Leon Morales-Quezada

Cerebellar Transcranial Direct Current Stimulation (ctDCS) A Novel Approach to Understanding Cerebellar Function in Health and Disease

The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions.

Simultaneous EEG Monitoring During Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that delivers weak electric currents through the scalp. This constant electric current induces shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Although tDCS has most of its neuromodulatory effects on the underlying cortex, tDCS effects can also be observed in distant neural networks. Therefore, concomitant EEG monitoring of the effects of tDCS can provide valuable information on the mechanisms of tDCS. In addition, EEG findings can be an important surrogate marker for the effects of tDCS and thus can be used to optimize its parameters. This combined EEG-tDCS system can also be used for preventive treatment of neurological conditions characterized by abnormal peaks of cortical excitability, such as seizures. Such a system would be the basis of a non-invasive closed-loop device. In this article, we present a novel device that is capable of utilizing tDCS and EEG simultaneously. For that, we describe in a step-by-step fashion the main procedures of the application of this device using schematic figures, tables and video demonstrations. Additionally, we provide a literature review on clinical uses of tDCS and its cortical effects measured by EEG techniques.

Neurophysiologic predictors of motor function in stroke

PURPOSE Understanding the neural mechanisms of stroke recovery is of paramount importance for neurorehabilitation. METHODS For this purpose, we analyzed several TMS and EEG variables and their association with motor recovery. Thirty-five subjects with chronic stroke were recruited. The neurophysiological examination included assessments by transcranial magnetic stimulation (TMS), intra- and inter-hemispheric EEG coherence in different frequency bands (e.g. alpha (8-13 Hz)) as determined by quantitative electroencephalography (qEEG). Motor function was measured by Fugl-Meyer (FM). Multiple univariate and multivariate linear regression analyses were performed to identify the predictors for FM. RESULTS Multivariate analyses, showed a significant interaction effect of motor threshold (MT) in the lesioned hemisphere and beta coherence in the unlesioned hemisphere. This interaction suggests that higher beta activity in the unlesioned hemisphere strengthens the negative association between MT and FM scores. CONCLUSIONS Our results suggest that MT in the lesioned hemisphere is the strongest predictors of motor recovery after stroke. Moreover, cortical activity in the unlesioned hemisphere measured by qEEG provides additional information, specifying the association between MT and FM scores. Therefore, complementary application of EEG and TMS can help constitute a better model of the lesioned and the unlesioned hemispheres that supports the importance of bihemispheric activity in recovery.

Transcranial Direct Current Stimulation in Mesial Temporal Lobe Epilepsy and Hippocampal Sclerosis

BACKGROUND Transcranial direct current stimulation (tDCS) has been evaluated in medication refractory epilepsy patients. The results have been inconclusive and protocols have varied between studies. OBJECTIVE To evaluate the safety and efficacy of two protocols of tDCS in adult patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS). METHODS This is a randomized placebo-controlled, double-blinded clinical trial, with 3 arms, 3 sessions, 5 sessions and placebo stimulation. Frequency of seizures (SZs), interictal epileptiform discharges (IEDs) and adverse effects (AEs) were registered before and after treatment, and at 30 and 60 days follow-up. Descriptive statistics, k-related samples, Friedmans test, and relative risk (RR) estimation were used for analysis. RESULTS We included twenty-eight subjects (3d n = 12, 5d n = 8, placebo n = 8), 16/28 (57%) men, age 37.8(±10.9) years old. There was a significant reduction of the frequency of SZs at one (p = 0.001) and two (p = 0.0001) months following cathodal tDCS compared to baseline in the 3 arms (p = 0.0001). The mean reduction of SZ frequency at two months in both active groups was significantly higher than placebo (-48% vs. -6.25%, p < 0.008). At 3 days (-43.4% vs. -6.25%, p < 0.007) and 5 days (-54.6% vs. -6.25%, p < 0.010) individual groups showed a greater reduction of SZs. A significant IED reduction effect was found between baseline and immediately after interventions (p = 0.041) in all groups. Side effects were minor. CONCLUSIONS Cathodal tDCS technique of 3 and 5 sessions decreased the frequency of SZs and IEDs (between baseline and immediately post-tDCS) in adult patients with MTLE-HS compared to placebo tDCS.

Intensity-dependent effects of transcranial pulsed current stimulation on interhemispheric connectivity: a high-resolution qEEG, sham-controlled study.

Defining optimal parameters for stimulation is a critical step in the development of noninvasive neuromodulation techniques. Transcranial pulsed current stimulation (tPCS) is emerging as another option in the field of neuromodulation; however, little is known about its mechanistic effects on electrical brain activity and how it can modulate its oscillatory patterns. The aim of this study was to identify the current intensity needed to exert an effect on quantitative electroencephalogram (qEEG) measurements. Forty healthy volunteers were randomized to receive a single session of sham or active stimulation at 0.2, 1, or 2 mA current intensity with a random frequency with an oscillatory pulsed range between 1 and 5 Hz. We conducted an exploratory frequency domain analysis to detect changes in absolute power for theta, alpha, and beta frequency bands and also interhemispheric coherence for alpha, theta, and four different sub-bands. Cognitive and nonspecific adverse effects were also recorded. Our results showed that both 1 and 2 mA can modulate interhemispheric coherence at the fronto-temporal areas for the theta band as compared with sham, while 2 mA also increased the low-beta and high-beta interhemispheric coherence at the same anatomical location. There were no group differences for adverse effects and participants could not guess correctly whether they received active versus sham stimulation. On the basis of our results, we conclude that tPCS is associated with an intensity-dependent facilitatory effect on interhemispheric connectivity. These results can guide future tPCS applications and will define its role as a neuromodulatory technique in the field.

Optimal random frequency range in transcranial pulsed current stimulation indexed by quantitative electroencephalography.

Given the recent results provided by previous investigations on transcranial pulsed current stimulation (tPCS) demonstrating its modulatory effects on cortical connectivity; we aimed to explore the application of different random pulsed frequencies. The utility of tPCS as a neuromodulatory technique for cognition performance will come as additional frequency ranges are tested with the purpose to find optimal operational parameters for tPCS. This study was designed to analyze the effects of tPCS using the following random frequencies; 1–5, 6–10, and 11–15 Hz compared with sham on quantitative electroencephalographic changes in the spectral power and interhemispheric coherence of each electroencephalographic frequency band. This was a parallel, randomized, double-blinded, sham-controlled trial. Forty healthy individuals older than 18 years were eligible to participate. The main outcomes were differences in the spectral power analysis and interhemispheric coherence as measured by quantitative electroencephalography. Participants were randomly allocated to four groups of random frequency stimulation and received a single session of stimulation for 20 min with a current intensity of 2 mA delivered by bilateral periauricular electrode clips. We found that a random pulsed frequency between 6–10 Hz significantly increased the power and coherence in frontal and central areas for the alpha band compared with sham stimulation, while 11–15 Hz tPCS decreased the power for the alpha and theta bandwidth. Our findings corroborate the hypothesis that a random frequency ranging into the boundaries of 6–10 Hz induces changes in the naturally occurring alpha oscillatory activity, providing additional data for further studies with tPCS.

Neural signature of tDCS, tPCS and their combination: Comparing the effects on neural plasticity

Transcranial pulsed current stimulation (tPCS) and transcranial direct current stimulation (tDCS) are two noninvasive neuromodulatory brain stimulation techniques whose effects on human brain and behavior have been studied individually. In the present study we aimed to quantify the effects of tDCS and tPCS, individually and in combination, on cortical activity, sensitivity and pain-related assessments in healthy individuals in order to understand their neurophysiological mechanisms and potential applications in clinical populations. A total of 48 healthy individuals participated in this randomized double blind sham controlled study. Participants were randomized to receive a single stimulation session of either: active or sham tPCS and active or sham tDCS. Quantitative electroencephalography (qEEG), sensitivity and pain assessments were used before and after each stimulation session. We observed that tPCS had a higher effect on power, as compared to tDCS, in several bandwidths on various cortical regions: the theta band in the parietal region (p=0.021), the alpha band in the temporal (p=0.009), parietal (p=0.0063), and occipital (p<0.0001) regions. We found that the combination of tPCS and tDCS significantly decreased power in the low beta bandwidth of the frontal (p=0.0006), central (p=0.0001), and occipital (p=0.0003) regions, when compared to sham stimulation. Additionally, tDCS significantly increased power in high beta over the temporal (p=0.0015) and parietal (p=0.0007) regions, as compared to sham. We found no effect on sensitivity or pain-related assessments. We concluded that tPCS and tDCS have different neurophysiological mechanisms, elicit distinct signatures, and that the combination of the two leads to no effect or a decrease on qEEG power. Further studies are required to examine the effects of these techniques on clinical populations in which EEG signatures have been found altered.

A Framework for Understanding the Relationship between Descending Pain Modulation, Motor Corticospinal, and Neuroplasticity Regulation Systems in Chronic Myofascial Pain.

Myofascial pain syndrome (MPS) is a leading cause of chronic musculoskeletal pain. However, its neurobiological mechanisms are not entirely elucidated. Given the complex interaction between the networks involved in pain process, our approach, to providing insights into the neural mechanisms of pain, was to investigate the relationship between neurophysiological, neurochemical and clinical outcomes such as corticospinal excitability. Recent evidence has demonstrated that three neural systems are affected in chronic pain: (i) motor corticospinal system; (ii) internal descending pain modulation system; and (iii) the system regulating neuroplasticity. In this cross-sectional study, we aimed to examine the relationship between these three central systems in patients with chronic MPS of whom do/do not respond to the Conditioned Pain Modulation Task (CPM-task). The CPM-task was to immerse her non-dominant hand in cold water (0−1°C) to produce a heterotopic nociceptive stimulus. Corticospinal excitability was the primary outcome; specifically, the motor evoked potential (MEP) and intracortical facilitation (ICF) as assessed by transcranial magnetic stimulation (TMS). Secondary outcomes were the cortical excitability parameters [current silent period (CSP) and short intracortical inhibition (SICI)], serum brain-derived neurotrophic factor (BDNF), heat pain threshold (HPT), and the disability related to pain (DRP). We included 33 women, (18–65 years old). The MANCOVA model using Bonferronis Multiple Comparison Test revealed that non-responders (n = 10) compared to responders (n = 23) presented increased intracortical facilitation (ICF; mean ± SD) 1.43 (0.3) vs. 1.11 (0.12), greater motor-evoked potential amplitude (μV) 1.93 (0.54) vs. 1.40 (0.27), as well a higher serum BDNF (pg/Ml) 32.56 (9.95) vs. 25.59 (10.24), (P < 0.05 for all). Also, non-responders presented a higher level of DRP and decreased HPT (P < 0.05 for all). These findings suggest that the loss of net descending pain inhibition was associated with an increase in ICF, serum BDNF levels, and DRP. We propose a framework to explain the relationship and potential directionality of these factors. In this framework we hypothesize that increased central sensitization leads to a loss of descending pain inhibition that triggers compensatory mechanisms as shown by increased motor cortical excitability.

QEEG indexed frontal connectivity effects of transcranial pulsed current stimulation (tPCS): A sham-controlled mechanistic trial.

Transcranial pulsed current stimulation (tPCS) is a non-invasive brain stimulation technique that employs weak, pulsed current at different frequency ranges, inducing electrical currents that reach cortical and subcortical structures. Very little is known about its effects on brain oscillations and functional connectivity and whether these effects are dependent on the frequency of stimulation. Our aim was to evaluate the effects of tPCS with different frequency ranges in cortical oscillations indexed by high-resolution qEEG changes for power and interhemispheric coherence. Thirty-eight healthy subjects were enrolled and received a single 20-min session of either sham or active stimulation with 1 Hz, 100 Hz or random frequency (1-5 Hz). We conducted an exploratory analysis to detect changes in mean power for theta, alpha and beta, and interhemispheric coherence for alpha and theta and four different sub-bands cognitive and non-specific adverse effects were recorded. We found that active stimulation with a random frequency ranging between 1 and 5 Hz is able to significantly increase functional connectivity for the theta and low-alpha band as compared to sham and active stimulation with either 1 or 100 Hz. Based on these findings, we discuss the possible effects of tPCS on resting functional connectivity for low-frequency bands in fronto-temporal areas. Future studies should be conducted to investigate the potential benefit of these induced changes in pathologic states.

Duration Dependent Effects of Transcranial Pulsed Current Stimulation (tPCS) Indexed by Electroencephalography.

To explore the duration of tPCS after effects given different durations of stimulation on power and interhemispheric coherence of the EEG frequency bands. Our hypothesis was that longer tPCS duration would induce a differential effect on the EEG analysis and a longer duration of after effects on the EEG frequency bands.