Kohitij Kar

Transcranial electrical stimulation over visual cortex evokes phosphenes with a retinal origin

Transcranial electrical stimulation (tES) is a promising therapeutic tool for a range of neurological diseases. Understanding how the small currents used in tES spread across the scalp and penetrate the brain will be important for the rational design of tES therapies. Alternating currents applied transcranially above visual cortex induce the perception of flashes of light (phosphenes). This makes the visual system a useful model to study tES. One hypothesis is that tES generates phosphenes by direct stimulation of the cortex underneath the transcranial electrode. Here, we provide evidence for the alternative hypothesis that phosphenes are generated in the retina by current spread from the occipital electrode. Building on the existing literature, we first confirm that phosphenes are induced at lower currents when electrodes are placed farther away from visual cortex and closer to the eye. Second, we explain the temporal frequency tuning of phosphenes based on the well-known response properties of primate retinal ganglion cells. Third, we show that there is no difference in the time it takes to evoke phosphenes in the retina or by stimulation above visual cortex. Together, these findings suggest that phosphenes induced by tES over visual cortex originate in the retina. From this, we infer that tES currents spread well beyond the area of stimulation and are unlikely to lead to focal neural activation. Novel stimulation protocols that optimize current distributions are needed to overcome these limitations of tES.

Transcranial Alternating Current Stimulation Attenuates Visual Motion Adaptation

Transcranial alternating current stimulation (tACS) is used in clinical applications and basic neuroscience research. Although its behavioral effects are evident from prior reports, current understanding of the mechanisms that underlie these effects is limited. We used motion perception, a percept with relatively well known properties and underlying neural mechanisms to investigate tACS mechanisms. Healthy human volunteers showed a surprising improvement in motion sensitivity when visual stimuli were paired with 10 Hz tACS. In addition, tACS reduced the motion-after effect, and this reduction was correlated with the improvement in motion sensitivity. Electrical stimulation had no consistent effect when applied before presenting a visual stimulus or during recovery from motion adaptation. Together, these findings suggest that perceptual effects of tACS result from an attenuation of adaptation. Important consequences for the practical use of tACS follow from our work. First, because this mechanism interferes only with adaptation, this suggests that tACS can be targeted at subsets of neurons (by adapting them), even when the applied currents spread widely throughout the brain. Second, by interfering with adaptation, this mechanism provides a means by which electrical stimulation can generate behavioral effects that outlast the stimulation.

Social closeness and feedback modulate susceptibility to the framing effect.

Although we often seek social feedback (SFB) from others to help us make decisions, little is known about how SFB affects decisions under risk, particularly from a close peer. We conducted two experiments using an established framing task to probe how decision-making is modulated by SFB valence (positive, negative) and the level of closeness with feedback provider (friend, confederate). Participants faced mathematically equivalent decisions framed as either an opportunity to keep (gain frame) or lose (loss frame) part of an initial endowment. Periodically, participants were provided with positive (e.g., “Nice!”) or negative (e.g., “Lame!”) feedback about their choices. Such feedback was provided by either a confederate (Experiment 1) or a gender-matched close friend (Experiment 2). As expected, the framing effect was observed in both experiments. Critically, an individuals susceptibility to the framing effect was modulated by the valence of the SFB, but only when the feedback provider was a close friend. This effect was reflected in the activation patterns of ventromedial prefrontal cortex and posterior cingulate cortex, regions involved in complex decision-making. Taken together, these results highlight social closeness as an important factor in understanding the impact of SFB on neural mechanisms of decision-making.

Transcranial Alternating Current Stimulation Attenuates Neuronal Adaptation

We previously showed that brief application of 2 mA (peak-to-peak) transcranial currents alternating at 10 Hz significantly reduces motion adaptation in humans. This is but one of many behavioral studies showing that weak currents applied to the scalp modulate neural processing. Transcranial stimulation has been shown to improve perception, learning, and a range of clinical symptoms. Few studies, however, have measured the neural consequences of transcranial current stimulation. We capitalized on the strong link between motion perception and neural activity in the middle temporal (MT) area of the macaque monkey to study the neural mechanisms that underlie the behavioral consequences of transcranial alternating current stimulation. First, we observed that 2 mA currents generated substantial intracranial fields, which were much stronger in the stimulated hemisphere (0.12 V/m) than on the opposite side of the brain (0.03 V/m). Second, we found that brief application of transcranial alternating current stimulation at 10 Hz reduced spike-frequency adaptation of MT neurons and led to a broadband increase in the power spectrum of local field potentials. Together, these findings provide a direct demonstration that weak electric fields applied to the scalp significantly affect neural processing in the primate brain and that this includes a hitherto unknown mechanism that attenuates sensory adaptation. SIGNIFICANCE STATEMENT Transcranial stimulation has been claimed to improve perception, learning, and a range of clinical symptoms. Little is known, however, how transcranial current stimulation generates such effects, and the search for better stimulation protocols proceeds largely by trial and error. We investigated, for the first time, the neural consequences of stimulation in the monkey brain. We found that even brief application of alternating current stimulation reduced the effects of adaptation on single-neuron firing rates and local field potentials; this mechanistic insight explains previous behavioral findings and suggests a novel way to modulate neural information processing using transcranial currents. In addition, by developing an animal model to help understand transcranial stimulation, this study will aid the rational design of stimulation protocols for the treatment of mental illnesses, and the improvement of perception and learning.

Commentary: On the possible role of stimulation duration for after-effects of transcranial alternating current stimulation

In their recent article, Struber et al. (2015) demonstrate that 1s application of transcranial alternating current stimulation (tACS) do not lead to any significant changes in the phase and amplitude of the electroencephalogram (EEG) signal. Therefore, they concluded that it is too short to induce synaptic plasticity. This is a very important observation that sheds light on possible underlying mechanisms of tACS. Although the results clearly show the absence of certain specific tACS-induced electrophysiological after-effects when applied only for 1s, some additional considerations need to be made in order to fully interpret these null results as well as probe the mechanism of tACS at shorter timescales. An important question is whether at these smaller time scales, the lack of prolonged entrainment during the post stimulation session necessarily reflect a lack of tACS efficacy. Alternatively, these results might also suggest that for 1s stimulation paradigms, we are simply looking at the wrong electrophysiological measure. At these smaller time scales, changes in measures such as spike rate adaptation (Fernandez et al., 2011; Kar and Krekelberg, 2014), spike time precision (Reato et al., 2010), neurovascular coupling (Zheng et al., 2011; Kar and Wright, 2014) are likely to be more relevant for behavioral aftereffects. The EEG signal typically comprises of synchronized oscillations across the superficial cortex (for review, see Buzsaki et al., 2012). Hence it might be more sensitive to changes in entrainment whereas much less sensitive to these subtle effects (which might also still be behaviorally relevant). However, some of these changes might indeed be a result of changes in short-term synaptic plasticity (which is a very broad term). It must however be noted that the aforementioned mechanisms could also be a direct result of network entrainment during tACS but lack entrainment related features in the EEG measured at the scalp in the post tACS session. One way to test this hypothesis further, would be to use the method introduced by Helfrich et al. (2014) to remove the tACS-induced artifacts for the 1s tACS period, and estimate changes in EEG during stimulation. This would be very informative to test whether tACS applied at the individual alpha frequency (IAF) for 1s could entrain the underlying cortex at all. Then we would be able to say whether the lack of effect is despite similar entrainment during tACS. The effects of tACS on the underlying cortex often depends on the presence of an experimental task that actively recruits the underlying brain area or otherwise, produces a specific brain state. For instance, Kar and Krekelberg (2014) demonstrated, that tACS induced changes in human motion discrimination performance is only present when tACS was paired with the visual motion stimulus. Ten Hertz tACS applied for 4s reduced the after-effects of motion adaptation and the effects scaled with how much adaptation there was to begin with. Similarly, Feurra et al. (2013) also demonstrated the state dependent effects of tACS on the motor cortex. Given this brain state dependency of the tACS induced effects, it remains unclear whether the lack of tACS-induced aftereffect reported in the study could be due to an absence of an appropriate brain state in the stimulated area. In this regard, it might be interesting to probe the brain areas while doing a relevant task. Choosing the stimulation intensity is also a key consideration during tACS studies (Groppa et al., 2010). However, it is crucial to consider the confounding aspects of tACS-induced phosphenes (Kar and Krekelberg, 2012) and tactile sensations (Feurra et al., 2011). I argue that lower stimulation amplitudes might not necessarily control for phosphenes and these low amplitudes might fail to induce the desired cortical effects (entrainment). First, the accuracy of the threshold values are highly depended on the sensitivity of the adaptive method used to estimate them. In addition, we can never rule out the effects of subthreshold retinal stimulation during tACS. Hence, it is important to consider other strategies to design control experiments to rule out general effects of tACS (phosphenes, tactile sensations, reduced/increased arousal etc.). Some recent studies have used brain laterization to test their hypotheses (Kar and Krekelberg, 2014). But, given the large current spread during tACS and asymmetries between the two hemispheres of the human brain, this is not always feasible. Therefore, control strategies remain a challenging issue for tACS experiments. The Struber et al. (2015) study provides a lead into the hypothesis that tACS mechanisms vary according to stimulation duration. This can be addressed in future experiments, where the stimulation duration can be varied as an independent variable to systematically map out its relationship with the boost in entrainment, changes in coherence and other short-term plasticity related changes.

tACS- What goes on inside? The neural consequences of transcranial alternating current stimulation

There is considerable evidence for clinical and behavioral efficacy of transcranial alternating current stimulation (tACS). The effects range from suppressing Parkinsonian tremors to augmenting human learning and memory. Despite widespread use, the neurobiological mechanism of actions of tACS on the brain is unclear. We have taken a threefold approach to probe tACS mechanisms. First, we examined the behavioral effects of tACS on human motion perception. Second, we used known motion models to generate predictions about neural mechanisms that could produce the effects. Third, we tested these predictions by directly measuring tACS-induced neural activity changes in the macaque brain.

Transcranial electrical stimulation affects adaptation of MT/V5 neurons in awake behaving macaques

Despite widespread use in clinical and behavioral studies, the mechanisms of action of transcranial electrical stimulation (tES) are poorly understood. We partially attribute this to the lack of in-vivo animal models and have started to probe the influence of tES on the wellexplored macaque visual system, specifically area MT. Previously we have shown that tES reduces the motion aftereffect in human subjects. This leads to the hypothesis that neurons adapt less during tES.

Using an animal learning model of the hippocampus to simulate human fMRI data

Recent human fMRI studies have shown that the hippocampal region is essential for probabilistic category learning, memory formation-retrieval and context based performance. We present an artificial neural network model that can qualitatively simulate the BOLD signal for these tasks. The model offers ideas on the functional architecture and the relationship between the hippocampus and other brain structures. We also show that symptoms of neurobiological diseases like Parkinsons disease (PD) and Schizophrenia can be simulated and studied using the model.