Anli Liu

Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016.

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.

Transcranial magnetic stimulation for refractory focal status epilepticus in the intensive care unit

PURPOSE To examine the efficacy and safety profile of antiepileptic repetitive transcranial magnetic stimulation (rTMS) for refractory status epilepticus (RSE) in the intensive care unit (ICU) setting. In addition, hypothetical concerns about electrical interference of rTMS with ICU equipment have been previously raised. METHODS We describe two cases of RSE treated with rTMS in the ICU. RESULTS In one case, rTMS contributed to decreased seizure frequency; in the second case, rTMS transiently decreased seizure frequency. In both cases, rTMS was safe and did not interfere with the functioning of the ICU equipment. CONCLUSION rTMS is a potential therapy for RSE when conventional therapies have failed. Future studies should investigate the efficacy of various rTMS stimulation parameters, safety issues, and bioengineering considerations in the ICU setting.

Exploring the efficacy of a 5-day course of transcranial direct current stimulation (TDCS) on depression and memory function in patients with well-controlled temporal lobe epilepsy

INTRODUCTION Depression and memory dysfunction significantly impact the quality of life of patients with epilepsy. Current therapies for these cognitive and psychiatric comorbidities are limited. We explored the efficacy and safety of transcranial direct current stimulation (TDCS) for treating depression and memory dysfunction in patients with temporal lobe epilepsy (TLE). METHODS Thirty-seven (37) adults with well-controlled TLE were enrolled in a double-blinded, sham-controlled, randomized, parallel-group study of 5 days of fixed-dose (2 mA, 20 min) TDCS. Subjects were randomized to receive either real or sham TDCS, both delivered over the left dorsolateral prefrontal cortex. Patients received neuropsychological testing and a 20-minute scalp EEG at baseline immediately after the TDCS course and at 2- and 4-week follow-up. RESULTS There was improvement in depression scores immediately after real TDCS, but not sham TDCS, as measured by changes in the Beck Depression Inventory (BDI change: -1.68 vs. 1.27, p<0.05) and NDDI-E (-0.83 vs. 0.9091, p=0.05). There was no difference between the groups at the 2- or 4-week follow-up. There was no effect on delayed or working memory performance. Transcranial direct current stimulation was well-tolerated and did not increase seizure frequency or interictal discharge frequency. Transcranial direct current stimulation induced an increase in delta frequency band power over the frontal region and delta, alpha, and theta band power in the occipital region after real stimulation compared to sham stimulation, although the difference did not reach statistical significance. DISCUSSION This study provides evidence for the use of TDCS as a safe and well-tolerated nonpharmacologic approach to improving depressive symptoms in patients with well-controlled TLE. However, there were no changes in memory function immediately following or persisting after a stimulation course. Further studies may determine optimal stimulation parameters for maximal mood benefit.

Does HIV age your brain

Since the introduction of highly active antiretroviral therapy in 1996, the epidemiologic profile of HIV-associated neurocognitive disorder (HAND) has shifted drastically. Although HIV-associated dementia has nearly disappeared from clinical practice, presymptomatic and milder variants of HAND affect up to 50% of patients on chronic antiretroviral therapy.1,2 Furthermore, the predominant phenotype has evolved from a subcortical dementia to a mixed cortical-subcortical cognitive syndrome affecting attention, executive, and memory systems, as well as slowing processing speed.2 Yet, subtler forms of HAND often remain undetected. One Swedish HIV study found that only 27% of their patient cohort complained of cognitive dysfunction, but 67% actually demonstrated objective deficits on cognitive testing.3

Response to letter to the editor: Safety of transcranial direct current stimulation: Evidence based update 2016

We respond to concerns raised by Godinho et al. about the Bikson et al. tDCS safety review [1]. As stated in the opening sentence, our report provided an update “based on published Serious Adverse Effects in human trials and irreversible brain damage in animal models”. Further, we carefully defined the scope of the review, “In this review, tDCS safety indicates the absence of a Serious Adverse Effect including brain tissue injury related to tDCS application.” We developed precise criteria for a Serious Adverse Effect. A systematic review of all adverse events, includingminor side effects that may affect the acceptability and tolerability of tDCS (as suggested by Godhino et al.) was outside the scope of our review, and addressed elsewhere including recently by our coauthors [2]. Adverse event underreporting occurs in most medical fields. We dedicated our assessment to published reports specifically of Serious Adverse Events, assuming reporting a Serious Adverse Event (e.g. hospitalization) is more reliable than mild well-known tDCS side effects (e.g. itching). Speculation regarding unpublished adverse events was not incorporated into our evidence-based approach. Causality was explicit to our definition of Serious Adverse Effect namely: “based on scientific judgment is determined to be caused or aggravated by the application of direct current to the head.” Exact methodology to estimate the volume of tDCS sessions was indicated in the relevant section, but safety considerations were based on the complete tDCS literature as assessed by authors with domain expertise. We underscore that our conclusions are derived from, and are explicitly limited to, stated definitions such that the discourse by Godinho et al. does not affect the validity of our methodology. To the extent that Godinho et al. do not provide evidence for a Serious Adverse Effect by tDCS, the review conclusion is unchanged. -Marom Bikson, Pnina Grossman, Greg Kronberg, Paulo S ergio Boggio, Andre R. Brunoni, Leigh Charvet, Felipe Fregni, Brita Fritsch, Bernadette Gillick, Roy H. Hamilton, Benjamin M. Hampstead, Adam Kirton, Helena Knotkova, David Liebetanz, Anli Liu, Colleen Loo, Michael A. Nitsche, Janine Reis, Jessica D. Richardson, Alexander Rotenberg, Peter Turkeltaub, Adam Woods.

Parahippocampal and entorhinal resection extent predicts verbal memory decline in an epilepsy surgery cohort

The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (±1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material.

Hippocampal signature of associative memory measured by chronic ambulatory intracranial EEG

Some patients with medically refractory focal epilepsy are chronically implanted with a brain-responsive neurostimulation device (the RNS® System), permitting neurophysiological measurements at millisecond resolution. This clinical device can be adapted to measure hippocampal dynamics time-locked to cognitive tasks. We illustrate the technique with a proof of concept in three patients previously implanted with the RNS System as they engage in an associative memory task, measured months apart. Hippocampal activity measured in successful encoding in RNS System patients mirrors that in surgical patients during intracranial electroencephalography (iEEG), suggesting that chronic iEEG allows sensitive measurements of hippocampal physiology over prolonged timescales.

Author Correction: Low frequency transcranial electrical stimulation does not entrain sleep rhythms measured by human intracranial recordings

It has come to our attention that we did not specify whether the stimulation magnitudes we report in this Article are peak amplitudes or peak-to-peak. All references to intensity given in mA in the manuscript refer to peak-to-peak amplitudes, except in Fig. 2, where the model is calibrated to 1 mA peak amplitude, as stated. In the original version of the paper we incorrectly calibrated the computational models to 1 mA peak-to-peak, rather than 1 mA peak amplitude. This means that we divided by a value twice as large as we should have. The correct estimated fields are therefore twice as large as shown in the original Fig. 2 and Supplementary Figure 11. The corrected figures are now properly calibrated to 1 mA peak amplitude. Furthermore, the sentence in the first paragraph of the Results section ‘Intensity ranged from 0.5 to 2.5 mA (current density 0.125–0.625 mA mA/cm2), which is stronger than in previous reports’, should have read ‘Intensity ranged from 0.5 to 2.5 mA peak to peak (peak current density 0.0625–0.3125 mA/cm2), which is stronger than in previous reports.’ These errors do not affect any of the Article’s conclusions.

Application of RNS in refractory epilepsy: Targeting insula.

Although responsive neurostimulation (RNS) is approved for treatment of resistant focal epilepsy in adults, little is known about response to treatment of specific cortical targets. We describe the experience of RNS targeting the insular lobe. We identified patients who had RNS implantation with at least one electrode within the insula between April 2014 and October 2015. We performed a retrospective review of preoperative clinical features, imaging, electrocardiogram (EEG), intraoperative electrocorticography (ECoG), and postoperative seizure outcome. Eight patients with at least 6 months of postimplant follow‐up were identified. Ictal localization was inconclusive with MRI or scalp EEG findings. Intracranial EEG monitoring or intraoperative ECoG demonstrated clear ictal onsets and/or frequent interictal discharges in the insula. Four patients demonstrated overall 50–75% reduction in seizure frequency. Two patients did not show appreciable seizure improvement. One patient has experienced a 75% reduction of seizure frequency, and another is nearly seizure free postoperatively. There were no reported direct complications of insular RNS electrode placement or stimulation, though two patients had postoperative complications thought to be related to craniotomy (hydrocephalus and late infection). Our study suggests that insular RNS electrode placement in selected patients is relatively safe and that RNS treatment may benefit selected patients with insular epilepsy.

Transcranial Magnetic Stimulation in the Treatment of Neurological Disease

Transcranial magnetic stimulation (TMS) holds great potential in the treatment of a host of neurological conditions due to its ability to focally modulate—suppress or enhance—activity in targeted cortical brain regions and modify activity across specific brain networks. Results from early trials in a number of neurological indications are presented, including stroke rehabilitation, Parkinson’s disease, tinnitus, chronic pain, migraine, and epilepsy. We emphasize both the challenges, such as the limited efficacy to date in tinnitus, as well as the opportunities, such as the use of TMS in epilepsy caused by focal/cortical lesions. However, to establish TMS as a clinically valuable neurological therapeutic intervention, a number of hurdles must be overcome, including accurate targeting of the treatment, characterization of its therapeutic benefit for specific patients/symptoms, proof of efficacy in multicenter trials that are adequately blinded and powered, proof of the durability of the effects, and assessment of potential adverse effects of cumulative dose and repeated application. [Psychiatr Ann. 2014; 44(6):299–304.] Transcranial magnetic stimulation (TMS) utilizes electromagnetic induction to generate current in human brain tissue, thereby influencing cortical excitability and modulating behavior.1 Over the past two decades, there has also been a concerted effort to develop the therapeutic potential of TMS for a wide variety of neuropsychiatric disorders. This effort has had the most success in the treatment of depression, where the beneficial effects of TMS have been established in large multicenter trials, approval from the U.S. Food and Drug Administration (FDA) has been obtained, and TMS has been adopted into clinical practice. Outside of depression, the therapeutic potential of TMS has also been explored in a wide range of neurological conditions. Preliminary results are promising, with beneficial effects often seen in disorders with limited therapeutic alternatives. However, challenges remain as many of the studies are small, efficacy is variable, and the clinical utility is uncertain. Despite these limitations, TMS holds great promise in the therapeutic armamentarium for neurology, but its broader application in clinical practice will require larger multisite controlled Mouhsin M. Shafi, MD, PhD; Anli Liu, MD; Michael D. Fox, MD; Alvaro Pascual-Leone, MD; and Daniel Z. Press, MD