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Burn injuries are devastating traumas, often leading to life-long consequences that extend beyond the observable burn scar. In the context of the nervous system, burn injury patients commonly develop chronic neurological disorders and have been suggested to have impaired motor cortex function, but the long-lasting impact on neurons and glia in the brain is unknown. Using a mouse model of non-severe burn injury, excitatory and inhibitory neurons in the primary motor cortex were labelled with fluorescent proteins using adeno-associated viruses (AAVs). A total of 5 weeks following the burn injury, virus labelled excitatory and inhibitory neurons were isolated using fluorescence-activated cell sorting (FACS). In addition, microglia and astrocytes from the remaining cortical tissue caudal to the motor cortex were immunolabelled and isolated with FACS. Whole transcriptome RNA-sequencing was used to identify any long-lasting changes to gene expression in the different cell types. RNA-seq analysis showed changes to the expression of a small number of genes with known functions in excitatory neurons and microglia, but not in inhibitory neurons or astrocytes. Specifically, genes related to GABA-A receptors in excitatory neurons and several cellular functions in microglia were found to be downregulated in burn injured mice. These findings suggest that non-severe burn injuries lead to long lasting transcriptomic changes in the brain, but only in specific cell types. Our findings provide a broad overview of the long-lasting impact of burn injuries on the central nervous system which may help identify potential therapeutic targets to prevent neurological dysfunction in burn patients. [ABSTRACT FROM AUTHOR]

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals’ genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current “one-size-fits-all” approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth. [ABSTRACT FROM AUTHOR]

Introduction: Overreliance on habit is linked with disorders, such as drug addiction and obsessive-compulsive disorder, and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and for therapeutic outcomes. In this study, we researched the brains of ephrin-A2A5-/- mice, which previously showed perseverative behavior in progressive-ratio tasks, associated with low cellular activity in the nucleus accumbens. We investigated whether rTMS treatment had altered the activity of the dorsal striatum in a way that suggested altered hierarchical recruitment of brain regions from the ventral striatum to the dorsal striatum, which is linked to abnormal habit formation. Methods: Brain sections from a limited number of mice that underwent training and performance on a progressive ratio task with and without low-intensity rTMS (LI-rTMS) were taken from a previous study. We took advantage of the previous characterization of perseverative behavior to investigate the contribution of different neuronal subtypes and striatal regions within this limited sample. Striatal regions were stained for c-Fos as a correlate of neuronal activation for DARPP32 to identify medium spiny neurons (MSNs) and for GAD67 to identify GABA-ergic interneurons. Results and discussion: Contrary to our hypothesis, we found that neuronal activity in ephrin-A2A5-/- mice still reflected the typical organization of goal- directed behavior. There was a significant difference in the proportion of neuronal activity across the striatum between experimental groups and control but no significant effects identifying a specific regional change. However, there was a significant group by treatment interaction which suggests that MSN activity is altered in the dorsomedial striatum and a trend suggesting that rTMS increases ephrin-A2A5-/- MSN activity in the DMS. Although preliminary and inconclusive, the analysis of this archival data suggests that investigating circuit-based changes in striatal regions may provide insight into chronic rTMS mechanisms that could be relevant to treating disorders associated with perseverative behavior. [ABSTRACT FROM AUTHOR]

Background: Resting-state functional MRI (rs-fMRI) in rodent models have the potential to bridge invasive experiments and observational human studies, increasing our understanding of functional alterations in the brains of patients with depression. A major limitation in current rodent rs-fMRI studies is that there has been no consensus on healthy baseline resting-state networks (RSNs) that are reproducible in rodents. Therefore, the present study aimed to construct reproducible RSNs in a large dataset of healthy rats and then evaluate functional connectivity changes within and between these RSNs following a chronic restraint stress (CRS) model within the same animals. Methods: A combined MRI dataset of 109 Sprague Dawley rats at baseline and after two weeks of CRS, collected during four separate experiments conducted by our lab in 2019 and 2020, was re-analysed. The mICA and gRAICAR toolbox were first applied to detect optimal and reproducible ICA components and then a hierarchical clustering algorithm (FSLNets) was applied to construct reproducible RSNs. Ridge-regularized partial correlation (FSLNets) was used to evaluate the changes in the direct connection between and within identified networks in the same animals following CRS. Results: Four large-scale networks in anesthetised rats were identified: the DMNlike, spatial attention-limbic, corpus striatum, and autonomic network, which are homologous across species. CRS decreased the anticorrelation between DMNlike and autonomic network. CRS decreased the correlation between amygdala and a functional complex (nucleus accumbens and ventral pallidum) in the right hemisphere within the corpus striatum network. However, a high individual variability in the functional connectivity before and after CRS within RSNs was observed. Conclusion: The functional connectivity changes detected in rodents following CRS differ from reported functional connectivity alterations in patients with depression. A simple interpretation of this difference is that the rodent response to CRS does not reflect the complexity of depression as it is experienced by humans. Nonetheless, the high inter-subject variability of functional connectivity within networks suggests that rats demonstrate different neural phenotypes, like humans. Therefore, future efforts in classifying neural phenotypes in rodents might improve the sensitivity and translational impact of models used to address aetiology and treatment of psychiatric conditions including depression. [ABSTRACT FROM AUTHOR]

Non-invasive brain stimulation is a growing field with potentially wide-ranging clinical and basic science applications due to its ability to transiently and safely change brain excitability. In this study we include two types of stimulation: repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS). Single session stimulations with either technique have previously been reported to induce changes in attention. To better understand and compare the effectiveness of each technique and the basis of their effects on cognition we assessed changes to both temporal and visuospatial attention using an attentional blink task and a line bisection task following offline stimulation with an intermittent theta burst (iTBS) rTMS protocol or 10 Hz tACS. Additionally, we included a novel rTMS stimulation technique, low-intensity (LI-)rTMS, also using an iTBS protocol, which uses stimulation intensities an order of magnitude below conventional rTMS. Animal models show that low-intensity rTMS modulates cortical excitability despite sub-action potential threshold stimulation. Stimulation was delivered in healthy participants over the right posterior parietal cortex (rPPC) using a within-subjects design (n = 24). Analyses showed no evidence for an effect of any stimulation technique on spatial biases in the line bisection task or on magnitude of the attentional blink. Our results suggests that rTMS and LI-rTMS using iTBS protocol and 10 Hz tACS over rPPC do not modulate performance in tasks assessing visuospatial or temporal attention. [ABSTRACT FROM AUTHOR]

Tinnitus, a phantom auditory perception that can seriously affect quality of life, is generally triggered by cochlear trauma and associated with aberrant activity throughout the auditory pathways, often referred to as hyperactivity. Studies suggest that non-auditory structures, such as prefrontal cortex (PFC), may be involved in tinnitus generation, by affecting sensory gating in auditory thalamus, allowing hyperactivity to reach the cortex and lead to perception. Indeed, human studies have shown that repetitive transcranial magnetic stimulation (rTMS) of PFC can alleviate tinnitus. The current study investigated whether this therapeutic effect is achieved through inhibition of thalamic hyperactivity, comparing effects of two common clinical rTMS protocols with sham treatment, in a guinea pig tinnitus model. Animals underwent acoustic trauma and once tinnitus developed were treated with either intermittent theta burst stimulation (iTBS), 20 Hz rTMS, or sham rTMS (10 days, 10 min/day; weekdays only). Tinnitus was reassessed and extracellular recordings of spontaneous tonic and burst firing rates in auditory thalamus made. To verify effects in PFC, densities of neurons positive for calcium-binding proteins, calbindin and parvalbumin, were investigated using immunohistochemistry. Both rTMS protocols significantly reduced tinnitus compared to sham. However, spontaneous tonic firing decreased following 20 Hz stimulation and increased following iTBS in auditory thalamus. Burst rate was significantly different between 20 Hz and iTBS stimulation, and burst duration was increased only after 20 Hz treatment. Density of calbindin, but not parvalbumin positive neurons, was significantly increased in the most dorsal region of PFC indicating that rTMS directly affected PFC. Our results support the involvement of PFC in tinnitus modulation, and the therapeutic benefit of rTMS on PFC in treating tinnitus, but indicate this is not achieved solely by suppression of thalamic hyperactivity. [ABSTRACT FROM AUTHOR]

Cocaine use disorder and methamphetamine use disorder are chronic, relapsing disorders with no US Food and Drug Administration-approved interventions. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool that has been increasingly investigated as a possible therapeutic intervention for substance use disorders. rTMS may have the ability to induce beneficial neuroplasticity in abnormal circuits and networks in individuals with addiction. The aim of this review is to highlight the rationale and potential for rTMS to treat cocaine and methamphetamine dependence: we synthesize the outcomes of studies in healthy humans and animal models to identify and understand the neurobiological mechanisms of rTMS that seem most involved in addiction, focusing on the dopaminergic and glutamatergic systems. rTMS-induced changes to neurotransmitter systems include alterations to striatal dopamine release and metabolite levels, as well as to glutamate transporter and receptor expression, which may be relevant for ameliorating the aberrant plasticity observed in individuals with substance use disorders. We also discuss the clinical studies that have used rTMS in humans with cocaine and methamphetamine use disorders. Many such studies suggest changes in network connectivity following acute rTMS, which may underpin reduced craving following chronic rTMS. We suggest several possible future directions for research relating to the therapeutic potential of rTMS in addiction that would help fill current gaps in the literature. Such research would apply rTMS to animal models of addiction, developing a translational pipeline that would guide evidence-based rTMS treatment of cocaine and methamphetamine use disorder. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique, which has brain network-level effects in healthy individuals and is also used to treat many neurological and psychiatric conditions in which brain connectivity is believed to be abnormal. Despite the fact that rTMS is being used in a clinical setting and animal studies are increasingly identifying potential cellular and molecular mechanisms, little is known about how these mechanisms relate to clinical changes. This knowledge gap is amplified by non-overlapping approaches used in preclinical and clinical rTMS studies: preclinical studies are mostly invasive, using cellular and molecular approaches, while clinical studies are non-invasive, including functional magnetic resonance imaging (fMRI), TMS electroencephalography (EEG), positron emission tomography (PET), and behavioral measures. A non-invasive method is therefore needed in rodents to link our understanding of cellular and molecular changes to functional connectivity changes that are clinically relevant. fMRI is the technique of choice for examining both short and long term functional connectivity changes in large-scale networks and is becoming increasingly popular in animal research because of its high translatability, but, to date, there have been no reports of animal rTMS studies using this technique. This review summarizes the main studies combining different rTMS protocols with fMRI in humans, in both healthy and patient populations, providing a foundation for the design of equivalent studies in animals. We discuss the challenges of combining these two methods in animals and highlight considerations important for acquiring clinically-relevant information from combined rTMS/fMRI studies in animals. We believe that combining rTMS and fMRI in animal models will generate new knowledge in the following ways: functional connectivity changes can be explored in greater detail through complementary invasive procedures, clarifying mechanism and improving the therapeutic application of rTMS, as well as improving interpretation of fMRI data. And, in a more general context, a robust comparative approach will refine the use of animal models of specific neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

Non-invasive brain stimulation (NIBS) by electromagnetic fields appears to benefit human neurological and psychiatric conditions, although the optimal stimulation parameters and underlying mechanisms remain unclear. Although, in vitro studies have begun to elucidate cellular mechanisms, stimulation is delivered by a range of coils (from commercially available human stimulation coils to laboratory-built circuits) so that the electromagnetic fields induced within the tissue to produce the reported effects are ill-defined. Here, we develop a simple in vitro stimulation device with plug-and-play features that allow delivery of a range of stimulation parameters. We chose to test low intensity repetitive magnetic stimulation (LI-rMS) delivered at three frequencies to hindbrain explant cultures containing the olivocerebellar pathway. We used computational modeling to define the parameters of a stimulation circuit and coil that deliver a unidirectional homogeneous magnetic field of known intensity and direction, and therefore a predictable electric field, to the target. We built the coil to be compatible with culture requirements: stimulation within an incubator; a flat surface allowing consistent position and magnetic field direction; location outside the culture plate to maintain sterility and no heating or vibration. Measurements at the explant confirmed the induced magnetic field was homogenous and matched the simulation results. To validate our system we investigated biological effects following LI-rMS at 1 Hz, 10 Hz and biomimetic high frequency, which we have previously shown induces neural circuit reorganization. We found that gene expression was modified by LI-rMS in a frequency-related manner. Four hours after a single 10-min stimulation session, the number of c-fos positive cells increased, indicating that our stimulation activated the tissue. Also, after 14 days of LI-rMS, the expression of genes normally present in the tissue was differentially modified according to the stimulation delivered. Thus we describe a simple magnetic stimulation device that delivers defined stimulation parameters to different neural systems in vitro. Such devices are essential to further understanding of the fundamental effects of magnetic stimulation on biological tissue and optimize therapeutic application of human NIBS. [ABSTRACT FROM AUTHOR]

The article examines the role of human developmental biology resource (HDBR) expression for studying prenatal human brain development. Topics include obtaining of human embryonic and fetal tissues from the medical research council (MRC)/Wellcome-Trust funded HDBR, carrying out of single nucleotide polymorphisms (SNP) genotyping according to the Illumina Infinium LCG Quad Assay protocol; quantifying of DNA was quantified on the QuBit system; and extraction of RNA from human embryonic.

Repetitive transcranial magnetic stimulation (rTMS) is primarily used in humans to change the state of corticospinal excitability. To assess the efficacy of different rTMS stimulation protocols, motor evoked potentials (MEPs) are used as a readout due to their non-invasive nature. Stimulation of the motor cortex produces a response in a targeted muscle, and the amplitude of this twitch provides an indirect measure of the current state of the cortex. When applied to the motor cortex, rTMS can alter MEP amplitude, however, results are variable between participants and across studies. In addition, the mechanisms underlying any change and its locus are poorly understood. In order to better understand these effects, MEPs have been investigated in vivo in animal models, primarily in rats. One major difference in protocols between rats and humans is the use of general anesthesia in animal experiments. Anesthetics are known to affect plasticity-like mechanisms and so may contaminate the effects of an rTMS protocol. In the present study, we explored the effect of anesthetic on MEP amplitude, recorded before and after intermittent theta burst stimulation (iTBS), a patterned rTMS protocol with reported facilitatory effects. MEPs were assessed in the brachioradialis muscle of the upper forelimb under two anesthetics: a xylazine/zoletil combination and urethane. We found MEPs could be induced under both anesthetics, with no differences in the resting motor threshold or the average baseline amplitudes. However, MEPs were highly variable between animals under both anesthetics, with the xylazine/zoletil combination showing higher variability and most prominently a rise in amplitude across the baseline recording period. Interestingly, application of iTBS did not facilitate MEP amplitude under either anesthetic condition. Although it is important to underpin human application of TMS with mechanistic examination of effects in animals, caution must be taken when selecting an anesthetic and in interpreting results during prolonged TMS recording. [ABSTRACT FROM AUTHOR]

Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12 mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron-core. Peak magnetic field strength for the air and iron-cores were 90 and 120 mT, respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at 1 Hz but varied at 10 Hz. Finite element modeling of 10 Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 and 12.7 V/m, within the skull and the brain, respectively. Delivering 10 Hz rTMS to the motor cortex of anaesthetized rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n = 4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting. [ABSTRACT FROM AUTHOR]