CM-Pf deep brain stimulation in polyneuromodulation for epilepsy.

OBJECTIVE: Neuromodulation is a viable option for patients with drug-resistant epilepsies. We reviewed the management of patients with two deep brain neurostimulators. In addition, patients implanted with a device targeting the centromedian-parafascicular (CM-Pf) nuclear complex supplements this report to provide an illustrative case to implantation and programming a patient with three active devices. METHODS: A narrative review using PubMed and Embase identified patients with drug-resistant epilepsy implanted with more than one neurostimulator was performed. Combinations of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) were identified. We provide a background of a newly reported case of an adult with a triple implant eventually responding to CM-Pf DBS as the third implant following suboptimal benefit from VNS and RNS. RESULTS: In review of the literature, dual-device therapy is increasing in reports of use with combinations of VNS, RNS, and DBS to treat patients with drug-resistant epilepsy. We review dual-device implants with thalamic DBS device combinations, functional neural networks, and programming patients with dual devices. CM-Pf is a new target for DBS and has shown a variable response in focal epilepsy. We report the unique case of 28-year-old male with drug-resistant focal epilepsy who experienced a 75% seizure reduction with CM-Pf DBS as his third device after suboptimal responses to VNS and RNS. After 9 months, he also experienced seizure freedom from recurrent focal to bilateral tonic-clonic seizures. No medical or surgical complications or safety issues were encountered. CONCLUSION: We demonstrate safety and feasibility in an adult combining active VNS, RNS, and CM-Pf DBS. Patients with dual-device therapy who experience a suboptimal response to initial device use at optimized settings should not be considered a neuromodulation "failure." Strategies to combine devices require a working knowledge of brain networks.

High-Frequency Stimulation of the Centromedian Thalamic Nucleus Aborts Seizures and Ictal Apnea.

SUMMARY: A 32-year-old right-handed woman presented with medically and surgically refractory left temporal neocortical epilepsy secondary to focal cortical dysplasia who underwent stereoelectroencephalography involving the centromedian nucleus of the thalamus. With the use of real-time stereoelectroencephalography monitoring, four electroclinical seizures were aborted by administering high-frequency stimulation at the centromedian nucleus at seizure onset. Seizures before stimulation were all associated with ictal apnea, while those with stimulation had no ictal apnea. This case demonstrates how providing high-frequency stimulation to the centromedian nucleus of the thalamus can abort electroclinical seizures and ictal apnea.

Propofol differentially induces unconsciousness and respiratory depression through distinct interactions between GABAA receptor and GABAergic neuron in corresponding nuclei.

Propofol is the most commonly used intravenous anesthetic worldwide. It can induce loss of consciousness prior to the occurrence of severe respiratory suppression, which is also a pharmacodynamic feature of all general anesthetics. However, the neural mechanisms underlying this natural phenomenon are controversial and highly related to patient safety. In the present study, we demonstrated that the pharmacodynamic effects of propofol (50 and 100 µM) on suppression of consciousness-related excitatory postsynaptic currents in the medial prefrontal cortex (mPFC) and centromedian nucleus of the thalamus (CMT) were lower than those in the kernel respiratory rhythmogenesis nucleus pre-Bötzinger complex (PrBo). Furthermore, we unexpectedly found that the GABAA receptor ß3 subunit is the key target for propofol's action and that it is mutually and exclusively expressed in GABAergic neurons. It is also more abundant in the mPFC and CMT, but mainly co-localized with GABAergic neurons in the PrBo. As a result, the differentiated expression pattern should mediate more neuron suppression through the activation of GABAergic neurons in the mPFC and CMT at low doses of propofol (50 µM). However, PrBo GABAergic neurons were only activated by propofol at a high dose (100 µM). These results highlight the detailed pharmacodynamic effects of propofol on consciousness-related and respiration-related nuclei and provide the distinct interaction mechanism between the ß3 subunit and GABAergic neurons in mediating the suppression of consciousness compared to the inhibition of respiration.

Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing.

Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et al., 2019). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)-, and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.

Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry.

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures. The anti-absence seizure drug ethosuximide blocks SWDs and rescues behavioral arrests and social memory impairment in the knockout mice. Restoring GABAergic transmission either by optogenetic activation of the thalamic reticular nucleus (nRT) presynaptic terminals or postsynaptic NLG2 expression in the thalamic neurons reduces the SWDs and behavioral arrests in the knockout mice. These results indicate that NLG2-mediated GABAergic transmission at the nRT-thalamic circuit represents a common mechanism underlying both epileptic seizures and ASD.

Differentiating tic electrophysiology from voluntary movement in the human thalamocortical circuit.

OBJECTIVES: Tourette syndrome is a neurodevelopmental disorder commonly associated with involuntary movements, or tics. We currently lack an ideal animal model for Tourette syndrome. In humans, clinical manifestation of tics cannot be captured via functional imaging due to motion artefacts and limited temporal resolution, and electrophysiological studies have been limited to the intraoperative environment. The goal of this study was to identify electrophysiological signals in the centromedian (CM) thalamic nucleus and primary motor (M1) cortex that differentiate tics from voluntary movements. METHODS: The data were collected as part of a larger National Institutes of Health-sponsored clinical trial. Four participants (two males, two females) underwent monthly clinical visits for collection of physiology for a total of 6 months. Participants were implanted with bilateral CM thalamic macroelectrodes and M1 subdural electrodes that were connected to two neurostimulators, both with sensing capabilities. MRI scans were performed preoperatively and CT scans postoperatively for localisation of electrodes. Electrophysiological recordings were collected at each visit from both the cortical and subcortical implants. RESULTS: Recordings collected from the CM thalamic nucleus revealed a low-frequency power (3-10 Hz) increase that was time-locked to the onset of involuntary tics but was not present during voluntary movements. Cortical recordings revealed beta power decrease in M1 that was present during tics and voluntary movements. CONCLUSION: We conclude that a human physiological signal was detected from the CM thalamus that differentiated tic from voluntary movement, and this physiological feature could potentially guide the development of neuromodulation therapies for Tourette syndrome that could use a closed-loop-based approach.

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy.

The precise circuit of the substantia nigra pars reticulata (SNr) involved in temporal lobe epilepsy (TLE) is still unclear. Here we found that optogenetic or chemogenetic activation of SNr parvalbumin+ (PV) GABAergic neurons amplifies seizure activities in kindling- and kainic acid-induced TLE models, whereas selective inhibition of these neurons alleviates seizure activities. The severity of seizures is bidirectionally regulated by optogenetic manipulation of SNr PV fibers projecting to the parafascicular nucleus (PF). Electrophysiology combined with rabies virus-assisted circuit mapping shows that SNr PV neurons directly project to and functionally inhibit posterior PF GABAergic neurons. Activity of these neurons also regulates seizure activity. Collectively, our results reveal that a long-range SNr-PF disinhibitory circuit participates in regulating seizure in TLE and inactivation of this circuit can alleviate severity of epileptic seizures. These findings provide a better understanding of pathological changes from a circuit perspective and suggest a possibility to precisely control epilepsy.

Deep brain stimulation of the thalamic centromedian-parafascicular nucleus improves behavioural and neuronal traits in a rat model of Tourette.

Deficient prepulse inhibition (PPI) of the acoustic startle reaction after injection of the dopamine receptor agonist apomorphine has been experimentally used to model certain aspects of Tourette syndrome (TS) in rats. Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) complex alleviates tics in patients with TS. The CM-Pf projects to striatal regions, which might mediate the effect of DBS via the cortico basal-ganglia circuitry implicated in the pathophysiology of TS. We tested the effect of CM-Pf DBS on apomorphine-induced deficient PPI and on striatal neuronal activity in rats. Electrodes were stereotaxically implanted bilaterally in the CM-Pf of adult male Sprague Dawley rats. Thereafter, rats were stimulated (150 µA and 130 Hz) or sham-stimulated (no application of current) to test the effect on apomorphine-induced deficient PPI (vehicle and 1.0 mg/kg). Additionally, the neuronal activity of the dorsomedial striatum (DMS) and the nucleus accumbens (NAC), as well as its coherence with the sensorimotor cortex (SM-Ctx) was recorded after apomorphine injection and CM-Pf DBS. CM-Pf DBS prevented the apomorphine-induced PPI-deficit. In striatal neurons apomorphine enhanced burst activity, as well as oscillatory theta band coherence with SM-Ctx electrocorticogram (SM-Ctx ECoG), which was reduced by CM-Pf DBS. Overall, the effect was stronger in the NAC than in the DMS. Modulation of neuronal activity in striatal regions may mediate the effects of CM-Pf DBS on PPI. This model may be used to test and improve novel neuro-modulation strategies.

A Central Amygdala Input to the Parafascicular Nucleus Controls Comorbid Pain in Depression.

While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABACeA) project to glutamatergic neurons in the parafascicular nucleus (GluPF). These GluPF neurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing. Enhanced inhibition of the GABACeA→GluPF→S2 pathway is found in mice exhibiting CP symptoms. Reversing this pathway using chemogenetic or optogenetic approaches alleviates CP symptoms. Together, the current study demonstrates the putative importance of the GABACeA→GluPF→S2 pathway in controlling at least some aspects of CP.

Thalamocortical disconnection affects the somatic marker and social cognition: a case report.

Thalamo-cortical connectivity was characterised in a patient with bilateral infarct of the thalami, without evidence of cognitive deficits in everyday life. Patient underwent social and emotional tests, Iowa Gambling Task (IGT), with and without concomitant heart rate variability (HRV) recording and at 3T-MRI to assess thalamo-cortical connectivity. Patient showed impairment at the IGT, in somatic marker, in emotions and theory of mind. MRI documented a bilateral damage of the centromedian-parafascicular complex. Patient's thalamic lesions disconnected brain areas involved in decision-making and autonomic regulation, affecting the somatic marker and resulting in the neuropsychological deficit exhibited by L.C.

The centromedian nucleus: Anatomy, physiology, and clinical implications.

Of all the truncothalamic nuclei, the centromedian-parafascicular nuclei complex (CM-Pf) is the largest and is considered the prototypic thalamic projection system. Located among the caudal intralaminar thalamic nuclei, the CM-Pf been described by Jones as "the forgotten components of the great loop of connections joining the cerebral cortex via the basal ganglia". The CM, located lateral relative to the Pf, is a major source of direct input to the striatum and also has connections to other, distinct region of the basal ganglia as well as the brainstem and cortex. Functionally, the CM participates in sensorimotor coordination, cognition (e.g. attention, arousal), and pain processing. The role of CM as 'gate control' function by propagating only salient stimuli during attention-demanding tasks has been proposed. Given its rich connectivity and diverse physiologic role, recent studies have explored the CM as potential target for neuromodulation therapy for Tourette syndrome, Parkinson's disease, generalized epilepsy, intractable neuropathic pain, and in restoring consciousness. This comprehensive review summarizes the structural and functional anatomy of the CM and its physiologic role with a focus on clinical implications.

Activation of noradrenergic terminals in the reticular thalamus delays arousal from propofol anesthesia in mice.

Electroencephalogram monitoring during propofol (PRO) anesthesia typically features low-frequency oscillations, which may be involved with thalamic reticular nucleus (TRN) modulation. TRN receives noradrenergic inputs from the locus coeruleus (LC). We hypothesized that specific noradrenergic connections in the TRN may contribute to the emergence from PRO anesthesia. Intranuclei norepinephrine (NE) injections (n = 10) and designer receptors exclusively activated by designer drugs (DREADDs) (n = 10) were used to investigate the role of noradrenergic inputs from the LC to the TRN during PRO anesthesia. Whole-cell recording in acute brain slice preparations was used to identify the type of adrenoceptor that regulates noradrenergic innervation in the TRN. An intracerebral injection of NE into the TRN delays arousal in mice recovering from PRO anesthesia (means ± sd; 486.6 ± 57.32 s for the NE injection group vs. 422.4 ± 48.19 s for the control group; P = 0.0143) and increases the cortical-δ (0.1-4 Hz, 25.4 ± 2.9 for the NE injection group vs. 21.0 ± 1.7 for the control group; P = 0.0094) oscillation. An intra-TRN injection of NE also decreased the EC50 of PRO-induced unconsciousness (57.05 ± 1.78 mg/kg for the NE injection group vs. 72.44 ± 3.23 mg/kg for the control group; P = 0.0096). Moreover, the activation of LC-noradrenergic nerve terminals in the TRN using DREADDs increased the recovery time [466.1 ± 44.57 s for the clozapine N-oxide (CNO) injection group vs. 426.1 ± 38.75 s for the control group; P = 0.0033], decreased the EC50 of PRO-induced unconsciousness (64.77 ± 3.40 mg/kg for the CNO injection group vs. 74.00 ± 2.08 mg/kg for the control group; P = 0.0081), and increased the cortical-δ oscillation during PRO anesthesia (23.29 ± 2.58 for the CNO injection group vs. 19.56 ± 1.9 for the control group; P = 0.0213). In addition, whole-cell recording revealed that NE augmented the inhibitory postsynaptic currents in the TRN neurons via the α1-adrenoceptor. Our data indicated that enhanced NE signaling at the noradrenergic terminals of the LC-TRN projection delays arousal from general anesthesia, which is likely mediated by the α1-adrenoceptor activation. Our findings open a door for further understanding of the functions of various LC targets in both anesthesia and arousal.-Zhang, Y., Fu, B., Liu, C., Yu, S., Luo, T., Zhang, L., Zhou, W., Yu, T. Activation of noradrenergic terminals in the reticular thalamus delays arousal from propofol anesthesia in mice.

Subcortical electrophysiological activity is detectable with high-density EEG source imaging.

Subcortical neuronal activity is highly relevant for mediating communication in large-scale brain networks. While electroencephalographic (EEG) recordings provide appropriate temporal resolution and coverage to study whole brain dynamics, the feasibility to detect subcortical signals is a matter of debate. Here, we investigate if scalp EEG can detect and correctly localize signals recorded with intracranial electrodes placed in the centromedial thalamus, and in the nucleus accumbens. Externalization of deep brain stimulation (DBS) electrodes, placed in these regions, provides the unique opportunity to record subcortical activity simultaneously with high-density (256 channel) scalp EEG. In three patients during rest with eyes closed, we found significant correlation between alpha envelopes derived from intracranial and EEG source reconstructed signals. Highest correlation was found for source signals in close proximity to the actual recording sites, given by the DBS electrode locations. Therefore, we present direct evidence that scalp EEG indeed can sense subcortical signals.

Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain Stimulation.

Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy and are refractory to all current medical and surgical therapies in about one-sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the central lateral nucleus of the intralaminar thalamus (CL) and the pontine nucleus oralis (PnO) bilaterally during focal limbic seizures restored normal-appearing cortical electrophysiology and markedly improved behavioral arousal. In contrast, single-site bilateral stimulation of CL or PnO alone was insufficient to achieve the same result. These findings support the "network inhibition hypothesis" that focal limbic seizures impair consciousness through widespread inhibition of subcortical arousal. Driving subcortical arousal function would be a novel therapeutic approach to some forms of refractory epilepsy and may be compatible with devices already in use for responsive neurostimulation. Multisite deep brain stimulation of subcortical arousal structures may benefit not only patients with epilepsy but also those with other disorders of consciousness.

Thalamocortical network activity enables chronic tic detection in humans with Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Deep brain stimulation (DBS) is an emerging therapy for severe cases of TS. We studied two patients with TS implanted with bilateral Medtronic Activa PC + S DBS devices, capable of chronic recordings, with depth leads in the thalamic centromedian-parafascicular complex (CM-PF) and subdural strips over the precentral gyrus. Low-frequency (1-10 Hz) CM-PF activity was observed during tics, as well as modulations in beta rhythms over the motor cortex. Tics were divided into three categories: long complex, complex, and simple. Long complex tics, tics involving multiple body regions and lasting longer than 5 s, were concurrent with a highly detectable thalamocortical signature (average recall [sensitivity] 88.6%, average precision 96.3%). Complex tics were detected with an average recall of 63.9% and precision of 36.6% and simple tics an average recall of 39.3% and precision of 37.9%. The detections were determined using data from both patients.

Distinct temporal spike and local field potential activities in the thalamic parafascicular nucleus of parkinsonian rats during rest and limb movement.

Several studies have suggested that the thalamic centromedian-parafascicular (CM/PF or the PF in rodents) is implicated in the pathophysiology of Parkinson's disease (PD). However, inconsistent changes in the neuronal firing rate and pattern have been reported in parkinsonian animals. To investigate the impact of a dopaminergic cell lesion on PF extracellular discharge in behaving rats, the PF neural activities in the spike and local field potential (LFP) were recorded in unilaterally 6-hydroxydopamine- (6-OHDA) lesioned and neurologically intact control rats during rest and limb movement. During rest, the two PF neuronal subtypes was less spontaneously active, with no difference in the spike firing rates between the control and lesioned rats; only the lesioned rats reshaped their spike firing pattern. Furthermore, the simultaneously recorded LFP in the lesioned rats exhibited a significant increase in power at 12-35 and 35-70Hz and a decrease in power at 0.7-12Hz. During the execution of a voluntary movement, two subtypes of PF neurons were identified by a rapid increase in the discharge activity in both the control and lesioned rats. However, dopamine lesioning was associated with a decrease in neuronal spiking fire rate and reshaping in the firing pattern in the PF. The simultaneously recorded LFP activity exhibited a significant increase in power at 12-35Hz and a decrease in power at 0.7-12Hz compared with the control rats. These findings indicate that 6-OHDA induces modifications in PF spike and LFP activities in rats during rest and movement and suggest that PF dysfunction may be an important contributor to the pathophysiology of parkinsonian motor impairment.

Participation of the thalamic CM-Pf complex in movement performance in patients with dystonia.

INTRODUCTION: The centrum medianum- parafascicular complex of the human thalamus has a critical influence on cortical activity and significantly influences somatosensory function, arousal, and attention. In addition to its cortical connections, this region of the intralaminar thalamic nuclei is also connected to motor areas of the basal ganglia and the brain stem. OBJECTIVE: The goal of this study was to identify movement-related neurons in the centrum medianum-parafascicular complex and analyze the changes in their activity during voluntary movements in patients with cervical dystonia. METHODS: Single-unit activity was recorded during the micro-electrode-guided surgical ablation procedures in patients with cervical dystonia. The neural responses and synchronous electromyographic signals of the neck and finger flexor muscles were simultaneously recorded. RESULTS: We found the following 3 types of movement-sensitive neurons in the centrum medianum-parafascicular complex: neurons that responded selectively to voluntary hand movement (hand-only neurons), neurons that selectively responded to neck movements (neck-only neurons), neurons responding to both hand and neck movements (combined neurons). We discovered the following 3 patterns of movement-related changes in neural activity: an increase in the firing rate, a reduction in the bursting activity, and short-term oscillations and synchronization with neighboring neurons. The most pronounced and prolonged responses were observed during movements involving neck muscles as well as during involuntary dystonic movements. CONCLUSION: The centrum medianum-parafascicular complex of the thalamus is a component of the subcortical network that participates in motor behavior and may be involved in the pathophysiology of cervical dystonia. © 2016 International Parkinson and Movement Disorder Society.

The neurobiology of thalamic amnesia: Contributions of medial thalamus and prefrontal cortex to delayed conditional discrimination.

Although medial thalamus is well established as a site of pathology associated with global amnesia, there is uncertainty about which structures are critical and how they affect memory function. Evidence from human and animal research suggests that damage to the mammillothalamic tract and the anterior, mediodorsal (MD), midline (M), and intralaminar (IL) nuclei contribute to different signs of thalamic amnesia. Here we focus on MD and the adjacent M and IL nuclei, structures identified in animal studies as critical nodes in prefrontal cortex (PFC)-related pathways that are necessary for delayed conditional discrimination. Recordings of PFC neurons in rats performing a dynamic delayed non-matching-to position (DNMTP) task revealed discrete populations encoding information related to planning, execution, and outcome of DNMTP-related actions and delay-related activity signaling previous reinforcement. Parallel studies recording the activity of MD and IL neurons and examining the effects of unilateral thalamic inactivation on the responses of PFC neurons demonstrated a close coupling of central thalamic and PFC neurons responding to diverse aspects of DNMTP and provide evidence that thalamus interacts with PFC neurons to give rise to complex goal-directed behavior exemplified by the DNMTP task.

Damage to the dorsomedial thalamic nucleus, central lateral intralaminar thalamic nucleus, and midline thalamic nuclei on the right-side impair executive function and attention under conditions of high demand but not low demand.

This study reports a patient, OG, with a unilateral right-sided thalamic lesion. High resolution 3T magnetic resonance imaging revealed damage to the parvicellular and magnocellular subdivisions of the dorsomedial thalamus (DMT), the central lateral intralaminar nucleus (also known as the paralamellar DMT), the paraventricular and the central medial midline thalamic nuclei. According to the neuropsychological literature, the DMT, the midline and intralaminar thalamic nuclei influence a wide array of cognitive functions by virtue of their modulatory influences on executive function and attention, and this is particularly indicated under conditions of low arousal or high cognitive demand. We explored this prediction in OG, and compared his performance on a range of low and high demand versions of tests that tapped executive function and attention to a group of 6 age- and IQ-matched controls. OG, without exception, significantly under performed on the high-demand attention and executive function tasks, but performed normally on the low-demand versions. These findings extend and refine current understanding of the effects of thalamic lesion on attention and executive function.

Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies.

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.