Noninvasive stimulation of the temporoparietal junction: a systematic review

Imaging and lesion studies have suggested numerous roles for the temporoparietal junction (TPJ), for example in attention and neglect, social cognition, and self/other processing. These studies cannot establish causal relationships, and the importance and relevance of (and interrelationships between) proposed roles remain controversial. This review examined studies that use noninvasive transcranial stimulation (NTS) to explore TPJ function. Of 459 studies identified, 40 met selection criteria. The strengths and weaknesses of NTS-relevant parameters used are discussed, and methodological improvements suggested. These include the need for careful selection of stimulation sites and experimental tasks, and use of neuronavigation and concurrent functional activity measures. Without such improvements, overlapping and discrete functions of the TPJ will be difficult to disentangle. Nevertheless, the contributions of these studies to theoretical models of TPJ function are discussed, and the clinical relevance of TPJ stimulation explored. Some evidence exists for TPJ stimulation in the treatment of auditory hallucinations, tinnitus, and depersonalisation disorder. Further examination of the TPJ in conditions such as autism spectrum disorder is also warranted.

Graphene/tri-block copolymer composites prepared via RAFT polymerizations for dual controlled drug delivery via pH stimulation and biodegradation

A novel tri-block copolymer poly(oxopentanoate ethyl methacrylate)-block-poly(pyridyl disulfide ethyl acrylate)-block-poly(ethylene glycol acrylate) [poly(OEMA-b-PDEA-b-PEGA)], retaining active keto groups and pyridyl disulfide (PDS) side functionalities, was synthesized as a drug delivery vehicle using reversible addition-fragmentation chain transfer (RAFT) polymerization method. One mimic drug pyridine-2-thione (PT) was introduced into the monomer, PDEA for copolymerization. The other mimic drug O-benzylhydroxylamine (BHA) was conjugated with tri-block copolymer via efficient oxime coupling chemistry, followed by the attachment onto graphene via π-π stacking interaction to obtain a graphene/tri-block copolymer composite. 1H NMR, UV-vis absorption spectroscopy, fluorescence spectroscopy, gel permeation chromatography (GPC), atomic force microscope (AFM) and transmission electron microscope (TEM) were used to verify the successful step-wise preparation of the tri-block copolymer and drug loaded composite. In vitro release behaviors of BHA and PT from graphene/tri-block copolymer composite via dual drug release mechanisms were investigated. BHA can be released under acid environment, while PT will be released in the presence of reducing agents, such as dithiothreitol (DTT) or glutathione (GSH). It can be envisioned that this novel composite could be exploited as a novel intracellular drug delivery system via dual release mechanisms.

Facilitating effects of transcranial direct current stimulation on motor imagery brain-computer interface with robotic feedback for stroke rehabilitation

OBJECTIVE: To investigate the efficacy and effects of transcranial direct current stimulation (tDCS) on motor imagery brain-computer interface (MI-BCI) with robotic feedback for stroke rehabilitation. DESIGN: A sham-controlled, randomized controlled trial. SETTING: Patients recruited through a hospital stroke rehabilitation program. PARTICIPANTS: Subjects (N=19) who incurred a stroke 0.8 to 4.3 years prior, with moderate to severe upper extremity functional impairment, and passed BCI screening. INTERVENTIONS: Ten sessions of 20 minutes of tDCS or sham before 1 hour of MI-BCI with robotic feedback upper limb stroke rehabilitation for 2 weeks. Each rehabilitation session comprised 8 minutes of evaluation and 1 hour of therapy. MAIN OUTCOME MEASURES: Upper extremity Fugl-Meyer Motor Assessment (FMMA) scores measured end-intervention at week 2 and follow-up at week 4, online BCI accuracies from the evaluation part, and laterality coefficients of the electroencephalogram (EEG) from the therapy part of the 10 rehabilitation sessions. RESULTS: FMMA score improved in both groups at week 4, but no intergroup differences were found at any time points. Online accuracies of the evaluation part from the tDCS group were significantly higher than those from the sham group. The EEG laterality coefficients from the therapy part of the tDCS group were significantly higher than those of the sham group. CONCLUSIONS: The results suggest a role for tDCS in facilitating motor imagery in stroke.

Radio frequency energy harvesting from a feeding source in a passive deep brain stimulation device for murine preclinical research

This paper presents the development of an energy harvesting circuit for use with a head-mountable deep brain stimulation (DBS) device. It consists of a circular planar inverted-F antenna (PIFA) and a Schottky diode-based Cockcroft-Walton 4-voltage rectifier. The PIFA has the volume of π × 10(2) × 1.5 mm(3), resonance frequency of 915 MHz, and bandwidth of 16 MHz (909-925 MHz) at a return loss of -10 dB. The rectifier offers maximum efficiency of 78% for the input power of -5 dBm at a 5 kΩ load resistance. The developed rectenna operates efficiently at 915 MHz for the input power within -15 dBm to +5 dBm. For operating a DBS device, the DC voltage of 2 V is recorded from the rectenna terminal at a distance of 55 cm away from a 26.77 dBm transmitter in free space. An in-vitro test of the DBS device is presented.

Transcranial magnetic stimulation in autism spectrum disorder: challenges, promise, and roadmap for future research

Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental syndrome characterized by impairments in social communication, by the presence of restricted and repetitive behaviors, interests and activities, and by abnormalities in sensory reactivity. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD. Recent studies suggest that TMS measures provide rapid and noninvasive pathophysiological ASD biomarkers. Furthermore, repetitive TMS (rTMS) may represent a novel treatment strategy for reducing some of the core and associated ASD symptoms. However, the available literature on the TMS use in ASD is preliminary, composed of studies with methodological limitations. Thus, off-label clinical rTMS use for therapeutic interventions in ASD without an investigational device exemption and outside of an IRB approved research trial is premature pending further, adequately powered and controlled trials. Leaders in this field have gathered annually for a two-day conference (prior to the 2014 and 2015 International Meeting for Autism Research, IMFAR) to share recent progress, promote collaboration across laboratories, and establish consensus on protocols. Here we review the literature in the use of TMS in ASD in the context of the unique challenges required for the study and exploration of treatment strategies in this population. We also suggest future directions for this field of investigations. While its true potential in ASD has yet to be delineated, TMS represents an innovative research tool and a novel, possibly transformative approach to the treatment of neurodevelopmental disorders. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Affective dysfunction in a mouse model of Rett syndrome: therapeutic effects of environmental stimulation and physical activity

Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2tm1Tam mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behavior of the Mecp2+ / - mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes. Mecp2+ / - mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating hypothalamic-pituitary-adrenal axis dysregulation. EE of Mecp2+ / - mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder.

Cathodal transcranial Direct Current Stimulation (tDCS) to the right cerebellar hemisphere affects motor adaptation during gait

The cerebellum appears to play a key role in the development of internal rules that allow fast, predictive adjustments to novel stimuli. This is crucial for adaptive motor processes, such as those involved in walking, where cerebellar dysfunction has been found to increase variability in gait parameters. Motor adaptation is a process that results in a progressive reduction in errors as movements are adjusted to meet demands, and within the cerebellum, this seems to be localised primarily within the right hemisphere. To examine the role of the right cerebellar hemisphere in adaptive gait, cathodal transcranial direct current stimulation (tDCS) was administered to the right cerebellar hemisphere of 14 healthy adults in a randomised, double-blind, crossover study. Adaptation to a series of distinct spatial and temporal templates was assessed across tDCS condition via a pressure-sensitive gait mat (ProtoKinetics Zeno walkway), on which participants walked with an induced 'limp' at a non-preferred pace. Variability was assessed across key spatial-temporal gait parameters. It was hypothesised that cathodal tDCS to the right cerebellar hemisphere would disrupt adaptation to the templates, reflected in a failure to reduce variability following stimulation. In partial support, adaptation was disrupted following tDCS on one of the four spatial-temporal templates used. However, there was no evidence for general effects on either the spatial or temporal domain. This suggests, under specific conditions, a coupling of spatial and temporal processing in the right cerebellar hemisphere and highlights the potential importance of task complexity in cerebellar function.

Low-frequency brain stimulation to the left dorsolateral prefrontal cortex increases the negative impact of social exclusion among those high in personal distress

The dorsolateral prefrontal cortex (DLPFC) is thought to play a key role in the cognitive control of emotion and has therefore, unsurprisingly, been implicated in the regulation of physical pain perception. This brain region may also influence the experience of social pain, which has been shown to activate similar neural networks as seen in response to physical pain. Here, we applied sham or active low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC, previously shown to exert bilateral effects in pain perception, in healthy participants. Following stimulation, participants played the “Cyberball Task”; an online ball-tossing game in which the subject participant is included or excluded. Compared to sham, rTMS did not modulate behavioural response to social exclusion. However, within the active rTMS group only, greater trait personal distress was related to enhanced negative outcomes to social exclusion. These results add further support to the notion that the effect of brain stimulation is not homogenous across individuals, and indicates the need to consider baseline individual differences when assessing response to brain stimulation. This seems particularly relevant in social neuroscience investigations, where trait factors may have a meaningful effect.

Efficacy of neurostimulation to treat symptoms of Mal de Debarquement Syndrome. A preliminary study using repetitive transcranial magnetic stimulation

Mal de debarquement syndrome (MdDS) is a rare and poorly understood condition of perceived continual motion. Using a multiple-case design (n = 13; 8 f; 63.5 ± 12.6 years), this study investigated the efficacy of eight 20-min sessions, over 4 weeks, of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral pre-frontal cortex. Compared to sham, rTMS demonstrated improvement in balance and confidence in daily living activities. rTMS shows promise for the treatment of MdDS. However, larger trials with longer intervention periods are required.

Examining the feasibility and tolerability of a clinically informed multisite, repetitive transcranial magnetic stimulation protocol

BACKGROUND: Multi-site repetitive transcranial magnetic stimulation (rTMS) has been applied experimentally in the treatment of obsessive compulsive disorder (OCD). NEW METHOD: This study was conducted to systematically evaluate the safety, tolerability and neurocognitive effects of rTMS applied to three cortical regions over a period of three months. NEW METHOD: Twenty healthy participants aged 22-33 years were randomly allocated to receive one session of active or sham stimulation of low and high frequency rTMS applied sequentially to the pre-supplementary motor area, right-dorsolateral prefrontal cortex and left-orbitofrontal cortex totalling 9min. Tolerability and safety was evaluated using a standardised safety questionnaire. Neurocognitive functioning was examined using the Cambridge Neuropsychological Test Automated Battery and measures of verbal fluency from the Delis-Kaplan Executive Functioning Test™ at five time points over three months. RESULTS: The protocol was safe and tolerable. Frequencies of minor adverse effects were higher in active (17 endorsements) than sham (1 endorsement) conditions. No between group differences in neurocognitive functioning were identified over three months. COMPARISON WITH EXISTING METHOD: This study is the first to evaluate the feasibility of low and high frequency parameters applied sequentially in a single session to the three selected cortical regions whilst providing neurocognitive data. CONCLUSIONS: rTMS applied sequentially over three cortical regions was found to be safe and tolerable in healthy individuals with no major neurocognitive effects over three months. Such findings can be used to inform the development of rTMS protocols involving multi-site stimulation for OCD.

Osteoclast formation elicited by interleukin-33 stimulation is dependent upon the type of osteoclast progenitor

Osteoclasts are bone resorbing multinucleated cells (MNCs) derived from macrophage progenitors. IL-33 has been reported to drive osteoclastogenesis independently of receptor activator of NFκB ligand (RANKL) but this remains controversial as later studies did not confirm this. We found IL-33 clearly elicited functional dentine-resorbing osteoclast formation from human adult monocytes. However, monocytes from only 3 of 12 donors responded this way, while all responded to RANKL. Human cord blood-derived progenitors and murine bone marrow macrophages lacked an osteoclastogenic response to IL-33. In RAW264.7 cells, IL-33 elicited NFκB and p38 responses but not NFATc1 signals (suggesting poor osteoclastogenic responses) and formed only mononuclear tartrate-resistant acid phosphatase positive (TRAP(+)) cells. Since TGFβ boosts osteoclastogenesis in RAW264.7 cells we employed an IL-33/TGFβ co-treatment, which resulted in small numbers of MNCs expressing key osteoclast markers TRAP and calcitonin receptors. Thus, IL-33 possesses weak osteoclastogenic activity suggesting pathological significance and, perhaps, explaining previous conflicting reports.

Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex

High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200μA; 90μs) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKIIα/β), glycogen synthase kinase 3 (GSK3α/β) and AMP-activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100μg/day, 14days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH-treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKIIα/β and GSK3α/β significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKIIα/β, GSK3α/β, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKIIα/β, and GSK3α/β in the LHb together with the downregulation of CaMKIIα/β, GSK3α/β, and AMPK in the IL, contribute to the antidepressant actions of DBS.

A miniature energy harvesting rectenna for operating a head-mountable deep brain stimulation device

This paper presents design, implementation, and evaluation of a miniature rectenna for energy harvesting applications. The rectenna produces DC power from a distant microwave energy transmitter. The generated DC power is then utilized to operate a head-mountable deep brain stimulation device. The rectenna consists of a miniature three-layer planar inverted-F antenna and a Schottky-diode-based bridge rectifier. The antenna has a volume of π × 6 × 1.584 mm3, a resonance frequency of 915 MHz with a simulated bandwidth of 18 MHz (907-925 MHz), and a measured bandwidth of 18 MHz (910-928 MHz) at the return loss of -10 dB. A dielectric substrate of FR-4 of εr = 4.5 and δ = 0.02 is used for simulation and fabrication of the antenna and the rectifier due to its low cost. An L-section impedance matching circuit is employed between the antenna and the rectifier to reduce the mismatch loss. The impedance matching circuit operates as a low-pass filter eliminating higher order harmonics. A deep brain stimulation device is successfully operated by the rectenna at a distance of 20 cm away from a microwave energy transmitter of power 26.77 dBm. The motivation of this paper includes creation of a deep brain stimulation device that operates indefinitely without a battery. From the application standpoint, the developed energy harvesting rectenna facilitates long-term deep brain stimulation of laboratory animals for preclinical research investigating neurological disorders.

Anodal transcranial direct current stimulation of the motor cortex increases cortical voluntary activation and neural plasticity

INTRODUCTION: We examined the cumulative effect of 4 consecutive bouts of non-invasive brain stimulation on corticospinal plasticity and motor performance, and whether these responses were influenced by the brain-derived neurotrophic factor (BDNF) polymorphism.

METHODS: In a randomized double-blinded cross-over design, changes in strength and indices of corticospinal plasticity were analyzed in 14 adults who were exposed to 4 consecutive sessions of anodal and sham transcranial direct current stimulation (tDCS). Participants also undertook a blood sample for BDNF genotyping (N=13).

RESULTS: We observed a significant increase in isometric wrist flexor strength with transcranial magnetic stimulation revealing increased corticospinal excitability, decreased silent period duration, and increased cortical voluntary activation compared to sham tDCS.

DISCUSSION: The results show that 4 consecutive sessions of anodal tDCS increased cortical voluntary activation manifested as an improvement in strength. Induction of corticospinal plasticity appears to be influenced by the BDNF polymorphism.