Brain Pacemaker Research Articles

Specific Absorption Rate and Temperature Distributions in the Human Head with Implanted Deep Brain Stimulation Subjected to Mobile Phone Electromagnetic Radiation

Deep Brain Stimulation (DBS), also known as the brain pacemaker, has gradually evolved from a scientific experiment into an effective clinical treatment for movement disorders as a method of improving movement disorders. At present, there are few studies on the effects of 5G mobile phone antenna radiation on the heads of adult patients implanted with DBS. In this study, COMSOL Multiphysics was used to establish a mobile phone model with a 5G/4G patch antenna, a real human head, and the DBS models. Then, we calculated the specific absorption rate (SAR) of various layers of the head tissues with the mobile phone at different distances from the human head, as well as the temperature change rule of the head and the DBS irradiated by the antenna for 30 min. The simulation results showed that when the frequency is 3500 MHz, the electromagnetic radiation of the phone to the patient’s head is generally greater than that of the 2400 MHz. When at 3500 MHz, the distance between the phone and the head is inversely proportional to the SAR value; thus, when the distance between the phone and the head is 1 cm, the maximum SAR value—which is 1.132 W/kg—appeared in the skin layer of the head with implanted DBS. But it is worth noting that the largest temperature rise appeared in the brain layer at 2400 MHz and at a distance of 1 cm, which is 0.2148 °C. Although the SAR values and temperature rise obtained from all simulations are below the limits of 2 W/kg and +1 °C specified by the International Commission on Non-Ionizing Radiation Protection (ICNIRP), we still recommend that patients with implanted DBS maintain a distance when using the phones.

New Technologies to Diagnose and Treat Mental Health Problems

This article introduces three novel approaches and technologies to the field of mental health and psychiatry, these are: digital sensors, neural network computing, and neuromodulation pacemakers to the brain. Sensors built into devises such as smartphones and smart watches can monitor and diagnose mental disorders. Neural computing simulate how the brain may function in health and disease, thus offering valuable information about possible causes for these disorders. Finally therapeutic interventions can be achieved with brain-pacemakers technologies. Have you ever wondered what technologies such as smartphones could have to do with mental health? When we talk about mental health problems, we are usually referring to difficulties with emotions and thoughts that can affect our daily functioning. There are three new technologies that are revolutionizing how we diagnose and treat mental disorders. The first is the smartphone. Smartphone-based technology enables continuous monitoring of a patient’s mental state and allows doctors to diagnosis, evaluate, and even treat patients from afar. The second technology is neural computing, which seeks to understand the physical, brain-based causes of mental illnesses. Finally, brain pacemaker technologies may make it possible to cure mental illnesses in the same way that pacemakers currently cure heart problems. Keep reading to hear the details of each of these fascinating advances in mental healthcare!

Dynamic modulation of genomic enhancer elements in the suprachiasmatic nucleus, the site of the mammalian circadian clock.

The mammalian suprachiasmatic nucleus (SCN), located in the ventral hypothalamus, synchronizes and maintains daily cellular and physiological rhythms across the body, in accordance with environmental and visceral cues. Consequently, the systematic regulation of spatiotemporal gene transcription in the SCN is vital for daily timekeeping. So far, the regulatory elements assisting circadian gene transcription have only been studied in peripheral tissues, lacking the critical neuronal dimension intrinsic to the role of the SCN as central brain pacemaker. By using histone-ChIP-seq, we identified SCN-enriched gene regulatory elements that associated with temporal gene expression. Based on tissue-specific H3K27ac and H3K4me3 marks, we successfully produced the first-ever SCN gene-regulatory map. We found that a large majority of SCN enhancers not only show robust 24-h rhythmic modulation in H3K27ac occupancy, peaking at distinct times of day, but also possess canonical E-box (CACGTG) motifs potentially influencing downstream cycling gene expression. To establish enhancer-gene relationships in the SCN, we conducted directional RNA-seq at six distinct times across the day and night, and studied the association between dynamically changing histone acetylation and gene transcript levels. About 35% of the cycling H3K27ac sites were found adjacent to rhythmic gene transcripts, often preceding the rise in mRNA levels. We also noted that enhancers encompass noncoding, actively transcribing enhancer RNAs (eRNAs) in the SCN, which in turn oscillate, along with cyclic histone acetylation, and correlate with rhythmic gene transcription. Taken together, these findings shed light on genome-wide pretranscriptional regulation operative in the central clock that confers its precise and robust oscillation necessary to orchestrate daily timekeeping in mammals.

The circadian clock in the mouse habenula is set by catecholamines.

Circadian rhythms are those variations in behavioral and molecular processes of organisms that follow roughly 24h cycles in the absence of any external cue. The hypothalamic suprachiasmatic nucleus (SCN) harbors the principal brain pacemaker driving circadian rhythms. The epithalamic habenula (Hb) contains a self-sustained circadian clock functionally coupled to the SCN. Anatomically, the Hb projects to the midbrain dopamine (DA) and serotonin (5-HT) systems, and it receives inputs from the forebrain, midbrain, and brainstem. The SCN is set by internal signals such as 5-HT or melatonin from the raphe nuclei and pineal gland, respectively. However, how the Hb clock is set by internal cues is not well characterized. Hence, in the present study, we determined whether DA, noradrenaline (NA), 5-HT, and the neuropeptides orexin (ORX) and vasopressin influence the Hb circadian clock. Using PER2::Luciferase transgenic mice, we found that the amplitude of the PER2 protein circadian oscillations from Hb explants was strongly affected by DA and NA. Importantly, these effects were dose-and region (rostral vs. caudal) dependent for NA, with a main effect in the caudal part of the Hb. Furthermore, ORX also induced a significant change in the amplitude of PER2 protein oscillations in the caudal Hb. In conclusion, catecholaminergic (DA, NA) and ORXergic transmission impacts the clock properties of the Hb clock likely contributing to the circadian regulation of motivated behaviors. Accordingly, pathological conditions that lead in alterations of catecholamine or ORX activity (drug intake, compulsive feeding) might affect the Hb clock and conduct to circadian disturbances.

CLOCKWORK ORANGE promotes CLOCK-CYCLE activation via the putative Drosophila ortholog of CLOCK INTERACTING PROTEIN CIRCADIAN

The Drosophila circadian clock is driven by a transcriptional feedback loop in which CLOCK-CYCLE (CLK-CYC) binds E-boxes to transcribe genes encoding the PERIOD-TIMELESS (PER-TIM) repressor, which releases CLK-CYC from E-boxes to inhibit transcription. CLOCKWORK ORANGE (CWO) reinforces PER-TIM repression by binding E-boxes to maintain PER-TIM bound CLK-CYC off DNA, but also promotes CLK-CYC transcription through an unknown mechanism. To determine how CWO activates CLK-CYC transcription, we identified CWO target genes that are upregulated in the absence of CWO repression, conserved in mammals, and preferentially expressed in brain pacemaker neurons. Among the genes identified was a putative ortholog of mouse Clock Interacting Protein Circadian (Cipc), which represses CLOCK-BMAL1 transcription. Reducing or eliminating Drosophila Cipc expression shortens period, while overexpressing Cipc lengthens period, which is consistent with previous work showing that Drosophila Cipc represses CLK-CYC transcription in S2 cells. Cipc represses CLK-CYC transcription invivo, but not uniformly, as per is strongly repressed, tim less so, and vri hardly at all. Long period rhythms in cwo mutant flies are largely rescued when Cipc expression is reduced or eliminated, indicating that increased Cipc expression mediates the period lengthening of cwo mutants. Consistent with this behavioral rescue, eliminating Cipc rescues the decreased CLK-CYC transcription in cwo mutant flies, where per is strongly rescued, tim is moderately rescued, and vri shows little rescue. These results suggest a mechanism for CWO-dependent CLK-CYC activation: CWO inhibition of CIPC repression promotes CLK-CYC transcription. This mechanism may be conserved since cwo and Cipc perform analogous roles in the mammalian circadian clock.

Toward living neuroprosthetics: developing a biological brain pacemaker as a living neuromodulatory implant for improving parkinsonian symptoms

Objective. Therapeutic intervention for Parkinson’s disease (PD) via deep brain stimulation (DBS) represents the current paradigm for managing the advanced stages of the disease in patients when treatment with pharmaceuticals becomes inadequate. Although DBS is the prevailing therapy in these cases, the overall effectiveness and reliability of DBS can be diminished over time due to hardware complications and biocompatibility issues with the electronic implants. To achieve a lifetime solution, we envision that the next generation of neural implants will be entirely ‘biological’ and ‘autologous’, both physically and functionally. Thus, in this study, we set forth toward developing a biological brain pacemaker for treating PD. Our focus is to investigate engineering strategies for creating a multicellular biological circuit that integrates innate biological design and function while incorporating principles of neuromodulation to create a biological mechanism for delivering high-frequency stimulation with cellular specificity. Approach. We engineer a 3D multicellular circuit design built entirely from biological and biocompatible components using established tissue engineering protocols to demonstrate the feasibility of creating a living neural implant. Furthermore, using 2D co-culture systems, we investigate the physiologically relevant parameters that would be necessary to further develop a therapeutic benefit of high-frequency stimulation with cellular specificity within our construct design. Main results. Our results demonstrate the feasibility of fabricating a 3D multicellular circuit device in an implantable form. Furthermore, we show we can organize cellular materials to create potential functional connections in normal physiological conditions, thus laying down the foundation of designing a high-frequency pacing system for selective and controlled therapeutic neurostimulation. Significance. The findings from this study may lead to the future development of autologous living neural implants that both circumvent the issues inherent in electronic neural implants and form more biocompatible devices with lifelong robustness to repair and restore motor functions, with the ultimate benefit for patients with PD.

Crosstalk between vrille transcripts, proteins, and regulatory elements controlling circadian rhythms and development in Drosophila.

SummaryThe vrille (vri) gene encodes a transcriptional repressor required for Drosophila development as well as circadian behavior in adults. Alternate first exons produce vri transcripts predicted to produce a short VRI isoform during development and long VRI in adults. A vri mutant (vriΔ679) lacking long VRI transcripts is viable, confirming that short VRI is sufficient for developmental functions, yet behavioral rhythms in vriΔ679 flies persist, showing that short VRI is sufficient for clock output. E-box regulatory elements that drive rhythmic long VRI transcript expression are required for developmental expression of short VRI transcripts. Surprisingly, long VRI transcripts primarily produce short VRI in adults, apparently due to a poor Kozak sequence context, demonstrating that short VRI drives circadian behavior. Thus, E-box-driven long VRI transcripts primarily control circadian rhythms via short VRI, whereas the same E-boxes drive short VRI transcripts that control developmental functions using short VRI.

Cardiac Surgery in a Patient with Implanted Brain Pacemaker: A Case Report

AbstractParkinson’s disease, a neurodegenerative disorder, affects approximately 1% of population older than 60 years. Patients with Parkinson’s disease with intractable symptoms often require placement of deep brain stimulator, conventionally known as brain pacemaker. Patients implanted with this device pose specific challenges to the anesthesiologist in view of the primary illness, possible drug interactions, risk of cerebral hemorrhage from anticoagulant therapy, and potential for device malfunction by electromagnetic interference during cardiac surgery. The authors describe perioperative management of a patient with implanted brain pacemaker who underwent aortic valve replacement at their institution.

Deep brain stimulation

Deep brain stimulation Abstract. Deep brain stimulation, a neurosurgical therapy, consists of implanting electrodes in certain brain regions via which electrical impulses are applied by means of a neurostimulator (brain pacemaker). The therapeutic efficacy has been scientifically proven in various neurological and psychiatric indications. Deep Brain Stimulation offers a treatment option for severe disease progression and inadequate response to medication. Fluctuations and dyskinesias in Parkinson's disease, dystonia, refractory tremor and epilepsy, and certain pain syndromes are approved indications for deep brain stimulation in Switzerland.

CLOCK stabilizes CYCLE to initiate clock function in Drosophila

The Drosophila circadian clock keeps time via transcriptional feedback loops. These feedback loops are initiated by CLOCK-CYCLE (CLK-CYC) heterodimers, which activate transcription of genes encoding the feedback repressors PERIOD and TIMELESS. Circadian clocks normally operate in ∼150 brain pacemaker neurons and in many peripheral tissues in the head and body, but can also be induced by expressing CLK in nonclock cells. These ectopic clocks also require cyc, yet CYC expression is restricted to canonical clock cells despite evidence that cyc mRNA is widely expressed. Here we show that CLK binds to and stabilizes CYC in cell culture and in nonclock cells in vivo. Ectopic clocks also require the blue light photoreceptor CRYPTOCHROME (CRY), which is required for both light entrainment and clock function in peripheral tissues. These experiments define the genetic architecture required to initiate circadian clock function in Drosophila, reveal mechanisms governing circadian activator stability that are conserved in perhaps all eukaryotes, and suggest that Clk, cyc, and cry expression is sufficient to drive clock expression in naive cells.

Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function.

Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila.

The Drosophila Receptor Protein Tyrosine Phosphatase LAR Is Required for Development of Circadian Pacemaker Neuron Processes That Support Rhythmic Activity in Constant Darkness But Not during Light/Dark Cycles.

In animals, circadian clocks drive daily rhythms in physiology, metabolism, and behavior via transcriptional feedback loops. Because key circadian transcriptional activators and repressors are regulated by phosphorylation, we screened for phosphatases that alter activity rhythms when their expression was reduced. One such phosphatase, leukocyte-antigen-related (LAR), abolishes activity rhythms, but does not disrupt feedback loop function. Rather,Lardisrupts clock output by eliminating axonal processes from clock neurons that release pigment-dispersing factor (PDF) neuropeptide into the dorsal brain, but PDF expression persists in their cell bodies and remaining projections. In contrast to flies that lack PDF, flies that lackLaranticipate lights-on and lights-off transitions normally, which suggests that the remaining PDF expression mediates activity during light/dark cycles.

MiR-124 Regulates the Phase of Drosophila Circadian Locomotor Behavior.

In animals, molecular circadian clocks control the timing of behavioral activities to optimize them with the day/night cycle. This is critical for their fitness and survival. The mechanisms by which the phase of circadian behaviors is determined downstream of the molecular pacemakers are not yet well understood. Recent studies indicate that miRNAs are important regulators of circadian outputs. We found that miR-124 shapes diurnal behavioral activity and has a striking impact on the phase of circadian locomotor behavior. Surprisingly, the period and phase of the neural circadian pacemakers driving locomotor rhythms are unaffected. Therefore, miR-124 is a critical modulator of the circadian output pathways that control circadian behavioral rhythms.

Brain pacemaker in prefrontal cortex: from functional neurocircuitry modulation to behavioral regulation in neuropsychiatric disorders

Brain pacemaker in prefrontal cortex: from functional neurocircuitry modulation to behavioral regulation in neuropsychiatric disorders

RETRACTED: Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks

SummaryCircadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles.

Cryptochrome-dependent and -independent circadian entrainment circuits in Drosophila.

Entrainment to environmental light/dark (LD) cycles is a central function of circadian clocks. In Drosophila, entrainment is achieved by Cryptochrome (CRY) and input from the visual system. During activation by brief light pulses, CRY triggers the degradation of TIMELESS and subsequent shift in circadian phase. This is less important for LD entrainment, leading to questions regarding light input circuits and mechanisms from the visual system. Recent studies show that different subsets of brain pacemaker clock neurons, the morning (M) and evening (E) oscillators, have distinct functions in light entrainment. However, the role of CRY in M and E oscillators for entrainment to LD cycles is unknown. Here, we address this question by selectively expressing CRY in different subsets of clock neurons in a cry-null (cry(0)) mutant background. We were able to rescue the light entrainment deficits of cry(0) mutants by expressing CRY in E oscillators but not in any other clock neurons. Par domain protein 1 molecular oscillations in the E, but not M, cells of cry(0) mutants still responded to the LD phase delay. This residual light response was stemming from the visual system because it disappeared when all external photoreceptors were ablated genetically. We concluded that the E oscillators are the targets of light input via CRY and the visual system and are required for normal light entrainment.

Cognitive Function and Calcium. Cognitive improvement through T type calcium channel stimulation

Low-threshold Ca2+ spikes are mediated by T-type Ca2+ channels, which have fast inactivation and slow deactivation kinetics (transient) , and single channel conductance. The activation are triggered by -60 to -65 mV. T-type Ca2+ channels are predominantly expressed in the brain and heart pacemaker cells. Three subtypes of T-type Ca2+ channels Cav3.1 (α1G), Cav3.2 (α1H), Cav3.3 (α1I) encoding by CACNA1G, CACNA1H, CACNA1I genes have been cloned. Although high-threshold voltage-gated Ca2+ channels have auxiliary α2δ, β, γ subunits, T-type Ca2+ channels are composed only by α1 subunit. Although T-type Ca2+ channels are involved in the pace making in heart and a robust low-threshold Ca2+ spike in neurons, the physiological functions in the memory and synaptic plasticity remain unclear. In this paper, I would like to focus on the pathophysiological relevance of T-type Ca2+ channels in the brain functions including cognition.

Investigation of the therapeutic applications, neuroanatomical targets and emerging technologies in deep brain stimulation surgery

Background First developed in France in 1987, Deep Brain Stimulation (DBS) is a neurosurgical intervention that involves the implantation of a brain pacemaker, which electrically stimulates specific brain nuclei.1 The FDA approved DBS for treatment for Essential Tremor in 1997, Parkinson’s Disease in 2002 and Dystonia in 2003.1 More recently, DBS has been indicated in management of neuropsychiatric disorders such as: Chronic Pain, Major Depression, Obsessive Compulsive Disorder and Anorexia Nervosa. Although effective, the exact mode of function of DBS remains poorly understood. Up to 2012, literature search yielded 84 peer-reviewed DBS studies that included over 296 psychiatric patients.2 The Canadian United Health Network (UHN) Krembil Neuroscience Centre is pioneering DBS research. Current neuroimaging, intra-operative electrophysiology and emerging DBS electrode and targeting technologies have improved DBS accuracy, effectiveness and acceptability. Objective: To examine the role of DBS in the management of motor and neuropsychiatric disorders and to provide, for the first time, a review of all anatomical DBS targets to date. To evaluate the accuracy of emerging DBS targeting and electrode technologies.

ALTERATIONS OF DYNAMICS OF HUMAN ELECTROENCEPHALOGRAM SPECTRAL PARAMETERS DURING DAILY GEOMAGNETIC FIELD VARIATIONS

The technique of identifying the nature of daily changes in spectral power relations of the basic rhythm brain activity and geomagnetic field variations has been proposed. There has been carried out an analysis of electroencephalogram (EEG) alpha activity spectral power recording at every minute in the morning, afternoon and evening during 5 days (12 recordings, 30 minutes each) in three healthy volunteers compared to every-minute variations of the total geomagnetic field vector (TGMFV). It has been established that in cases of increased TGMFV evening values, general alpha EEG-activity could increase, indicating an increase in internal synchronization of the brain pacemaker structures, and it could be reduced reflecting desynchronizing effects of the reticular formation on the cerebral cortex. There have been detected three variations of individual sensitivity of the brain parts to increased TGMFV indices - increased spectral power of EEG alpha-activity predominantly in the right temporal brain part, reduced spectral power of this EEG type predominantly in the left frontal-temporal brain part and a reaction of the total spectral power reduction of EEG alpha-activity.

GW182 Controls Drosophila Circadian Behavior and PDF-Receptor Signaling

The neuropeptide PDF is crucial for Drosophila circadian behavior: it keeps circadian neurons synchronized. Here, we identify GW182 as a key regulator of PDF signaling. Indeed, GW182 downregulation results in phenotypes similar to those of Pdf and Pdf-receptor (Pdfr) mutants. gw182 genetically interacts with Pdfr and cAMP signaling, which is essential for PDFR function. GW182 mediates miRNA-dependent gene silencing through its interaction with AGO1. Consistently, GW182's AGO1 interaction domain is required for GW182's circadian function. Moreover, our results indicate that GW182 modulates PDFR signaling by silencing the expression of the cAMP phosphodiesterase DUNCE. Importantly, this repression is under photic control, and GW182 activity level--which is limiting in circadian neurons--influences the responses of the circadian neural network to light. We propose that GW182's gene silencing activity functions as a rheostat for PDFR signaling and thus profoundly impacts the circadian neural network and its response to environmental inputs.