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Disorders of consciousness (DoC) are states of impaired arousal or awareness. Deep brain stimulation (DBS) is a potential treatment, but outcomes vary, possibly due to differences in patient characteristics, electrode placement, or stimulation of specific brain networks. We studied 40 patients with DoC who underwent DBS targeting the thalamic centromedian-parafascicular complex. Better-preserved gray matter, especially in the striatum, correlated with consciousness improvement. Stimulation was most effective when electric fields extended into parafascicular and subparafascicular nuclei-ventral to the centromedian nucleus, near the midbrain-and when it engaged projection pathways of the ascending arousal network, including the hypothalamus, brainstem, and frontal lobe. Moreover, effective DBS sites were connected to networks similar to those underlying impaired consciousness due to generalized absence seizures and acquired lesions. These findings support the therapeutic potential of DBS for DoC, emphasizing the importance of precise targeting and revealing a broader link between effective DoC treatment and mechanisms underlying other conscciousness-impairing conditions., Competing Interests: COMPETING INTERESTS AELW, MR, HF, FLWVJS, JT, SBS, JL, MMJC, KB, MUF, RJ, JEI, PWC, DF, ADB, BLE, and DC have no competing interests to report. MDF has intellectual property on the use of brain connectivity imaging to analyze lesions and guide brain stimulation, has consulted for Magnus Medical, Soterix, Abbott, Boston Scientific, and Tal Medical, and has received research funding from Neuronetics. AH reports lecture fees for Boston Scientific and is a consultant for Neuromodulation and Abbott. JDR has received past consulting payments from Medtronic, Corlieve, ClearPoint, Medtronic, and NeuroPace, and currently consults for Turing Medical.

The centromedian (CM) and anterior nucleus of the thalamus (ANT) are deep brain stimulation (DBS) targets for management of generalized, and focal drug resistant epilepsy (DRE), respectively. We report on a single center retrospective case series of 16 children and adults with DRE who underwent CM with simultaneous ANT (69 %) or CM without simultaneous ANT DBS (31 %). Seizure frequency, epilepsy severity, life satisfaction, and quality of sleep before and after DBS were compared. Baseline median seizure frequency was 323 seizures per month (IQR, 71-563 sz/mo). Median follow up time was 80 months (IQR 37-97 mo). Median seizure frequency reduction was 58 % (IQR 13-87 %, p = 0.002). Ten patients (63 %) reported ≥50 % seizure frequency reduction. Median seizure frequency reduction and responder rate were not significantly different for CM + ANT versus CM only. Seizure severity and life satisfaction were significantly improved. Three patients (19 %) developed device-related side effects, 2 of them (12.5 %) required surgical intervention. In a heterogenous population of children and adults with generalized, multifocal, posterior onset, and poorly localized DRE, CM with or without ANT DBS is feasible, relatively safe and is associated with reduced seizure frequency and severity, as well as improved life satisfaction. [ABSTRACT FROM AUTHOR]

• Very high frequency oscillations in the thalamus are not produced in the ventral caudate nucleus only. • High frequency oscillations in the ventral caudate nucleus reflect the synapses of thalamic neurons. • High frequency oscillations can be a specific landmark for sensory thalamus in anaesthetized patients. During deep brain stimulation (DBS) surgery, we analysed somatosensory evoked potentials (SSEPs) using microelectrode recordings (MERs) in patients under general anaesthesia. We obtained MERs from 5 patients with refractory epilepsy. Off-line analysis isolated local field potentials (LFPs, 2–200 Hz) and high frequency components (HFCs, 0.5–5 kHz). Trajectories were reconstructed off-line. The ventral caudate (V.c.) nucleus was most frequently recorded from (171 mm). Very high frequency oscillations (VHFOs) were recorded up to 8 mm in length from all 4 electrodes but were most frequently recorded from the V.c. The properties of VHFOs were similar among all nuclei (frequency >1500 Hz, amplitude ∼3 µV, starting time ∼14 ms, duration 8–9 ms). Consecutive recordings did not show any synchronization or propagation, but a new kind of potential (high frequency oscillation, HFO) appeared abruptly inside the V.c. (frequency = 848 ± 66 Hz, amplitude = 5.2 ± 1.8 µV starting at 17.7 ± 0.5 ms, spanning 3.4 ± 0.3 ms). VHFOs are widely extending and cannot be ascribed to the V.c. HFOs in patients under general anaesthesia can serve as a landmark to identify the V.c. in thalamic DBS surgery. Thalamic processing involves nuclei other than the V.c, and HFO can be used to improve DBS surgery. [ABSTRACT FROM AUTHOR]

Seizures have traditionally been considered hypersynchronous excitatory events and epilepsy has been separated into focal and generalized epilepsy based largely on the spatial distribution of brain regions involved at seizure onset. Epilepsy, however, is increasingly recognized as a complex network disorder that may be distributed and dynamic. Responsive neurostimulation (RNS) is a recent technology that utilizes intracranial electroencephalography (EEG) to detect seizures and delivers stimulation to cortical and subcortical brain structures for seizure control. RNS has particular significance in the clinical treatment of medically refractory epilepsy and brain–computer interfaces in epilepsy. Closed loop RNS represents an important step forward to understand and target nodes in the seizure network. The thalamus is a central network node within several functional networks and regulates input to the cortex; clinically, several thalamic nuclei are safe and feasible targets. We highlight the network theory of epilepsy, potential targets for neuromodulation in epilepsy and the first reported use of RNS as a first generation brain–computer interface to detect and stimulate the centromedian intralaminar thalamic nucleus in a patient with bilateral cortical onset of seizures. We propose that advances in network analysis and neuromodulatory techniques using brain–computer interfaces will significantly improve outcomes in patients with epilepsy. There are numerous avenues of future direction in brain–computer interface devices including multi-modal sensors, flexible electrode arrays, multi-site targeting, and wireless communication.

Seizures have traditionally been considered hypersynchronous excitatory events and epilepsy has been separated into focal and generalized epilepsy based largely on the spatial distribution of brain regions involved at seizure onset. Epilepsy, however, is increasingly recognized as a complex network disorder that may be distributed and dynamic. Responsive neurostimulation (RNS) is a recent technology that utilizes intracranial electroencephalography (EEG) to detect seizures and delivers stimulation to cortical and subcortical brain structures for seizure control. RNS has particular significance in the clinical treatment of medically refractory epilepsy and brain–computer interfaces in epilepsy. Closed loop RNS represents an important step forward to understand and target nodes in the seizure network. The thalamus is a central network node within several functional networks and regulates input to the cortex; clinically, several thalamic nuclei are safe and feasible targets. We highlight the network theory of epilepsy, potential targets for neuromodulation in epilepsy and the first reported use of RNS as a first generation brain–computer interface to detect and stimulate the centromedian intralaminar thalamic nucleus in a patient with bilateral cortical onset of seizures. We propose that advances in network analysis and neuromodulatory techniques using brain–computer interfaces will significantly improve outcomes in patients with epilepsy. There are numerous avenues of future direction in brain–computer interface devices including multi-modal sensors, flexible electrode arrays, multi-site targeting, and wireless communication. [ABSTRACT FROM AUTHOR]

T-type calcium channels (Ca3) are key mediators of thalamic bursting activity, but also regulate single cells excitability, dendritic integration, synaptic strength and transmitter release. These functions are strongly influenced by the subcellular and subsynaptic localization of Ca3 channels along the somatodendritic domain of thalamic cells. In Parkinson's disease, T-type calcium channels dysfunction in the basal ganglia-receiving thalamic nuclei likely contributes to pathological thalamic bursting activity. In this study, we analyzed the cellular, subcellular, and subsynaptic localization of the Ca3.1 channel in the ventral anterior (VA) and centromedian/parafascicular (CM/Pf) thalamic nuclei, the main thalamic targets of basal ganglia output, in normal and parkinsonian monkeys. All thalamic nuclei displayed strong Ca3.1 neuropil immunoreactivity, although the intensity of immunolabeling in CM/Pf was significantly lower than in VA. Ultrastructurally, 70-80 % of the Ca3.1-immunoreactive structures were dendritic shafts. Using immunogold labeling, Ca3.1 was commonly found perisynaptic to asymmetric and symmetric axo-dendritic synapses, suggesting a role of Ca3.1 in regulating excitatory and inhibitory neurotransmission. Significant labeling was also found at non-synaptic sites along the plasma membrane of thalamic neurons. There was no difference in the overall pattern and intensity of immunostaining between normal and parkinsonian monkeys, suggesting that the increased rebound bursting in the parkinsonian state is not driven by changes in Ca3.1 expression. Thus, T-type calcium channels are located to subserve neuronal bursting, but also regulate glutamatergic and non-glutamatergic transmission along the whole somatodendritic domain of basal ganglia-receiving neurons of the primate thalamus. [ABSTRACT FROM AUTHOR]

In light of postmortem human studies showing extensive degeneration of the center median (CM) and parafascicular (Pf) thalamic nuclei in Parkinson's disease patients, the present study assessed the extent of neuronal loss in CM/Pf of non-human primates that were rendered parkinsonian by repeated injections of low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to determine the course of CM/Pf degeneration during the MPTP intoxication, motor-asymptomatic animals with partial striatal dopamine denervation were also used. The Cavalieri's principle for volume estimation and the unbiased stereological cell count method with the optical dissector technique were used to estimate the total number of neurons in the CM/Pf. We found substantial neurons loss in the CM/Pf in both, motor-symptomatic MPTP-treated monkeys in which the striatal dopamine innervation was reduced by more than 80 %, and in motor-asymptomatic MPTP-treated animals with 40-50 % striatal dopamine loss. In MPTP-treated parkinsonian monkeys, 60 and 62 % neurons loss was found in CM and Pf, respectively, while partially dopamine-depleted asymptomatic animals displayed 59 and 52 % neurons loss in the CM and Pf, respectively. Thus, our study demonstrates that the CM/Pf neurons loss is an early phenomenon that occurs prior to the development of parkinsonian motor symptoms in these animals. In contrast, the neighboring mediodorsal nucleus of the thalamus was only mildly affected (18 % neurons loss) in the parkinsonian monkeys. Together with recent findings about the possible role of the CM/Pf-striatal system in cognition, our findings suggest that the pathology of the thalamostriatal system may precede the development of motor symptoms in PD, and may account for some of the cognitive deficits in attentional set-shifting often seen in these patients. Future studies in this animal model, and in monkeys with selective lesion of CM or Pf, are needed to further elucidate the role of the CM/Pf-striatal system in normal and parkinsonian conditions. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome. Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS. Methods: The combination of DBS and functional magnetic resonance imaging is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. With a within-subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n = 5). Results: Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS. Conclusions: Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of Tourette syndrome as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms. [Copyright &y& Elsevier]

Purpose Deep brain stimulation ( DBS) of the thalamus is an emerging surgical option for people with medically refractory epilepsy that is not suitable for resective surgery, or in whom surgery has failed. Our main aim was to evaluate the efficacy of bilateral centromedian thalamic nucleus ( CMN) DBS for seizure control in generalized epilepsy and frontal lobe epilepsy with a two-center, single-blind, controlled trial. Methods Participants were adults with refractory generalized or frontal lobe epilepsy. Seizure diaries were kept by patients/carers prospectively from enrollment. The baseline preimplantation period was followed by a control period consisting of a blind stimulation- OFF phase of at least 3 months, a 3-month blind stimulation- ON phase, and a 6-month unblinded stimulation- ON phase. The control period was followed by an unblinded long-term extension phase with stimulation- ON in those patients in whom stimulation was thought to be effective. Key Findings Eleven patients were recruited at King's College Hospital (London, United Kingdom United Kingdom) and at University Hospital La Princesa (Madrid, Spain). Among the five patients with frontal lobe epilepsy, only one patient had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, two patients with frontal lobe epilepsy had >50% improvement in seizure frequency. All six patients with generalized epilepsy had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, five of the six patients showed >50% improvement in the frequency of major seizures (one became seizure free, one had >99% improvement, and three had 60-95% reduction in seizure frequency). Among patients with generalized epilepsy, the DBS implantation itself appears to be effective, as two patients remained seizure free during 12 and 50 months with DBS OFF, and the remaining four had 50-91% improvement in the initial 3 months with DBS OFF. Significance DBS implantation and stimulation of the CMN appears to be a safe and efficacious treatment, particularly in patients with refractory generalized epilepsy. CMN stimulation was not as effective in frontal lobe epilepsy, which requires further studies. DBS of the CMN should be considered as a treatment option, particularly in patients with refractory generalized epilepsy syndromes. [ABSTRACT FROM AUTHOR]

Abstract: Neuronal loss in Parkinson''s Disease (PD) is seen in a number of brain regions in addition to the substantia nigra (SN). Among these is the thalamic parafascicular nucleus (PF), which sends glutamatergic projections to the striatum and receives GABAergic inputs from the SN. Recent data suggest that lesions of nigrostriatal dopamine axons cause a loss of PF neurons, which has been interpreted to suggest that the PF cell loss seen in PD is secondary to dopamine denervation. However, the extent of a PF dopamine innervation in the rat is unclear, and it is possible that PF cell loss in parkinsonism is independent of nigrostriatal dopamine degeneration. We characterized the dopamine innervation of the PF in the rat and determined if 6-hydroxydopamine SN lesions cause PF neuron degeneration. Dual-label immunohistochemistry revealed that almost all tyrosine hydroxylase-immunoreactive (TH-ir) axons in the PF also expressed dopamine-beta-hydroxylase and were therefore noradrenergic or adrenergic. Moreover, an antibody directed against dopamine revealed only very rare PF dopaminergic axons. Retrograde-tract tracing—immunohistochemistry did not uncover an innervation of the PF from midbrain dopamine neurons. Nigrostriatal dopamine neuron lesions did not elicit degeneration of PF cells, as reflected by a lack of FluoroJade C staining. Similarly, neither unilateral 6-OHDA lesions of nigrostriatal axons nor the dorsal noradrenergic bundle decreased the number of PF neurons or the number of PF neurons retrogradely-labeled from the striatum. These data suggest that the loss of thalamostriatal PF neurons in Parkinson''s Disease is a primary event rather than secondary to nigrostriatal dopamine degeneration. [Copyright &y& Elsevier]

Abstract: The striatum receives glutamatergic inputs from two main thalamostriatal systems that originate either from the centromedian/parafascicular complex (CM/PF-striatal system) or the rostral intralaminar, midline, associative and relay thalamic nuclei (non-CM/PF-striatal system). These dual thalamostriatal systems display striking differences in their anatomical and, most likely, functional organization. The CM/PF-striatal system is topographically organized, and integrated within functionally segregated basal ganglia–thalamostriatal circuits that process sensorimotor, associative and limbic information. CM/PF neurons are highly responsive to attention-related sensory stimuli, suggesting that the CM/PF-striatal system, through its strong connections with cholinergic interneurons, may play a role in basal ganglia-mediated learning, behavioral switching and reinforcement. In light of evidence for prominent CM/PF neuronal loss in Parkinson’s disease, we propose that the significant CM-striatal system degeneration, combined with the severe nigrostriatal dopamine loss in sensorimotor striatal regions, may alter normal automatic actions, and shift the processing of basal ganglia–thalamocortical motor programs towards goal-directed behaviors. [Copyright &y& Elsevier]

Abstract: The centromedian (CM)–parafascicular (PF) nuclear complex in the primate thalamus has reciprocal and specific connections with the basal ganglia. It has been argued that the thalamic CM–PF complex has a role in pain processing and attention. However, the functional relationship of this complex with the basal ganglia, which is considered to have a role in goal-directed movement, has not been well characterized. Here we present a hypothetical view that the thalamic CM–PF complex–basal ganglia circuit plays complementary roles in response bias. The basal ganglia are involved in creating ‘reward-based pre-action bias’, which facilitates the selection and execution of an action associated with a higher value. In contrast, when an action with a lower value is unexpectedly requested, the CM–PF induces an ‘externally driven rebiasing’ process in the striatum that aborts the pre-action bias and assists selecting and executing actions appropriate for unexpected situations. This model provides a framework for how the thalamic CM–PF complex and the basal ganglia function together in general for unexpected situations. [Copyright &y& Elsevier]

The reactions of neurons of the centromedian, mediodorsal, and posterior lateral nuclei of the thalamus to electrostimulation of its reticular nucleus were studied in experiments on anesthetized cats. A high reactivity of neurons of the centromedian (53.7%) and mediodorsal (48.3%) nuclei in comparison with the posterior lateral (10%) was established. 'Silent' neurons reacted by an excitatory type of reaction having a phasic chamber. Primary and secondary inhibitory reactions were noted among the spontaneously active neurons. The latent period of the excitatory reactions of the neurons of the centromedian nucleus varied from 5 to 33.6 msec (14.83±1.77 msec) and of the mediodorsal nucleus from 3.5 to 44.8 msec (18.03±2.5 msec). A high degree of convergence of reticular and somatovisceral signals on neurons of the centromedian nucleus (52.83%) and mediodorsal nucleus (53.5%) was found. An inhibitory type of interaction of central and peripheral influences was established. [ABSTRACT FROM AUTHOR]

Background: Neuropathic dental pain (NDP) is a chronic pain condition that is notoriously difficult to treat. To date, there are no deep brain stimulation (DBS) studies on this specific pain condition and no optimal target or "sweet spot" has ever been defined., Objective: To determine the optimal thalamic target for improving this condition by utilizing the steering abilities of a directional DBS electrode (Vercise CartesiaTM Model DB-2202-45, Boston Scientific)., Methods: A literature search and review of our database identified 3 potential thalamic targets. A directional lead was implanted in a patient with NDP and its current steering used to test the effects in each nucleus. The patient reported her pain after 2 wk of stimulation in a prospective randomized blinded trial of one. Quality of life measurements were performed before and after 3 mo on their best setting., Results: We identified 3 potential nuclei: the centromedian (CM), ventral posterior medial (VPM), and anterior pulvinar. The best results were during VPM stimulation (>90% reduction in pain) and CM stimulation (50% reduction). Following 3 mo of VPM-DBS in combination of lateral CM stimulation, their pain disability index dropped (from 25 to 0) and short form 36 improved (from 67.5 to 90)., Conclusion: VPM stimulation in combination with CM stimulation is a promising target for NDP. DBS electrode directionality can be used to test multiple targets and select a patient specific "sweet spot" for NDP treatment., (© Congress of Neurological Surgeons 2021.)