Neurochemical mechanisms underlying serotonergic modulation of neuroplasticity in humans.

BACKGROUND: Studies in animals and humans have shown that cortical neuroplasticity can be modulated by increasing serotonin levels by administering selective serotonin reuptake inhibitors (SSRI). However, little is known about the mechanistic background, especially the contribution of intracortical inhibition and facilitation, which depend on gamma-aminobutyric acid (GABA) and glutamate. OBJECTIVE: We aimed to explore the relevance of drivers of plasticity (glutamate- and GABA-dependent processes) for the effects of serotonin enhancement on tDCS-induced plasticity in healthy humans. METHODS: A crossover, partially double-blinded, randomized, and sham-controlled study was conducted in 21 healthy right-handed individuals. In each of the 7 sessions, plasticity was induced via transcranial direct current stimulation (tDCS). Anodal, cathodal, and sham tDCS were applied to the left motor cortex under SSRI (20 mg/40 mg citalopram) or placebo. Short-interval cortical inhibition (SICI) and intracortical facilitation (ICF) were monitored by paired-pulse transcranial magnetic stimulation for 5-6 h after intervention. RESULTS: Under placebo, anodal tDCS-induced LTP-like plasticity decreased SICI and increased ICF. In contrast, cathodal tDCS-elicited LTD-like plasticity induced the opposite effect. Under 20 mg and 40 mg citalopram, anodal tDCS did not affect SICI largely, while ICF was enhanced and prolonged. For cathodal tDCS, citalopram converted the increase of SICI and decrease of ICF into antagonistic effects, and this effect was dosage-dependent since it lasted longer under 40 mg when compared to 20 mg. CONCLUSION: We speculate that the main effects of acute serotonergic enhancement on tDCS-induced plasticity, the increase and prolongation of LTP-like plasticity effects, involves mainly the glutamatergic system.

A systematic review of randomized controlled trials on efficacy and safety of transcranial direct current stimulation in major neurodevelopmental disorders: ADHD, autism, and dyslexia.

OBJECTIVE: Among the target groups in child and adolescent psychiatry, transcranial direct current stimulation (tDCS) has been more applied in neurodevelopmental disorders specifically, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and dyslexia. This systematic review aims to provide the latest update on published randomized-controlled trials applying tDCS in these disorders for evaluating its efficacy and safety. METHODS: Based on a pre-registered protocol (PROSPERO: CRD42022321430) and using the PRISMA approach, a literature search identified 35 randomized controlled trials investigating the effects of tDCS on children and adolescents with ADHD (n = 17), ASD (n = 11), and dyslexia (n = 7). RESULTS: In ADHD, prefrontal anodal tDCS is reported more effective compared to stimulation of the right inferior frontal gyrus. Similarly in ASD, prefrontal anodal tDCS was found effective for improving behavioral problems. In dyslexia, stimulating temporoparietal regions was the most common and effective protocol. In ASD and dyslexia, all tDCS studies found an improvement in at least one of the outcome variables while 64.7% of studies (11 of 17) in ADHD found a similar effect. About 88% of all tDCS studies with a multi-session design in 3 disorders (16 of 18) reported a significant improvement in one or all outcome variables after the intervention. Randomized, double-blind, controlled trials consisted of around 70.5%, 36.3%, and 57.1% of tDCS studies in ADHD, ASD, and dyslexia, respectively. tDCS was found safe with no reported serious side effects in 6587 sessions conducted on 745 children and adolescents across 35 studies. CONCLUSION: tDCS was found safe and partially effective. For evaluation of clinical utility, larger randomized controlled trials with a double-blind design and follow-up measurements are required. Titration studies that systematically evaluate different stimulation intensities, duration, and electrode placement are lacking.

Sleep-dependent upscaled excitability, saturated neuroplasticity, and modulated cognition in the human brain.

Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta oscillations due to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data indicate that upscaled brain excitability and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance. Besides showing how brain physiology and cognition undergo changes (from neurophysiology to higher-order cognition) under sleep pressure, the findings have implications for variability and optimal application of noninvasive brain stimulation.

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.

Circadian disturbances, sleep difficulties and the COVID-19 pandemic.

The COVID-19 pandemic has imposed extraordinary and unpredictable changes on our lifestyle for an unknown duration. Consequently, core aspects of wellbeing including behavior, emotion, cognition, and social interactions are negatively affected. Sleep and circadian rhythms, with an extensive impact on physiology, behavior, emotion, and cognition are affected too. We provided an updated overview of the impact of the COVID-19 pandemic on circadian rhythms and sleep based on the results of published studies (n = 48) in three sections. First, we focus on circadian misalignment due to the pandemic in the general population (including shift workers, health staff, students) and COVID-19 patients and summarize the most critically contributing factors to circadian misalignment. Next, we address sleep difficulties and poor sleep quality during the pandemic, their contributing factors, rate and prevalence, and their effects on both the general population and COVID-19 patients. Finally, we summarize the currently applied/recommended interventions for aligning circadian rhythms and improving sleep quality in both, the general population, and COVID-19 patients during the pandemic situation. Briefly, circadian misalignment and sleep difficulties are common consequences of the pandemic in the general population (with elderly, students, children, health and night-work shifters as risk groups) and COVID-19 patients. Home confinement and its physiological, circadian, and psychological derivates are central to these difficulties. Symptoms severity, treatment progress, recovery duration, and even diagnosis of COVID-19 patients are considerably affected by circadian and sleep difficulties. Behavioral interventions for normalizing the factors that contribute to circadian and sleep difficulties are helpful.

Cognitive functions and underlying parameters of human brain physiology are associated with chronotype.

Circadian rhythms have natural relative variations among humans known as chronotype. Chronotype or being a morning or evening person, has a specific physiological, behavioural, and also genetic manifestation. Whether and how chronotype modulates human brain physiology and cognition is, however, not well understood. Here we examine how cortical excitability, neuroplasticity, and cognition are associated with chronotype in early and late chronotype individuals. We monitor motor cortical excitability, brain stimulation-induced neuroplasticity, and examine motor learning and cognitive functions at circadian-preferred and non-preferred times of day in 32 individuals. Motor learning and cognitive performance (working memory, and attention) along with their electrophysiological components are significantly enhanced at the circadian-preferred, compared to the non-preferred time. This outperformance is associated with enhanced cortical excitability (prominent cortical facilitation, diminished cortical inhibition), and long-term potentiation/depression-like plasticity. Our data show convergent findings of how chronotype can modulate human brain functions from basic physiological mechanisms to behaviour and higher-order cognition.

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.

Intensified electrical stimulation targeting lateral and medial prefrontal cortices for the treatment of social anxiety disorder: A randomized, double-blind, parallel-group, dose-comparison study.

BACKGROUND: Social Anxiety Disorder (SAD) is the most common anxiety disorder while remains largely untreated. Disturbed amygdala-frontal network functions are central to the pathophysiology of SAD, marked by hypoactivity of the lateral prefrontal cortex (PFC), and hypersensitivity of the medial PFC and the amygdala. The objective of this study was to determine whether modulation of the dorsolateral and medial PFC activity with a novel intensified stimulation protocol reduces SAD core symptoms, improves treatment-related variables, and reduces attention bias to threatening stimuli. METHODS: In this randomized, sham-controlled, double-blind trial, we assessed the efficacy of an intensified stimulation protocol (20 min, twice-daily sessions with 20 min intervals, 5 consecutive days) in two intensities (1 vs 2 mA) compared to sham stimulations. 45 patients with SAD were randomized in three tDCS arms (1-mA, 2-mA, sham). SAD symptoms, treatment-related variables (worries, depressive state, emotion regulation, quality of life), and attention bias to threatening stimuli (dot-probe paradigm) were assessed before and right after the intervention. SAD symptoms were also assessed at 2-month follow-up. RESULTS: Both 1-mA and 2-mA protocols significantly reduced fear/avoidance symptoms, worries and improved, emotion regulation and quality of life after the intervention compared to the sham group. Improving effect of the 2-mA protocol on avoidance symptoms, worries and depressive state was significantly larger than the 1-mA group. Only the 2-mA protocol reduced attention bias to threat-related stimuli, the avoidance symptom at follow-up, and depressive states, as compared to the sham group. CONCLUSIONS: Modulation of lateral-medial PFC activity with intensified stimulation can improve cognitive control, motivation and emotion networks in SAD and might thereby result in therapeutic effects. These effects can be larger with 2-mA vs 1-mA intensities, though a linear relationship between intensity and efficacy should not be concluded. Our results need replication in larger trials.

Hot and cold executive functions in the brain: A prefrontal-cingular network.

Executive functions, or cognitive control, are higher-order cognitive functions needed for adaptive goal-directed behaviours and are significantly impaired in majority of neuropsychiatric disorders. Different models and approaches are proposed for describing how executive functions are functionally organised in the brain. One popular and recently proposed organising principle of executive functions is the distinction between hot (i.e. reward or affective-related) versus cold (i.e. purely cognitive) domains of executive functions. The prefrontal cortex is traditionally linked to executive functions, but on the other hand, anterior and posterior cingulate cortices are hugely involved in executive functions as well. In this review, we first define executive functions, their domains, and the appropriate methods for studying them. Second, we discuss how hot and cold executive functions are linked to different areas of the prefrontal cortex. Next, we discuss the association of hot versus cold executive functions with the cingulate cortex, focusing on the anterior and posterior compartments. Finally, we propose a functional model for hot and cold executive function organisation in the brain with a specific focus on the fronto-cingular network. We also discuss clinical implications of hot versus cold cognition in major neuropsychiatric disorders (depression, schizophrenia, anxiety disorders, substance use disorder, attention-deficit hyperactivity disorder, and autism) and attempt to characterise their profile according to the functional dominance or manifest of hot-cold cognition. Our model proposes that the lateral prefrontal cortex along with the dorsal anterior cingulate cortex are more relevant for cold executive functions, while the medial-orbital prefrontal cortex along with the ventral anterior cingulate cortex, and the posterior cingulate cortex are more closely involved in hot executive functions. This functional distinction, however, is not absolute and depends on several factors including task features, context, and the extent to which the measured function relies on cognition and emotion or both.

Negative impact of COVID-19 pandemic on sleep quantitative parameters, quality, and circadian alignment: Implications for health and psychological well-being.

The COVID-19 pandemic has spread worldwide, affecting millions of people and exposing them to home quarantine, isolation, and social distancing. While recent reports showed increased distress and depressive/anxiety state related to COVID-19 crisis, we investigated how home quarantine affected sleep parameters in healthy individuals. 160 healthy individuals who were in home quarantine in April 2020 for at least one month participated in this study. Participants rated and compared their quantitative sleep parameters (time to go to bed, sleep duration, getting-up time) and sleep quality factors, pre-and during home quarantine due to the COVID-19 pandemic. Furthermore, participants' chronotype was determined to see if sleep parameters are differentially affected in different chronotypes. Time to fall asleep and get-up in the morning were significantly delayed in all participants, indicating a significant circadian misalignment. Sleep quality was reported to be significantly poorer in all participants and chronotypes. Poor sleep quality included more daily disturbances (more sleep disturbances, higher daily dysfunctions due to low quality of sleep) and less perceived sleep quality (lower subjective sleep quality, longer time taken to fall asleep at night, more use of sleep medication for improving sleep quality) during home quarantine. Home quarantine due to COVID-19 pandemic has a detrimental impact on sleep quality. Online interventions including self-help sleep programs, stress management, relaxation practices, stimulus control, sleep hygiene, and mindfulness training are available interventions in the current situation.

Differential role of prefrontal, temporal and parietal cortices in verbal and figural fluency: Implications for the supramodal contribution of executive functions.

Verbal and figural fluency are related to executive functions (EFs), but the extent to which they benefit from executive resources and their respective cortical representations is not clear. Moreover, different brain areas and cognitive functions are involved in fluency processing. This study investigated effects of modulation of cortical excitability in the left dorsolateral prefrontal cortex (l-DLPFC), left temporal area and right posterior parietal cortex (r-PPC) with transcranial direct current stimulation (tDCS), on verbal and figural fluency. Fifteen healthy adult participants received anodal l-DLPFC (F3), anodal left temporal (T3), anodal r-PPC (P4) and sham tDCS (15 min, 1.5 mA). After five minutes of stimulation, participants underwent the verbal fluency (i.e., semantic and phonemic fluency tasks) and figural fluency tasks. Participants significantly generated more words with phonemic cues during anodal l-DLPFC tDCS and more words with semantic cues during both anodal left temporal and anodal l-DLPFC tDCS. In contrast, they generated more unique figures under anodal r-PPC and anodal l-DLPFC tDCS. Our results implicate that prefrontal regions and EFs are shared anatomical correlates and cognitive processes relevant for both, verbal and figural fluency (supramodal contribution of DLPFC activation), whereas r-PPC and left temporal cortex are more specifically involved in figural and semantic fluency (modality-specific contribution).