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Noninvasive brain stimulation techniques are used in experimental and clinical fields for their potential effects on brain network dynamics and behavior. Transcranial electrical stimulation (TES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), has gained popularity because of its convenience and potential as a chronic therapy. However, a mechanistic understanding of TES has lagged behind its widespread adoption. Here, we review data and modelling on the immediate neurophysiological effects of TES in vitro as well as in vivo in both humans and other animals. While it remains unclear how typical TES protocols affect neural activity, we propose that validated models of current flow should inform study design and artifacts should be carefully excluded during signal recording and analysis. Potential indirect effects of TES (e.g., peripheral stimulation) should be investigated in more detail and further explored in experimental designs. We also consider how novel technologies may stimulate the next generation of TES experiments and devices, thus enhancing validity, specificity, and reproducibility. Transcranial electrical stimulation techniques, such as tDCS and tACS, are popular tools for neuroscience and clinical therapy, but how low-intensity current might modulate brain activity remains unclear. In this review, the authors review the evidence on mechanisms of transcranial electrical stimulation.

Craving is a core characteristic of drug addiction and eating disorders. A new study identifies an fMRI-based neural signature of craving that is common to both food and drugs, predicts self-reported craving, distinguishes drug users from non-users, and tracks the efficacy of a cognitive therapy technique to reduce craving.

Transcranial direct current stimulation (tDCS) is a technique where a weak direct electrical current is applied to the scalp with the goal of stimulating the brain. There is tremendous interest in the use of tDCS for treating brain disorders and improving brain function. However, the effects of tDCS have been highly variable across studies, leading to a debate over its efficacy. A major challenge is therefore to design tDCS protocols that yield predictable effects, which will require a better understanding of its basic mechanisms of action. One commonly discussed mechanism is that tDCS may alter synaptic plasticity, but the biophysics that support this interaction between tDCS and synaptic plasticity remain unclear. This dissertation is centered around a fundamental hypothesis; that tDCS can modulate the brain’s ongoing endogenous synaptic plasticity by altering the voltage dynamics in postsynaptic neurons. In chapters 1 and 2, I discuss how this hypothesis is built on decades of research characterizing effects of weak electric fields on neuronal membrane potential and the dependence of synaptic plasticity on membrane potential. In chapters 3 and 4, several experimental predictions of this theory are tested using a canonical model system for studying synaptic plasticity, the hippocampal brain slice. The theory accounts for the dependence of DCS effects on the temporal pattern of synaptic inputs and their location along a dendritic arbor, which may be sources of unexplained variability in human tDCS studies. An essential part of the proposed theory is that the effects of tDCS are mediated by the same cellular machinery that implements Hebbian synaptic plasticity. In chapter 4, we show that the effects of DCS therefore exhibit Hebbian properties, such as pathway specificity and associativity, whose role in associative learning has been studied extensively. These results suggest that tDCS can enhance associative learning and remain functionally specific by interacting with endogenous plasticity mechanisms. We further propose that clinical tDCS should be paired with tasks that induce plasticity to harness this phenomenon. In chapters 4 and 5, I present a computational model that incorporates established biophysical mechanisms for neuronal voltage dynamics, Hebbian synaptic plasticity, and membrane polarization due to weak electric fields. The model is in good agreement with our experimental results, demonstrating their consistency with the proposed theory. The model is then used to predict effects of tDCS with new synaptic input patterns and propose future brain slice experiments. The remaining chapters, 6 through 8, discuss the advances made by this work and important limitations. The theory and accompanying model provide a principled method for predicting effects on synaptic plasticity when tDCS is applied during training. However, it does not account for several observed effects of tDCS, such as on plasticity that is induced after stimulation has ended. Integrating the present theory with other potential mechanisms is therefore an important area for future research. Nonetheless, this work establishes a mechanistic framework for interpreting the effects of tDCS on synaptic plasticity and should aid in the design of tDCS protocols to facilitate associative learning.

Heroin addiction imposes a devastating toll on society. Poor inhibitory control is a common prefrontal cortex (PFC) impairment in addiction, and its potential recovery after treatment is unknown. We examined inhibitory control performance (stop-signal response time) and target detection sensitivity (d′) and brain activity in 26 individuals with heroin use disorder (the iHUD group) and 24 healthy controls (the HC group) at two time points, approximately 15 weeks apart. We found comparable stop-signal response time and a nonsignificant general d′ impairment trend in the iHUD group versus the HC group. The iHUD group generally (and at baseline) exhibited lower right anterior and dorsolateral PFC engagement versus the HC group, with increases at follow-up; right aPFC increases correlated with d′ increases in the iHUD group. In sum, baseline anterior PFC and dorsolateral PFC impairments in the iHUD group associated with individual differences in sensitivity improvements recovered at follow-up. These results highlight the anterior PFC and dorsolateral PFC as potential interventional targets for self-control recovery in heroin addiction.The authors examined the effect of psychosocial therapy, in addition to medication for heroin dependence, on inhibitory control brain activity and behavioral performance in individuals with heroin use disorder.

Temporal interference (TI) stimulation of the brain generates amplitude-modulated electric fields oscillating in the kHz range. A validated current-flow model of the human head estimates that amplitude-modulated electric fields are stronger in deep brain regions, while unmodulated electric fields are maximal at the cortical regions. The electric field threshold to modulate carbachol-induced gamma oscillations in rat hippocampal slices was determined for unmodulated 0.05-2 kHz sine waveforms, and 5 Hz amplitude-modulated waveforms with 0.1-2 kHz carrier frequencies. The neuronal effects are replicated with a computational network model to explore the underlying mechanisms. Experiment and model confirm the hypothesis that spatial selectivity of temporal interference stimulation depends on the phasic modulation of neural oscillations only in deep brain regions. This selectivity is governed by network adaption (e.g. GABAb) that is faster than the amplitude-modulation frequency. The applied current required depends on the neuronal membrane time-constant (e.g. axons) approaching the kHz carrier frequency of temporal interference stimulation. Footnotes * Author and affiliation updated

There is evidence that transcranial direct current stimulation (tDCS) can improve learning performance. Arguably, this effect is related to long term potentiation (LTP), but the precise biophysical mechanisms remain unknown. We propose that direct current stimulation (DCS) causes small changes in postsynaptic membrane potential during ongoing endogenous synaptic activity. The altered voltage dynamics in the postsynaptic neuron then modify synaptic strength via the machinery of endogenous voltage-dependent Hebbian plasticity. This hypothesis predicts that DCS should exhibit Hebbian properties, namely pathway specificity and associativity. We studied the effects of DCS applied during the induction of LTP in the CA1 region of rat hippocampal slices and using a biophysical computational model. DCS enhanced LTP, but only at synapses that were undergoing plasticity, confirming that DCS respects Hebbian pathway specificity. When different synaptic pathways cooperated to produce LTP, DCS enhanced this cooperation, boosting Hebbian associativity. Further slice experiments and computer simulations support a model where polarization of postsynaptic pyramidal neurons drives these plasticity effects through endogenous Hebbian mechanisms. The model is able to reconcile several experimental results by capturing the complex interaction between the induced electric field, neuron morphology, and endogenous neural activity. These results suggest that tDCS can enhance associative learning. We propose that clinical tDCS should be applied during tasks that induce Hebbian plasticity to harness this phenomenon, and that the effects should be task specific through their interaction with endogenous plasticity mechanisms. Models that incorporate brain state and plasticity mechanisms may help to improve prediction of tDCS outcomes.

There is evidence that transcranial direct current stimulation can boost learning performance. Arguably, this boost is related to synaptic plasticity. However, the precise effects on synaptic plasticity and its underlying mechanisms are not known. We hypothesized that direct current stimulation modulates endogenous Hebbian plasticity mechanisms due to its ability to polarize cellular membrane. To test this we induced long term plasticity (LTP) using theta-burst stimulation (TBS) in rat hippocampus, and measured the effects of concurrent direct current stimulation (DCS). Soma-depolarizing DCS increased TBS-induced LTP. Oscillating current stimulation is equally effective provided the soma-depolarizing phase is time-aligned with the theta-bursts, suggesting that only instantaneous depolarization is relevant. Importantly, the effect is pathway-specific and associative. These findings are consistent with classic theory on the role of post-synaptic membrane potential in Hebbian plasticity. These data suggest that the effects of direct current stimulation are specific because they modulate endogenous Hebbian plasticity, thus inheriting its exquisite functional specificity.

Drug-related cues hijack attention away from alternative reinforcers in drug addiction, inducing craving and motivating drug-seeking. However, the neural correlates underlying this biased processing, its expression in the real-world, and its relationship to cue-induced craving are not fully established, especially in opioid addiction. Here we tracked inter-brain synchronization in the Nucleus Accumbens (NAc), a hub of motivational salience, while heroin-addicted individuals and healthy control subjects watched the same engaging heroin-related movie. Strikingly, the left NAc was synchronized during drug scenes in the addicted individuals and non-drug scenes in controls, predicting scene- and movie-induced heroin craving in the former. Our results open a window into the neurobiology underlying shared drug-biased processing of naturalistic stimuli and cue-induced craving in opiate addiction as they unfold in the real world.

It is well established that non-synaptic mechanisms can generate electrographic seizures after blockade of synaptic function. We investigated the interaction of intact synaptic activity with non-synaptic mechanisms in the isolated CA1 region of rat hippocampal slices using the 'elevated-K+' model of epilepsy. Elevated K+ ictal bursts share waveform features with other models of electrographic seizures, including non-synaptic models where chemical synaptic transmission is suppressed, such as the low-Ca2+model. These features include a prolonged (several seconds) negative field shift associated with neuronal depolarization and superimposed population spikes. When population spikes are disrupted for up to several seconds, intracellular recording demonstrated that the prolonged suppression of population spikes during ictal activity was due to depolarization block of neurons. Elevated-K+ ictal bursts were often preceded by a build-up of 'pre-ictal' epileptiform discharges that were characterized as either 'slow-transition' (localized and with a gradual increase in population spike amplitude, reminiscent non-synaptic neuronal aggregate formation, presumed mediated by extracellular K+ concentrations ([K+])o accumulation), or 'fast-transition' (with a sudden increase in population spike amplitude, presumed mediated by field effects). When ictal activity had a fast-transition it was preceded by fast-transition pre-ictal activity; otherwise population spikes developed gradually at ictal event onset. Addition of bicuculline, a GABAA receptor antagonist, suppressed population spike generation during ictal activity, reduced pre-ictal activity, and increased the frequency of ictal discharges. Nipecotic acid and NNC-711, both of which block GABA re-uptake, increased population spike amplitude during ictal bursts and promoted the generation of pre-ictal activity. By contrast, addition of ionotropic glutamate-receptor antagonists (NBQX, D-APV) had no consistent effect on ictal burst waveform or frequency and did not fully suppress pre-ictal activity. Similarly, CGP 55848, a GABAB receptor antagonist, has no significant effect on pre-ictal activity or burst frequency (although it did increase burst duration slightly). Our results are consistent with the hypothesis that non-synaptic mechanisms underpin the generation of ictal bursts in CA1 and that GABAA synaptic mechanisms can shape event development by delaying event initiation and counteracting depolarization block.

This article offers an approach to providing integrated education for students with disabilities by effectively involving major stakeholders (building-level administrators, general education staff, special education staff, and students). A matrix displays categories of support (beliefs/values, content, methods, and adult-adult interactions) for each of these stakeholder groups. (DB)