The efficacy of use of transcranial direct current stimulation in the treatment of neurological disease & defect

Thesis (M.A.)--Boston UniversityNon-invasive brain stimulation techniques have recently become popular in the treatment of neurological diseases and disorders. Transcranial direct current stimulation [tDCS] is a method of brain stimulation whereby direct electrical current is passed through the intact scalp into the nervous tissue, producing lasting changes in neural activity of the stimulated areas. The polarity, or direction, of current flow in relation to the orientation of neural networks determines whether neuronal activity is enhanced or inhibited. The lasting increases or decreases in neuronal activity produced by tDCS have been used to shape cognitive function in various neurological diseases and disorders, including stroke, Parkinson’s disease, Alzheimer’s disease and depression. Currently, the mechanism of action for the effects caused by tDCS is not well understood. The goal of this thesis is to evaluate the efficacy of tDCS as a therapy for these brain disorders. The vast majority of these studies found strong and largely consistent evidence for the improvement of symptoms following tDCS for periods lasting up to several weeks when applied appropriately. While further refinement is needed to expand the effectiveness of tDCS treatment, the future looks promising

Studying and modifying brain function with non-invasive brain stimulation

In the past three decades, our understanding of brain–behavior relationships has been significantly shaped by research using non-invasive brain stimulation (NIBS) techniques. These methods allow non-invasive and safe modulation of neural processes in the healthy brain, enabling researchers to directly study how experimentally altered neural activity causally affects behavior. This unique property of NIBS methods has, on the one hand, led to groundbreaking findings on the brain basis of various aspects of behavior and has raised interest in possible clinical and practical applications of these methods. On the other hand, it has also triggered increasingly critical debates about the properties and possible limitations of these methods. In this review, we discuss these issues, clarify the challenges associated with the use of currently available NIBS techniques for basic research and practical applications, and provide recommendations for studies using NIBS techniques to establish brain–behavior relationships

Perspectives on adaptive dynamical systems

Adaptivity is a dynamical feature that is omnipresent in nature, socio-economics, and technology. For example, adaptive couplings appear in various real-world systems, such as the power grid, social, and neural networks, and they form the backbone of closed-loop control strategies and machine learning algorithms. In this article, we provide an interdisciplinary perspective on adaptive systems. We reflect on the notion and terminology of adaptivity in different disciplines and discuss which role adaptivity plays for various fields. We highlight common open challenges and give perspectives on future research directions, looking to inspire interdisciplinary approaches

Parameters Characterization and Cognitive-Behavioral Effects of Transcranial Pulsed Current Stimulation

Neuromodulation is being recognized as “technology impacting on the neural interface” And noninvasive brain stimulation (NIBS) is becoming an interesting alternative for this interface. Transcranial pulsed current stimulation (tPCS) is emerging as an option in the field of neuromodulation as a technique that employs weak, pulsed current at different frequency ranges, inducing electrical fields that reach cortical and subcortical structures; however, little is known about its properties and mechanistic effects on electrical brain activity and how it can modulate its oscillatory patterns. Moreover, there is not clear understanding in how tPCS can affect cognition and behavior or its neurophysiological correlates as indexed by autonomic responses. This research looked at the mechanisms behind tPCS in four randomized clinical trials; the main aim of each experiment was to evaluate the effects of tPCS in quantitative electroencephalography (qEEG) and cognitive-behavioral testing by exploring different parameters of stimulation. Based in the findings obtained per experiment, tPCS can be defined as a safe and tolerable technique that modulates the power spectrum of qEEG signals by means of applied randomized frequencies in a pre-defined range, tPCS also facilitates connectivity in the area of influence by the electrical field and this has an impact on optimization of performance by decreasing reaction times (RT) in attention switching task and by facilitating wide-ranging network processing as in the case of arithmetic functioning. This work also delivered an insight about the potential that tPCS has for future clinical applications.The Labuschagne-Foundation Spaulding Neurmodulation Cente

Induction of Hebbian associative plasticity through paired non-invasive brain stimulation of premotor-motor areas to elucidate the network's functional role

The ventral premotor cortex (PMv) is believed to play a pivotal role in a multitude of visuomotor behaviors, such as sensory-guided goal-directed visuomotor transformations, arbitrary visuomotor mapping, and hyper-learnt visuomotor associations underlying automatic imitative tendencies. All these functions are likely carried out through the copious projections connecting PMv to the primary motor cortex (M1). Yet, causal evidence investigating the functional relevance of the PMv-M1 network remains elusive and scarce. In the studies reported in this thesis we addressed this issue using a transcranial magnetic stimulation (TMS) protocol called cortico-cortical paired associative stimulation (ccPAS), which relies on multisite stimulation to induce Hebbian spike-timing dependent plasticity (STDP) by repeatedly stimulating the pathway connecting two target areas to manipulate their connectivity. Firstly, we show that ccPAS protocols informed by both short- and long-latency PMv-M1 interactions effectively modulate connectivity between the two nodes. Then, by pre-activating the network to apply ccPAS in a state-dependent manner, we were able to selectively target specific functional visuo-motor pathways, demonstrating the relevance of PMv-M1 connectivity to arbitrary visuomotor mapping. Subsequently, we addressed the PMv-to-M1 role in automatic imitation, and demonstrated that its connectivity manipulation has a corresponding impact on automatic imitative tendencies. Finally, by combining dual-coil TMS connectivity assessments and ccPAS in young and elderly individuals, we traced effective connectivity of premotor-motor networks and tested their plasticity and relevance to manual dexterity and force in healthy ageing. Our findings provide unprecedent causal evidence of the functional role of the PMv-to-M1 network in young and elderly individuals. The studies presented in this thesis suggest that ccPAS can effectively modulate the strength of connectivity between targeted areas, and coherently manipulate a networks’ behavioral output. Results open new research prospects into the causal role of cortico-cortical connectivity, and provide necessary information to the development of clinical interventions based on connectivity manipulation

Modulation of neural oscillations and associated behaviour by transcranial Alternating Current Stimulation (tACS)

Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that involves the application of weak electric currents to the scalp. tACS has the potential to be an inexpensive, easily administrable, and well-tolerated multi-purpose tool for cognitive and clinical neuroscience as it could be applied to establish the functional role of rhythmic brain activity, and to treat neural disorders, in particular those where these rhythms have gone awry. However, the mechanisms by which tACS produces both "online" and "offline" effects (that is, those that manifest during stimulation and those that last beyond stimulation offset) are to date still poorly understood. If the potential of tACS is to be harnessed effectively to alter brain activity in a controlled manner, it is fundamental to have a good understanding of how tACS interacts with neuronal dynamics, and of the conditions that promote its effect. This thesis describes three experiments that were conducted to elucidate the mechanisms by which tACS interacts with underlying neural network activity. Experiments 1 and 2 investigated the mechanism by which tACS at alpha frequencies (8 12 Hz, α-tACS) over occipital cortex induces the lasting aftereffects on posterior α power that were previously described in the literature. Two mechanisms have been suggested to underlie alpha power enhancement after α tACS: entrainment of endogenous brain oscillations and/or changes in oscillatory neural networks through spike timing-dependent plasticity (STDP). In Experiment 1, we tested to what extent plasticity can account for tACS-aftereffects when controlling for entrainment characteristics. To this end, we used a novel, intermittent α-tACS protocol and investigated the strength of the aftereffect as a function of phase continuity between successive tACS episodes, as well as the match between stimulation frequency and individual alpha frequency (IAF). Alpha aftereffects were successfully replicated with enhanced α power after intermittent stimulation compared to sham. These aftereffects did not exhibit any of the expected characteristics of prolonged entrainment in that they were independent of tACS phase-continuity and did not show stable phase alignment or synchronisation to the stimulation frequency. These results indicate that prolonged entrainment is insufficient to explain the aftereffects and suggest that the latter emerge through some form of network plasticity. To clarify the nature of these plasticity mechanisms, we then aimed to assess whether STDP could explain the α power increase. We developed a conceptual STDP model that predicted bi-directional changes in α power depending on the relative mismatch between the tACS frequency and IAF. After observing in Experiment 1 that tACS at frequencies slightly lower than the IAF produced α enhancement, Experiment 2 used a similar intermittent protocol that manipulated tACS frequency to be either slightly lower or higher than IAF to respectively enhance or suppress α activity. In addition, a control condition with continuous stimulation aimed to replicate previous results from other groups. However, we did not observe a systematic α power change in any of the active conditions. The lack of consistency between the two experiments raises concerns regarding the reproducibility and effect size of tACS aftereffects. The third experiment investigated the mechanism of online effects and tested predictions that were based on the assumption that entrainment is the underlying process mediating behavioural changes during tACS. We capitalised on two well-described phenomena: firstly, the association between α power lateralisation and visuospatial attention, and secondly, the fluctuation of perceptual performance with α phase. Specifically, the experiment tested whether event-related α-tACS applied over right parieto-occipital cortex can induce a visuospatial bias in a peripheral dot detection task that would reflect α power lateralisation, and whether detection performance depends on the phase of the tACS waveform. In control trials either no tACS or 40 Hz-tACS (gamma) was applied to make use of the putative opposing roles of alpha and gamma oscillations in visual processing. As expected from lateralised enhancement of alpha oscillations, visual detection accuracy was weakly impaired for targets presented in the left visual field, contralateral to tACS. However, this effect was neither frequency specific nor waveform phase-dependent. Therefore, it is unlikely that the negative effect of tACS on visuospatial performance reflects entrainment. Overall, the results of these experiments only partially met our hypotheses. Experiment 1 produced the α enhancement that was expected based on the literature while the follow-up experiment failed to reproduce these results under similar conditions. This outcome demonstrates at best that tACS aftereffects on α activity are not robust, may vary widely across individuals, and might be extremely sensitive to small changes in experimental parameters and state variables. The results of the third experiment call into question the assumption of online entrainment as basis for the observed behavioural effect. These findings point to the need for improved methodology, for more systematic and exhaustive exploration of the relative effects of tACS across different parameter settings, tasks, and individuals; and for the replication of promising but thus far often anecdotal results. They also inspire guidelines for more informative experimental designs

Investigation of brain networks for personalized rTMS in healthy subjects and patients with major depressive disorder: A translational study

Depression is a complex psychiatric disorder with emotional dysregulation at its core. The first line of treatment includes cognitive behaviour therapy and pharmacological antidepressants. However, up to one third of patients with depression fail to respond to these treatment interventions. The past decades have seen an increasing use of repetitive Transcranial Magnetic Stimulation (rTMS) in clinical studies, as an alternative treatment for depression. Several large-scale, multicentre randomized controlled trials have led the Food and Drugs Administration (FDA), USA to approve two rTMS protocols for clinical application in the treatment of depression - 10 Hz rTMS and intermittent Theta Burst Stimulation (iTBS). However, only 30-50% of patients receiving rTMS respond to the treatment. The large variability in response to rTMS likely stems from multiple reasons, one being the targeting method currently employed for delivering rTMS at the left dorsolateral prefrontal cortex (DLPFC). Previous functional connectivity studies have shown that stimulation at left DLPFC targets with larger negative correlation to the subgenual anterior cingulate cortex (sgACC) may result in greater therapeutic response than those with lower negative correlation. However, current use of rTMS ignores functional connectivity in choosing the left DLPFC target, thus largely discarding functional architectural differences of the brain across subjects. Furthermore, despite widespread clinical use of rTMS, the basic network mechanisms behind these rTMS protocols remain elusive. This work presents a novel personalization method of left DLPFC target selection based on their negative functional connectivity to the sgACC. The default mode network (DMN) is a large-scale brain network commonly involved in self-referential thought processing and plays an essential role in the pathophysiology of depression. I use the novel personalization method and identical study designs to delineate DMN mechanisms from a single session of 10 Hz rTMS and iTBS in healthy subjects. Arguably, an understanding of basic mechanisms of clinically relevant rTMS protocols in healthy subjects will help improve the current therapeutic effect of rTMS, and possibly expand the therapeutic role of rTMS. My work shows, for the first time, strong but different modulations of DMN connectivity by single personalized sessions of 10 Hz rTMS and iTBS. Such modulations can be predicted using the personality trait harm avoidance (HA). Given that initial results show that the method is robust and reproducible, its adaptation to patient cohorts is likely to result in improved therapeutic benefits. Therefore, the novel method of personalization is translated to clinical setting by using accelerated iTBS (aiTBS) in patients with depression. Additionally, a comparison is made between effects resulting from personalized and nonpersonalized (10-20 EEG system F3 position) aiTBS in patients with depression. By evaluating the DMN, and heart rate variability, I show precise modulatory effects of personalized aiTBS, which is not seen in the standard aiTBS group. The work presented here introduces an important method to reduce variability and increase precision in rTMS modulation by personalizing the left DLPFC target selection. Even though DMN and cardiac effects already point towards the advantage of personalization, the still preliminary analysis fails to show significant differences in treatment response. Lack of greater therapeutic benefits viii from personalized aiTBS in this ongoing study probably stems from a still limited sample size. In case personalization proves clinically advantageous to standard iTBS by the final sample size, this work can sediment the first step towards systems medicine in the field of psychiatry.2022-02-0

Lycium barbarum (wolfberry) polysaccharide facilitates ejaculatory behaviour in male rats

Poster Session AOBJECTIVE: Lycium barbarum (wolfberry) is a traditional Chinese medicine, which has been considered to have therapeutic effect on male infertility. However, there is a lack of studies support the claims. We thus investigated the effect of Lycium barbarum polysaccharide (LBP), a major component of wolfberry, on male rat copulatory behavior. METHOD: Sprague-Dawley rats were divided into two groups (n=8 for each group). The first group received oral feeding of LBP at dosage of 1mg/kg daily. The control group received vehicle (0.01M phosphate-buffered saline, served as control) feeding daily for 21 days. Copulatory tests were conducted at 7, 14 and 21 days after initiation of treatment. RESULTS: Compared to control animals, animals fed with 1mg/kg LBP showed improved copulatory behavior in terms of: 1. Higher copulatory efficiency (i.e. higher frequency to show intromission rather than mounting during the test), 2. higher ejaculation frequency and 3. Shorter ejaculation latency. The differences were found at all time points (Analyzed with two-tailed student’s t-test, p<0.05). There is no significant difference found between the two groups in terms of mount/intromission latency, which indicates no difference in time required for initiation of sexual activity. Additionally, no difference in mount frequency and intromission frequency was found. CONCLUSION: The present study provides scientific evidence for the traditional use of Lycium barbarum on male sexual behavior. The result provides basis for further study of wolfberry on sexual functioning and its use as an alternative treatment in reproductive medicine.postprintThe 30th Annual Meeting of the Australian Neuroscience Society, in conjunction with the 50th Anniversary Meeting of the Australian Physiological Society (ANS/AuPS 2010), Sydney, Australia, 31 January-3 February 2010. In Abstract Book of ANS/AuPS, 2010, p. 177, abstract no. POS-TUE-19

Transcranial magnetic stimulation combined with functional magnetic resonance imaging: From target identification to prediction of therapeutic effects in stroke patients

Repetitive transcranial magnetic stimulation (rTMS), particularly theta-burst stimulation (TBS), can be applied to modulate cortical excitability beyond the period of stimulation (Huang et al., 2005). Consequently, rTMS is regarded to have high therapeutic potential for treatment of various psychiatric and neurological diseases related to cortical hypo- or hyperexcitability such as stroke (Ridding & Rothwell, 2007). Whether rTMS induced effects are sufficiently robust to be useful in clinical settings is currently under intense investigation. The most challenging problem appears to be considerably high variability in rTMS induced effects both, across studies (Hoogendam et al., 2010) and individual patients (Ameli et al., 2009). Hence, the major goal of the present thesis was to improve rTMS intervention strategies in stroke patients suffering from chronic motor hand deficits by multimodal uses of (repetitive) TMS with state-of-the-art neuroimaging techniques. Sources of variance across studies are likely to be methodological in origin. They might result from different strategies to identify the cortical rTMS target position. Individual functional magnetic resonance (fMRI) data have been demonstrated to yield best spatial approximations of the most excitable TMS position compared to other techniques (Sparing et al., 2008). However, there is still a considerably large spatial mismatch between the cortical position showing highest movement-related fMRI signal and the cortical position yielding highest muscle responses when stimulated with TMS of up to 14 mm (Bastings et al., 1998; Boroojerdi et al., 1999; Herwig et al., 2002; Krings et al., 1997; Lotze et al., 2003; Sparing et al., 2008; Terao et al., 1998). The underlying cause of this spatial mismatch is unknown. Hence, the aim of the first study (Study I) of the present thesis was to test the hypothesis that the spatial mismatch between positions with highest fMRI signal change and positions with highest TMS excitability might be caused by the widely-used Gradient-Echo blood oxygenation level dependent (GRE-BOLD) fMRI technique. GRE-BOLD signal has been demonstrated to occur further downstream from the site of neural activity in large veins running on the cerebral surface (Uludag et al., 2009). Consequently, we tested the hypothesis that alternative fMRI sequences may localize neural activity (i) closer to the anatomical motor hand area, i.e. Brodmann Area 4 (BA4), and (ii) closer to the optimal TMS position than GRE-BOLD. The following alternative fMRI techniques were tested: (i) Spin-Echo (SE-BOLD) assessing blood oxygenation level dependent signal changes with decreased sensitivity for the macrovasculature at high magnetic fields (≥ 3 Tesla, Uludag et al., 2009) and (ii) arterial spin labelling (ASL), assessing local changes in cerebral blood flow (ASL-CBF) which have been shown to occur in close proximity to synaptic activity (Duong et al., 2000). GRE-BOLD, SE-BOLD, and ASL-CBF signal changes during right thumb abductions were obtained from 15 healthy young subjects at 3 Tesla. In 12 subjects, brain tissue at fMRI peak voxel coordinates was stimulated with neuronavigated TMS to investigate whether spatial differences between fMRI techniques are functionally relevant, i.e. impact on motor-evoked potentials (MEPs) recorded from a contralateral target muscle, which is involved in thumb abductions. A systematic TMS motor mapping was performed to identify the most excitable TMS position (i.e. the TMS hotspot) and the centre-of-gravity (i.e. the TMS CoG), which considers the spatial distribution of excitability in the pericentral region. Euclidean distances between TMS and fMRI positions were calculated for each fMRI technique. Results indicated that highest SE-BOLD and ASL-CBF signal changes occurred in the anterior wall of the central sulcus (BA4), whereas highest GRE-BOLD signal changes occurred significantly closer to the gyral surface where most large draining veins are located. fMRI techniques were not significantly different from each other in Euclidean distances to optimal TMS positions since optimal TMS positions were located considerably more anterior (and slightly surprisingly in premotor cortex (BA6) and not BA4). Stimulation of brain tissue at GRE-BOLD peak voxel coordinates with TMS resulted in significantly higher MEPs (compared to SE-BOLD and ASL-CBF coordinates). This was probably the case because GRE-BOLD positions tended to be located at the gyral crown, which was slightly (but not significantly) closer to the TMS hotspot position. Taken together, findings of Study I suggest that spatial differences between fMRI and TMS positions are not caused by spatial unspecificity of the widely-used GRE-BOLD fMRI technique. Hnece, other factors such as complex interactions between brain tissue and the TMS induced electric field (Opitz et al., 2011), could be the underlying cause. Identification of the cortical rTMS target position is particularly challenging in stroke patients since reorganization processes after stroke may shift both, fMRI and TMS positions in unknown direction and extend (Rossini et al., 1998). In the second study (Study II) of the present thesis, we therefore tested whether findings obtained from healthy young subjects in Study I do also apply to chronic stroke patients and older (i.e. age-matched) healthy control subjects. In this study, arterial spin labelling (ASL) was used to assess CBF and BOLD signal changes simultaneously during thumb abductions with the affected/non-dominant and the unaffected/dominant hand in 15 chronic stroke patients and 13 age-matched healthy control subjects at 3 Tesla. Brain tissue at fMRI peak voxel coordinates was stimulated with neuronavigated TMS to test whether spatial differences are functionally relevant and impact on MEPs. Systematic TMS motor mappings were performed for both hemispheres in overall 12 subjects (6 stroke patients and 6 healthy subjects). Euclidean distances between fMRI and TMS positions were calculated for each hemisphere and fMRI technique. In line with results of Study I, highest ASL-CBF signal changes were located in the anterior wall of the central sulcus (BA4), whereas highest ASL-BOLD signal changes occurred significantly closer to the gyral surface. In contrast to Study I, there were no significant differences between ASL-CBF and ASL-BOLD positions in MEPs when stimulated with neuronavigated TMS, which suggests that spatial differences (in depth) were not functionally relevant for TMS applications. In line with Study I, there were no significant differences between fMRI techniques in Euclidean distances to optimal TMS positions, since optimal TMS positions were located considerably more anterior than fMRI positions (in premotor cortex, i.e. BA6). Stroke patients showed overall larger displacements (between fMRI and TMS positions) on the ipsilesional (but not the contralesional) hemisphere compared to healthy subjects. However, none of the fMRI techniques yielded positions significantly closer to the optimal TMS position. Hence, functional reorganization may impact on spatial congruence between fMRI and TMS, but the effect is similar for ASL-CBF and ASL-BOLD. Pathomechanisms underlying stroke induced motor deficits are still poorly understood but a simplified model of hemispheric competition has been suggested, which proposes relative hypoexcitability of the ipsilesional hemisphere and hyperexcitability of the contralesional hemisphere leading to pathologically increased interhemispheric inhibition from the contralesional onto the ipsilesional hemisphere during movements of the paretic hand (Duque et al., 2005; Grefkes et al., 2008b, 2010; Murase et al., 2004). In line with the model of hemispheric competition, both increasing excitability of the ipsilesional hemisphere (Khedr et al., 2005; Talelli et al., 2007) as well as decreasing excitability of the contralesional hemisphere (Fregni et al., 2006; Di Lazzaro et al., 2008a) have been demonstrated to normalize cortical excitability towards physiological levels and/or ameliorate motor performance of the stroke affected hand. However, there is considerably high inter-individual variance and some patients may even show deteriorations of motor performance after rTMS (Ameli et al., 2009). Therefore, the aim of the third study (Study III) was to identify reliable predictors for TBS effects on motor performance of the affected hand in stroke patients, which appears essential for successful implementation of TBS in neurorehabilitation. Overall, 13 chronic stroke patients with unilateral motor hand deficit and 12 age-matched healthy control subjects were included in the study. All patients received 3 different TBS interventions on 3 different days: (i) intermittent TBS (iTBS, facilitatory) over the primary motor cortex (M1) of the ipsilesional hemisphere, (ii) continuous TBS (cTBS, inhibitory) over M1 of the contralesional hemisphere, and (iii) either iTBS or cTBS over a control stimulation site (to control for placebo effects). Motor performance was measured before and after each TBS session with 3 different motor tasks and an overall motor improvement score was calculated. All subjects participated in an fMRI experiment, in which they performed rhythmic fist closures with their affected/non-dominant and unaffected/dominant hand. A laterality index (LI), reflecting laterality of fMRI signal in cortical motor areas was calculated. Effective connectivity, i.e. the direct or indirect causal influence that activity in one area exerts on activity of another area (Friston et al., 1993a), was inferred from fMRI data by means of dynamic causal modelling (DCM). Due to relatively high inter-individual variance, neither iTBS nor cTBS was significantly different from control TBS in terms of average behavioural (or electrophysiological) changes over the group of patients. However, beneficial effects of iTBS over the ipsilesional hemisphere were predicted by a unilateral fMRI activation pattern during movements of the affected hand and by the integrity of the cortical motor network. The more pronounced the promoting influence from the ipsilesional supplementary motor area (SMA) onto ipsilesional M1 and the more pronounced the inhibitory effect originating from ipsilesional M1 onto contralesional M1, the better was the behavioural response to facilitatory iTBS applied to the ipsilesional hemisphere. No significant correlations were found for behavioural improvements following cTBS or behavioural changes of the unaffected hand. Taken together, Study III yielded promising results indicating that laterality of fMRI signal and integrity of the motor network architecture constitute promising predictors for response to iTBS. In patients in whom the connectivity pattern of the ipsilesional motor network resembled physiological network connectivity patterns (i.e. preserved inhibition of the contralesional hemisphere and supportive role of the SMA of the ipsilesional hemisphere), beneficial effects of iTBS over the ipsilesional hemisphere could be observed. In contrast, patients with severely disturbed motor networks did not respond to iTBS or even deteriorated