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Anatomical localizations of key nuclei thought to play a role in level of consciousness. See text for references. ACh = acetylcholine; CL = central lateral; CM-Pf = centromedian-parafascicular thalamus; FC = functional connectivity; GPe = globus pallidus externa; GPi = globus pallidus interna; LC = locus coeruleus; LO = lateral orbitofrontal cortex; MCS minimally conscious state; mPFC = medial prefrontal cortex; MR = midbrain raphe; NA = nucleus accumbens; NBM = nucleus basalis of Meynert; NE = norepinephrine; NTS = nucleus tractus solitarius; PAG = periaqueductal gray matter; PFC = prefrontal cortex; PH = posterior hypothalamus; PnO = pontine nucleus oralis; PPT = pedunculopontine tegmental area; PRF = pontine reticular formation; PTZ = pentylenetetrazol; RAS = reticular activating system; SC = superior colliculus; SNR = substantia nigra reticularis; STN = subthalamic nucleus; SWS = slowwave sleep; TBI = traumatic brain injury; TMN = tubulomammillary nucleus; VS = vegetative state; VTA = ventral tegmental area.
Source publication
When drug-resistant epilepsy is poorly localized or surgical resection is contraindicated, current neurostimulation strategies such as deep brain stimulation and vagal nerve stimulation can palliate the frequency or severity of seizures. However, despite medical and neuromodulatory therapy, a significant proportion of patients continue to experienc...
Context in source publication
Context 1
... have proposed numerous nodes within the con- sciousness network that may be investigated to modulate level of consciousness in the context of epilepsy (Fig. 2). Many of these areas have been targeted for indications other than improving consciousness; therefore, levels of arousal and cognitive function have been only second- arily evaluated (Table 1). The ethical aspect of DBS use for improving consciousness is prevalent in the literature about traumatic brain injury; although outside the ...
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Citations
... Building upon this, we further hypothesize that disruption to this critical network connection may impair awareness during seizures originating from temporal lobe structures through its interaction with motor-related cortical areas (cingulate cortex) and the thalamus. We therefore support the viewpoint that while the claustrum can influence the consciousness "master switch" of a brainstem and diencephalic origin, it is not the master switch itself (Blumenfeld, 2014;Gummadavelli et al., 2015). ...
The function of the claustrum and its role in neurological disorders remains a subject of interest in the field of neurology. Given the claustrum's susceptibility to seizure-induced damage, there is speculation that it could serve as a node in a dysfunctional epileptic network. This perspective article aims to address a pivotal question: Does the claustrum play a role in epilepsy? Building upon existing literature, we propose the following hypotheses for the involvement of the claustrum in epilepsy: (1) Bilateral T2/FLAIR magnetic resonance imaging (MRI) hyperintensity of the claustrum after status epilepticus represents a radiological phenomenon that signifies inflammation-related epileptogenesis; (2) The ventral claustrum is synonymous with a brain area known as 'area tempestas,' an established epileptogenic center; (3) The ventral subsector of the claustrum facilitates seizure generalization/propagation through its connections with limbic and motor-related brain structures; (4) Disruption of claustrum connections during seizures might contribute to the loss of consciousness observed in impaired awareness seizures; (5) Targeting the claustrum therapeutically could be advantageous in seizures that arise from limbic foci. Together, evidence from both clinical case reports and animal studies identify a significant role for the ventral claustrum in the generation, propagation, and intractable nature of seizures in a subset of epilepsy syndromes.
... It is therefore puzzling that limbic seizures typically are associated with impairment or even loss of consciousness (Englot et al., 2010). While we indeed consistently saw an increased release of noradrenaline in the hippocampus, it is very possible that noradrenergic transmission decreases in other areas relevant to consciousness (Gummadavelli et al., 2015) or that other mechanisms than release of noradrenaline in relation to seizure mediate impaired consciousness associated with limbic seizures. ...
... In fact, modulation of arousal in humans has been investigated using deep brain stimulation (DBS) techniques. However, these case-series were largely performed in cohorts with impaired consciousness, such as in patients with severe traumatic brain injury or stroke, and thus outcome measures were restricted to gross behavioral observations [25][26][27]. In addition, anatomical targets to-date have been limited to structures long identified as playing a role in sleep/wake regulation, including the pedunculopontine nucleus (PPN), medial thalamus, basal forebrain, and hypothalamus, with variable success. ...
... Our findings extend prior deep-brain stimulation studies in humans indicating that arousal level can be modulated with direct neural stimulation [25][26][27] by expanding both the patient population and the target selection. Given that our study is performed in participants without significant neural injury or neurodegeneration, the participants were able to articulate their experiences and provide more sensitive outcome measures of sleepiness and energy to facilitate comparison between different stimulation targets. ...
Background:
Humans routinely shift their sleepiness and wakefulness levels in response to emotional factors. The diversity of emotional factors that modulates sleep-wake levels suggests that the ascending arousal network may be intimately linked with networks that mediate mood. Indeed, while animal studies have identified select limbic structures that play a role in sleep-wake regulation, the breadth of corticolimbic structures that directly modulates arousal in humans remains unknown.
Objective:
We investigated whether select regional activation of the corticolimbic network through direct electrical stimulation can modulate sleep-wake levels in humans, as measured by subjective experience and behavior.
Methods:
We performed intensive inpatient stimulation mapping in two human participants with treatment resistant depression, who underwent intracranial implantation with multi-site, bilateral depth electrodes. Stimulation responses of sleep-wake levels were measured by subjective surveys (i.e. Stanford Sleepiness Scale and visual-analog scale of energy) and a behavioral arousal score. Biomarker analyses of sleep-wake levels were performed by assessing spectral power features of resting-state electrophysiology.
Results:
Our findings demonstrated three regions whereby direct stimulation modulated arousal, including the orbitofrontal cortex (OFC), subgenual cingulate (SGC), and, most robustly, ventral capsule (VC). Modulation of sleep-wake levels was frequency-specific: 100Hz OFC, SGC, and VC stimulation promoted wakefulness, whereas 1Hz OFC stimulation increased sleepiness. Sleep-wake levels were correlated with gamma activity across broad brain regions.
Conclusions:
Our findings provide evidence for the overlapping circuitry between arousal and mood regulation in humans. Furthermore, our findings open the door to new treatment targets and the consideration of therapeutic neurostimulation for sleep-wake disorders.
... It is therefore puzzling that limbic seizures typically are associated with impairment or even loss of consciousness (Englot et al., 2010). While we indeed consistently saw an increased release of noradrenaline in the hippocampus, it is very possible that noradrenergic transmission decreases in other areas relevant to consciousness (Gummadavelli et al., 2015) or that other mechanisms than release of noradrenaline in relation to seizure mediate impaired consciousness associated with limbic seizures. ...
The locus coeruleus (LC), a brainstem nucleus, is the sole source of noradrenaline in the neocortex, hippocampus and cerebellum. Noradrenaline is a powerful neuromodulator involved in the regulation of excitability and plasticity of large-scale brain networks. In this study, we assessed the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures evoked with perforant path stimulation. LC neurons were recorded in anesthetized rats using a multichannel electrophysiology probe and were identified based on electrophysiological characteristics or optogenetic tagging. The majority of LC neurons (55%) were inhibited during seizures, while only a subset of LC neurons (28%) was excited during seizures. Topographic analysis of multi-unit activity showed anatomical separation of neurons that were excited and inhibited during seizures. Changes in hippocampal noradrenaline transmission during seizures were assessed using a fluorescent biosensor for noradrenaline, GRABNE2m, in combination with fiber photometry in both anesthetized and awake rats. Our results indicate that acute electrically evoked hippocampal seizures are associated with strong changes in LC unit activity and strong and consistent time-locked release of noradrenaline. Understanding the role of mass release of noradrenaline during hippocampal seizures is likely to be important to understand seizure pathophysiology.
... 14 In both human trials and rat experimentations of epilepsy, stimulation of arousal regions such as the brainstem, basal forebrain, thalamus, and posterior hypothalamus (pHTH) led to increased arousal and activity, improvement in cognitive tasks, or reduced seizure frequency. 15 Of all these regions, the pHTH and NBM are two important subcortical arousal regions that have not been extensively studied in people with mTLE. ...
Objective:
This study sought to characterize resting-state functional MRI (fMRI) connectivity patterns of the posterior hypothalamus (pHTH) and the nucleus basalis of Meynert (NBM) in surgical patients with mesial temporal lobe epilepsy (mTLE), and to investigate potential correlations between functional connectivity of these arousal regions and neurocognitive performance.
Methods:
The study evaluated resting-state fMRI in 60 patients with preoperative mTLE and in 95 healthy controls. The authors first conducted voxel-wise connectivity analyses seeded from the pHTH, combined anterior and tuberal hypothalamus (atHTH; i.e., the rest of the hypothalamus), and the NBM ipsilateral (ipsiNBM) and contralateral (contraNBM) to the epileptogenic zone. Based on these results, the authors included the pHTH, ipsiNBM, and frontoparietal neocortex in a network-based statistic (NBS) analysis to elucidate a network that best distinguishes patients from controls. The connections involving the pHTH and ipsiNBM from this network were included in age-corrected pairwise region of interest (ROI) analysis, along with connections between arousal structures, including the pHTH, ipsiNBM, and brainstem arousal regions. Finally, patient functional connectivity was correlated with clinical neurocognitive testing scores for IQ as well as attention and concentration tests.
Results:
The voxel-wise analysis demonstrated that the pHTH, when compared with the atHTH, showed more widespread functional connectivity decreases in surgical mTLE patients when compared with controls. It was also observed that the ipsiNBM, but not the contraNBM, showed decreased functional connectivity in mTLE. The NBS analysis uncovered a perturbed network of frontoparietal regions, the pHTH, and ipsiNBM that distinguishes patients from controls. Age-corrected ROI analysis revealed functional connectivity decreases between the pHTH and bilateral superior frontal gyri, medial orbitofrontal cortices, rostral anterior cingulate cortices, and inferior parietal cortices in mTLE when compared with controls. For the ipsiNBM, there was reduced connectivity with bilateral medial orbitofrontal and rostral anterior cingulate cortices. Age-corrected ROI analysis also demonstrated upstream connectivity decreases from controls between the pHTH and the brainstem arousal regions, cuneiform/subcuneiform (CSC) nuclei, and ventral tegmental area, as well as the ipsiNBM and CSC nuclei. Reduced functional connectivity was also detected between the pHTH and ipsiNBM. Lastly, neurocognitive test scores for attention and concentration were found to be positively correlated with the functional connectivity between the pHTH and ipsiNBM, suggesting worse performance associated with connectivity perturbations.
Conclusions:
This study demonstrated perturbed resting-state functional connectivity of arousal regions in surgical mTLE and is one of the first investigations to demonstrate decreased functional connectivity of the pHTH with frontoparietal regions and other arousal regions. Connectivity disturbances in arousal regions may contribute to neurocognitive deficits in surgical mTLE patients.
... Similarly, in non-human primates, electrical stimulation of the intralaminar nuclei reversed propofolinduced unconsciousness, with concomitant reversal of electrophysiologic features of anesthesia [162]. These results suggest that, in addition to modulating seizures themselves, stimulation may be used palliatively to avert the debilitating loss of awareness in patients with seizures that impair consciousness [163]. ...
Introduction
Epilepsy is a common, often debilitating disease of hyperexcitable neural networks. While medically intractable cases may benefit from surgery, there may be no single, well-localized focus for resection or ablation. In such cases, approaching the disease from a network-based perspective may be beneficial.
Areas covered
Herein, the authors provide a narrative review of normal thalamic anatomy and physiology and propose general strategies for preventing and/or aborting seizures by modulating this structure. Additionally, they make specific recommendations for targeting the thalamus within different contexts, motivated by a more detailed discussion of its distinct nuclei and their respective connectivity. By describing important principles governing thalamic function and its involvement in seizure networks, the authors aim to provide a primer for those now entering this fast-growing field of thalamic neuromodulation for epilepsy.
Expert opinion
The thalamus is critically involved with the function of many cortical and subcortical areas, suggesting it may serve as a compelling node for preventing or aborting seizures, and so it has increasingly been targeted for the surgical treatment of epilepsy. As various thalamic neuromodulation strategies for seizure control are developed, there is a need to ground such interventions in a mechanistic, circuit-based framework.
... In principle, EEG measured during high vs low arousal, valence, and mental load, should elicit different EEG signatures (e.g., synchronization/desynchronization and corresponding increases/decreases in amplitude/power), as the mental states require differing levels of emotional or cognitive resources [76][77][78][79][80][81][82]. This would be expected from a researchgrade EEG device like Brainvision. ...
In the last decade there has been significant growth in the interest and application of using EEG (electroencephalography) outside of laboratory as well as in medical and clinical settings, for more ecological and mobile applications. However, for now such applications have mainly included military, educational, cognitive enhancement, and consumer-based games. Given the monetary and ecological advantages, consumer-grade EEG devices such as the Emotiv EPOC have emerged, however consumer-grade devices make certain compromises of data quality in order to become affordable and easy to use. The goal of this study was to investigate the reliability and accuracy of EPOC as compared to a research-grade device, Brainvision. To this end, we collected data from participants using both devices during three distinct cognitive tasks designed to elicit changes in arousal, valence, and cognitive load: namely, Affective Norms for English Words, International Affective Picture System, and the n-Back task. Our design and analytical strategies followed an ideographic person-level approach (electrode-wise analysis of vincentized repeated measures). We aimed to assess how well the Emotiv could differentiate between mental states using an Event-Related Band Power approach and EEG features such as amplitude and power, as compared to Brainvision. The Emotiv device was able to differentiate mental states during these tasks to some degree, however it was generally poorer than Brainvision, with smaller effect sizes. The Emotiv may be used with reasonable reliability and accuracy in ecological settings and in some clinical contexts (for example, for training professionals), however Brainvision or other, equivalent research-grade devices are still recommended for laboratory or medical based applications.
... Despite the variability in clinical results, the preclinical evidence for enhancing arousal and behavioral performance in intact animals during electrical stimulation of CL is more extensive 20 . Recent studies confirm that electrical stimulation of CL can effectively enhance arousal 21 and performance [22][23][24][25][26] in healthy rodents and in two rodent models of pathology, epilepsy [27][28][29][30] and TBI 31 . In anesthetized animals, optogenetic stimulation of CL in mice 32 and electrical stimulation of CL in rodents 26 and non-human primates (NHP) 33,34 demonstrate broad cortical and subcortical activations. ...
Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel ‘field-shaping’ methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.
... Neurostimulation targeted at subcortical arousal structures could be used to restore arousal and consciousness in the ictal and postictal periods. 38,39 Although the primary goal of epilepsy treatment is to stop seizures, current treatments do not work in all patients. Medications, surgical resection, or neurostimulation are often effective; however, given the large number of people living with epilepsy, this leaves a substantial population who have continued focal seizures with impaired consciousness. ...
Impaired consciousness during seizures severely affects quality of life for people with epilepsy but the mechanisms are just beginning to be understood. Consciousness is thought to involve large-scale brain networks, so it is puzzling that focal seizures often impair consciousness. Recent work investigating focal temporal lobe or limbic seizures in human patients and experimental animal models suggests that impaired consciousness is caused by active inhibition of subcortical arousal mechanisms. Focal limbic seizures exhibit decreased neuronal firing in brainstem, basal forebrain, and thalamic arousal networks, and cortical arousal can be restored when subcortical arousal circuits are stimulated during seizures. These findings open the possibility of restoring arousal and consciousness therapeutically during and following seizures by thalamic neurostimulation. When seizures cannot be stopped by existing treatments, targeted subcortical stimulation may improve arousal and consciousness, leading to improved safety and better psychosocial function for people with epilepsy.
... [6][7][8] A landmark trial demonstrated that deep brain stimulation (DBS) of the intralaminar central lateral thalamus improved function in a minimally conscious individual, 9 setting the stage for further investigation of this treatment modality to improve arousal and cognition. [10][11][12][13] Neurostimulation of the same region in nonhuman primates recently demonstrated behavioral arousal effects as well as increased neuronal firing in cortical circuits. 14 However, the physiological effects of intralaminar thalamic stimulation on cortical circuit function in humans requires further study. ...
... 16 Recent investigations using computational analysis methods have shed important light on the general relationship between cortical electroencephalographic (EEG) signals and neuronal activity underlying attention and arousal. A characteristic EEG pattern has been observed, with increases in broadband gamma , decreases in alpha (8)(9)(10)(11)(12)(13), and lesser increases in delta (1-4 Hz) frequency power seen in diverse conditions signifying overall increases in cortical population neuronal firing, arousal, and attention. [21][22][23][24][25] We therefore sought, using computational analysis methods and scalp EEG, to determine whether this characteristic neurophysiological pattern of cortical activation seen in attention and arousal is associated with therapeutic 130-Hz stimulation of the thalamic intralaminar CM nucleus. ...
... Gamma (25-100 Hz) power showed clear increases across a broad frequency range that progressively increased with stimulation voltage from 0 to 5 V. Meanwhile, alpha (8)(9)(10)(11)(12)(13)(14) and theta (4-7 Hz) power appeared to progressively decrease with increasing stimulus voltage, although the most prominent changes occurred at 4 V rather than 5 V ( Figure 2B). All stimulation power spectra crossed over the baseline (0 V) power spectrum at around 20 Hz, which explains the little observed changes in the beta (14-24 Hz) frequency band. ...
Objective
The intralaminar thalamus is well implicated in the processes of arousal and attention. Stimulation of the intralaminar thalamus has been used therapeutically to improve level of alertness in minimally conscious individuals and to reduce seizures in refractory epilepsy, both presumably through modulation of thalamocortical function. Little work exists that directly measures the effects of intralaminar thalamic stimulation on cortical physiological arousal in humans. Therefore, our goal was to quantify cortical physiological arousal in individuals with epilepsy receiving thalamic intralaminar deep brain stimulation.
Methods
We recorded scalp electroencephalogram (EEG) during thalamic intralaminar centromedian (CM) nucleus stimulation in 11 patients with medically refractory epilepsy. Participants underwent stimulation at 130 Hz and 300 µs for periods of 5 min alternating with 5 min of rest while stimulus voltage was titrated upward from 1 to 5 V. EEG signal power was analyzed in different frequency ranges in relation to stimulus strength and time.
Results
We found a progressive increase in broadband gamma (25–100 Hz) cortical EEG power (F = 7.64, p < .05) and decrease in alpha (8–13 Hz) power (F = 4.37, p < .05) with thalamic CM stimulation. Topographic maps showed these changes to be widely distributed across the cortical surface rather than localized to one region.
Significance
Previous work has shown that broadband increases in gamma frequency power and decreases in alpha frequency power are generally associated with states of cortical activation and increased arousal/attention. Our observed changes therefore support the possible role of cortical activation and increased physiological arousal in therapeutic effects of intralaminar thalamic stimulation for improving both epilepsy and attention. Further investigations with this approach may lead to methods for determining optimal deep brain stimulation parameters to improve clinical outcome in these disorders.
