Thalamic deep brain stimulation paradigm to reduce consciousness: Cortico-striatal dynamics implicated in mechanisms of consciousness

Anesthetic manipulations provide much-needed causal evidence for neural correlates of consciousness, but non-specific drug effects complicate their interpretation. Evidence suggests that thalamic deep brain stimulation (DBS) can either increase or decrease consciousness, depending on the stimulation target and parameters. The putative role of the central lateral thalamus (CL) in consciousness makes it an ideal DBS target to manipulate circuit-level mechanisms in cortico-striato-thalamic (CST) systems, thereby influencing consciousness and related processes. We used multi-microelectrode DBS targeted to CL in macaques while recording from frontal, parietal, and striatal regions. DBS induced episodes of abnormally long, vacant staring with low-frequency oscillations here termed vacant, perturbed consciousness (VPC). DBS modulated VPC likelihood in a frequency-specific manner. VPC events corresponded to decreases in measures of neural complexity (entropy) and integration (Φ*), proposed indices of consciousness, and substantial changes to communication in CST circuits. During VPC, power spectral density and coherence at low frequencies increased across CST circuits, especially in thalamo-parietal and cortico-striatal pathways. Decreased consciousness and neural integration corresponded to shifts in cortico-striatal network configurations that dissociated parietal and subcortical structures. Overall, the features of VPC and implicated networks were similar to those of absence epilepsy. As this same multi-microelectrode DBS method–but at different stimulation frequencies–can also increase consciousness in anesthetized macaques, it can be used to flexibly address questions of consciousness with limited confounds, as well as inform clinical investigations of other consciousness disorders.     

MEG can map short and long-term changes in brain activity following deep brain stimulation for chronic pain

Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain.     

脑深部电刺激的临床应用

脑深部电刺激(deep brain stimulation,DBS)是近20年来神经外科领域发展最迅猛的技术。DBS是通过刺激发生器发出的高频电脉冲信号刺激脑神经核团或神经传导束来调节异常的神经环路。DBS已经成为治疗特发性震颤、帕金森病、肌张力障碍等运动障碍病的常规手术方法。自1997年深部脑刺激通过美国FDA认证用于治疗特发性震颤以来,已有超过数万名运动障碍患者接受该疗法,而国内脑深部电刺激最早在1999年应用于帕金森病临床治疗,迄今也有数千例患者接受了植入手术。近年,脑起搏器的临床适应症不断扩大,从最初的运动障碍病逐渐发展到治疗其他神经和精神疾病,如抽动秽语综合征、强迫症、抑郁症、神经性厌食症、难治性疼痛、癫痫、植物状态和阿尔茨海默病等,虽然DBS的治疗机理还不很清楚,但可以预见未来DBS将成为众多神经和精神疾病的重要治疗方法。     

Translational principles of deep brain stimulation

Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.     

New insights offered by a computational model of deep brain stimulation

Deep brain stimulation (DBS) is a standard neurosurgical procedure used to treat motor symptoms in about 5% of patients with Parkinson's disease (PD). Despite the indisputable success of this procedure, the biological mechanisms underlying the clinical benefits of DBS have not yet been fully elucidated. The paper starts with a brief review on the use of DBS to treat PD symptoms. The second section introduces a computational model based on the population density approach and the Izhikevich neuron model. We explain why this model is appropriate for investigating macroscopic network effects and exploring the physiological mechanisms which respond to this treatment strategy (i.e., DBS). Finally, we present new insights into the ways this computational model may help to elucidate the dynamic network effects produced in a cerebral structure when DBS is applied.     

Deep brain stimulation

During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinsons disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experimental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose following STN–DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and extensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequency stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation-induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN–DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN–DBS indeed provides a slow-down of disease progression.     

Closed-loop deep brain stimulation is superior in ameliorating parkinsonism

Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson's disease (PD) management. However, the mechanisms underlying DBS effects remain enigmatic and are the subject of an ongoing debate. Here, we present and test a closed-loop stimulation strategy for PD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. Application of pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Furthermore, cortico-pallidal closed-loop stimulation has a significantly greater effect on akinesia and on cortical and pallidal discharge patterns than standard open-loop DBS and matched control stimulation paradigms. Thus, closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD. Such strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.     

A succession of anesthetic endpoints in the Drosophila brain

General anesthetics abolish behavioral responsiveness in all animals, and in humans this is accompanied by loss of consciousness. Whether similar target mechanisms and behavioral endpoints exist across species remains controversial, although model organisms have been successfully used to study mechanisms of anesthesia. In Drosophila, a number of key mutants have been characterized as hypersensitive or resistant to general anesthetics by behavioral assays. In order to investigate general anesthesia in the Drosophila brain, local field potential (LFP) recordings were made during incremental exposures to isoflurane in wild-type and mutant flies. As in higher animals, general anesthesia in flies was found to involve a succession of distinct endpoints. At low doses, isoflurane uncoupled brain activity from ongoing movement, followed by a sudden attenuation in neural correlates of perception. Average LFP activity in the brain was more gradually attenuated with higher doses, followed by loss of movement behavior. Among mutants, a strong correspondence was found between behavioral and LFP sensitivities, thereby suggesting that LFP phenotypes are proximal to the anesthetic's mechanism of action. Finally, genetic and pharmacological analysis revealed that anesthetic sensitivities in the fly brain are, like other arousal states, influenced by dopaminergic activity. These results suggest that volatile anesthetics such as isoflurane may target the same processes that sustain wakefulness and attention in the brain. LFP correlates of general anesthesia in Drosophila provide a powerful new approach to uncovering the nature of these processes.     

Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficient neurosurgical treatment for advanced Parkinson's disease. Non‐invasive metabolic neuroimaging during the course of DBS in animal models may contribute to our understanding of its action mechanisms. Here, DBS was adapted to in vivo proton magnetic resonance spectroscopy at 11.7 T in the rat to follow metabolic changes in main basal ganglia structures, the striatum, and the substantia nigra pars reticulata (SNr). Measurements were repeated OFF and ON acute and subchronic (7 days) STN‐DBS in control and parkinsonian (6‐hydroxydopamine lesion) conditions. Acute DBS reversed the increases in glutamate, glutamine, and GABA levels induced by the dopamine lesion in the striatum but not in the SNr. Subchronic DBS normalized GABA in both the striatum and SNr, and glutamate in the striatum. Taurine levels were markedly decreased under subchronic DBS in the striatum and SNr in both lesioned and unlesioned rats. Microdialysis in the striatum further showed that extracellular taurine was increased. These data reveal that STN‐DBS has duration‐dependent metabolic effects in the basal ganglia, consistent with development of adaptive mechanisms. In addition to counteracting defects induced by the dopamine lesion, prolonged DBS has proper effects independent of the pathological condition.

     

The national DBS brain tissue network pilot study: need for more tissue and more standardization

Over 70,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved through the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), which will further our understanding of DBS and brain function. The objectives of the tissue bank are twofold: (a) to provide a complete (clinical, imaging and pathological) database for DBS brain tissue samples, and (b) to make available DBS tissue samples to researchers, which will help our understanding of disease and underlying brain circuitry. Standard operating procedures for processing DBS brains were developed as part of the pilot project. Complete data files were created for individual patients and included demographic information, clinical information, imaging data, pathology, and DBS lead locations/settings. 19 DBS brains were collected from 11 geographically dispersed centers from across the U.S. The average age at the time of death was 69.3 years (51?C92, with a standard deviation or SD of 10.13). The male:female ratio was almost 3:1. Average post-mortem interval from death to brain collection was 10.6 h (SD of 7.17). The DBS targets included: subthalamic nucleus, globus pallidus interna, and ventralis intermedius nucleus of the thalamus. In 16.7% of cases the clinical diagnosis failed to match the pathological diagnosis. We provide neuropathological findings from the cohort, and perilead responses to DBS. One of the most important observations made in this pilot study was the missing data, which was approximately 25% of all available data fields. Preliminary results demonstrated the feasibility and utility of creating a National DBS-BTN resource for the scientific community. We plan to improve our techniques to remedy omitted clinical/research data, and expand the Network to include a larger donor pool. We will enhance sample preparation to facilitate advanced molecular studies and progenitor cell retrieval.     

Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor

Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor-null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.     

Regeneration of the central nervous system-principles from brain regeneration in adult zebrafish

Poor recovery of neuronal functions is one of the most common healthcare challenges for patients with different types of brain injuries and/or neurodegenerative diseases. Therapeutic interventions face two major challenges: (1) How to generate neurons de novo to replenish the neuronal loss caused by injuries or neurodegeneration (restorative neurogenesis) and (2) How to prevent or limit the secondary tissue damage caused by long-term accumulation of glial cells, including microglia, at injury site (glial scar). In contrast to mammals, zebrafish have extensive regenerative capacity in numerous vital organs, including the brain, thus making them a valuable model to improve the existing therapeutic approaches for human brain repair. In response to injuries to the central nervous system (CNS), zebrafish have developed specific mechanisms to promote the recovery of the lost tissue architecture and functionality of the damaged CNS. These mechanisms include the activation of a restorative neurogenic program in a specific set of glial cells (ependymoglia) and the resolution of both the glial scar and inflammation, thus enabling proper neuronal specification and survival. In this review, we discuss the cellular and molecular mechanisms underlying the regenerative ability in the adult zebrafish brain and conclude with the potential applicability of these mechanisms in repair of the mammalian CNS.     

Therapeutic rewiring by means of desynchronizing brain stimulation

We study possible anti-kindling effects of the standard high-frequency deep brain stimulation (HFDBS) and of a desynchronizing multisite coordinated reset stimulation (MCRS) theoretically in a mathematical model of the subthalamic nucleus (STN). The latter is an effective target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). Depending on the structures being activated, electrical pulses may have excitatory and/or inhibitory impact. According to our simulation results MCRS may achieve robust long-term anti-kindling (i.e., curative) effects, irrespectively, of the ratio between excitatory and inhibitory impact. This means, that during MCRS the STN unlearns its pathologic synaptic connections and reestablishes a physiological level of connectivity. In contrast, HFDBS has anti-kindling effects only if its impact is predominantly excitatory. Our results are relevant for selecting appropriate locations for DBS electrodes. In fact, even with HFDBS we may expect anti-kindling effects, provided the target is properly chosen.     

Developmental control of inositol phosphate biosynthesis is altered in the brain of both curly and phenotypically normal straight tail mutant mice

BACKGROUND : Altered levels of inositol phosphate in the central nervous system (CNS) are hypothesized to produce distorted brain signaling and lead to numerous neurologic maladies. Little is known of mechanisms controlling the complex metabolic flux of inositol phosphate. Less is known of controls that regulate inositol‐phosphate biosynthesis in the mammalian brain. The expression of 1L‐myo‐inositol?1 phosphate synthase (MIP), the only enzyme known to synthesize inositol phosphate, was studied in the brain of normal (CBA) and curly tail (CT) mutant mice. The CT strain exhibits a neural tube defect, spina bifida, responsive to inositol supplementation, but not to folic acid treatment. METHODS : Utilizing enzyme assays to determine the specific activity of MIP, Western blotting to detect expression, gas chromatography/mass spectrometry to measure inositol concentration, and statistical analyses to evaluate quantitative data, MIP expression was analyzed in newborn, young, and adult brains of CBA and CT (curly tail [ct‐CT] and straight tail [st‐CT]) mutant mice. RESULTS : Data analyses suggest there is a significant difference in MIP activity in the brain of CBA mice as compared to that of CT mutant mice and that temporal and spatial control of MIP expression and inositol concentrations are altered in the brain of both the ct‐CT and phenotypically normal st‐CT mutant. Moreover, two differentially expressed forms of MIP were identified in the adult mouse brain. CONCLUSIONS : These findings implicate a role for MIP in the maturation of the CNS and evoke a hypothesis regarding the regulation of inositol phosphate biosynthesis in brain development. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Deep brain stimulation of nucleus accumbens region in alcoholism affects reward processing

The influence of bilateral deep brain stimulation (DBS) of the nucleus nucleus (NAcc) on the processing of reward in a gambling paradigm was investigated using H(2)[(15)O]-PET (positron emission tomography) in a 38-year-old man treated for severe alcohol addiction. Behavioral data analysis revealed a less risky, more careful choice behavior under active DBS compared to DBS switched off. PET showed win- and loss-related activations in the paracingulate cortex, temporal poles, precuneus and hippocampus under active DBS, brain areas that have been implicated in action monitoring and behavioral control. Except for the temporal pole these activations were not seen when DBS was deactivated. These findings suggest that DBS of the NAcc may act partially by improving behavioral control.     

Information processing in brain microtubules

Models of the mind are based on the idea that neuron microtubules can perform computation. From this point of view, information processing is the fundamental issue for understanding the brain mechanisms that produce consciousness. The cytoskeleton polymers could store and process information through their dynamic coupling mediated by mechanical energy. We analyze the problem of information transfer and storage in brain microtubules, considering them as a communication channel. We discuss the implications of assuming that consciousness is generated by the subneuronal process.     

Differential effects of propofol and ketamine on critical brain dynamics

Whether the brain operates at a critical “tipping” point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as “dissociative anaesthesia”). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness.     

Optimal closed-loop deep brain stimulation using multiple independently controlled contacts

Deep brain stimulation (DBS) is a well-established treatment option for a variety of neurological disorders, including Parkinson’s disease and essential tremor. The symptoms of these disorders are known to be associated with pathological synchronous neural activity in the basal ganglia and thalamus. It is hypothesised that DBS acts to desynchronise this activity, leading to an overall reduction in symptoms. Electrodes with multiple independently controllable contacts are a recent development in DBS technology which have the potential to target one or more pathological regions with greater precision, reducing side effects and potentially increasing both the efficacy and efficiency of the treatment. The increased complexity of these systems, however, motivates the need to understand the effects of DBS when applied to multiple regions or neural populations within the brain. On the basis of a theoretical model, our paper addresses the question of how to best apply DBS to multiple neural populations to maximally desynchronise brain activity. Central to this are analytical expressions, which we derive, that predict how the symptom severity should change when stimulation is applied. Using these expressions, we construct a closed-loop DBS strategy describing how stimulation should be delivered to individual contacts using the phases and amplitudes of feedback signals. We simulate our method and compare it against two others found in the literature: coordinated reset and phase-locked stimulation. We also investigate the conditions for which our strategy is expected to yield the most benefit.     

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson’s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 MΩ was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.