identifying clinical and non-clinical predictors of response is relevant to personalize and adapt rTMS protocols in pharmaco-resistant OCD patients. Interpretation of rTMS efficacy should be done with caution due to the lack of a sham intervention condition.

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses.

Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.