Modulation of neuronal activity in human centromedian nucleus during an auditory attention and working memory task.

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5-45 Hz). Average peri­stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13-45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.

Deep brain stimulation of anterior nucleus and centromedian nucleus of thalamus in treatment for drug-resistant epilepsy.

INTRODUCTION: Drug-resistant epilepsy (DRE) remains poorly-controlled in c.33% of patients, and up to 50% of patients suffering from DRE are deemed not to be suitable candidates for resective surgery. For these patients, deep brain stimulation (DBS) may constitute the last resort in the treatment of DRE. STATE OF THE ART: We undertook a systematic review of the current literature on DBS efficacy and the safety of two thalamic nuclei-anterior nucleus of the thalamus (ANT) and the centromedian nucleus of the thalamus in the management of patients with DRE. A search using two electronic databases, the Medical Literature, Analysis, and Retrieval System on-line (MEDLINE) and the Cochrane Central Register of Controlled Trials (CEN-TRAL) was conducted. CLINICAL IMPLICATIONS: We found 30 articles related to ANT DBS and 13 articles related to CMN DBS which were further analysed. Based on the clinical research articles, we found a mean seizure frequency reduction for both thalamic nuclei. For ANT DBS, the mean seizure frequency reduction ranged from 48% to 75%, and for CMN DBS from 46.7% to 91%. The responder rate (defined as at least 50% reduction in seizure frequency) was reported to be 53.2-75% for patients after ANT DBS and 50-90% for patients after CMN DBS. FUTURE DIRECTIONS: ANT and CMN DBS appear to be safe and efficacious treatments, particularly in patients with refractory partial seizures and primary generalised seizures. ANT DBS reduces most effectively seizures originating in the temporal and frontal lobes. CMN DBS reduces mostly primary generalised tonic-clonic and atypical absences and atonic seizures. Seizures related to Lennox-Gastaut syndrome respond very favourably to CMN DBS.

Dysconnectivity of the parafascicular nucleus in Parkinson's disease: A dynamic causal modeling analysis.

BACKGROUND: Recent animal model studies have suggested that the parafascicular nucleus has the potential to be an effective deep brain stimulation target for Parkinson's disease. However, our knowledge on the role of the parafascicular nucleus in Parkinson's disease patients remains limited. OBJECTIVE: We aimed to investigate the functional alterations of the parafascicular nucleus projections in Parkinson's disease patients. METHODS: We enrolled 72 Parkinson's disease patients and 60 healthy controls, then utilized resting-state functional MRI and spectral dynamic causal modeling to explore the effective connectivity of the bilateral parafascicular nucleus to the dorsal putamen, nucleus accumbens, and subthalamic nucleus. The associations between the effective connectivity of the parafascicular nucleus projections and clinical features were measured with Pearson partial correlations. RESULTS: Compared with controls, the effective connectivity from the parafascicular nucleus to dorsal putamen was significantly increased, while the connectivity to the nucleus accumbens and subthalamic nucleus was significantly reduced in Parkinson's disease patients. There was a significantly positive correlation between the connectivity of parafascicular nucleus-dorsal putamen projection and motor deficits. The connectivity from the parafascicular nucleus to the subthalamic nucleus was negatively correlated with motor deficits and apathy, while the connectivity from the parafascicular nucleus to the nucleus accumbens was negatively associated with depression. CONCLUSION: The present study demonstrates that the parafascicular nucleus-related projections are damaged and associated with clinical symptoms of Parkinson's disease. Our findings provide new insights into the impaired basal ganglia-thalamocortical circuits and give support for the parafascicular nucleus as a potential effective neuromodulating target of the disease.

DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial).

OBJECTIVE: Prior uncontrolled studies have reported seizure reductions following deep brain stimulation (DBS) in patients with Lennox-Gastaut syndrome (LGS), but evidence from randomized controlled studies is lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for the treatment of LGS. METHODS: We conducted a prospective, double-blind, randomized study of continuous, cycling stimulation of CM-DBS, in patients with LGS. Following pre- and post-implantation periods, half received 3 months of stimulation (blinded phase), then all received 3 months of stimulation (unblinded phase). The primary outcome was the proportion of participants with ≥50% reduction in diary-recorded seizures in stimulated versus control participants, measured at the end of the blinded phase. A secondary outcome was the proportion of participants with a ≥50% reduction in electrographic seizures on 24-hour ambulatory electroencephalography (EEG) at the end of the blinded phase. RESULTS: Between November 2017 and December 2019, 20 young adults with LGS (17-37 years;13 women) underwent bilateral CM-DBS at a single center in Australia, with 19 randomized (treatment, n = 10 and control, n = 9). Fifty percent of the stimulation group achieved ≥50% seizure reduction, compared with 22% of controls (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 0.44-21.45, p = 0.25). For electrographic seizures, 59% of the stimulation group had ≥50% reduction at the end of the blinded phase, compared with none of the controls (OR= 23.25, 95% CI = 1.0-538.4, p = 0.05). Across all patients, median seizure reduction (baseline vs study exit) was 46.7% (interquartile range [IQR] = 28-67%) for diary-recorded seizures and 53.8% (IQR = 27-73%) for electrographic seizures. INTERPRETATION: CM-DBS in patients with LGS reduced electrographic rather than diary-recorded seizures, after 3 months of stimulation. Fifty percent of all participants had diary-recorded seizures reduced by half at the study exit, providing supporting evidence of the treatment effect. ANN NEUROL 2022;91:253-267.

Sensing with deep brain stimulation device in epilepsy: Aperiodic changes in thalamic local field potential during seizures.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is an effective therapeutic option in patients with drug-resistant epilepsy. Recent DBS devices with sensing capabilities enable chronic, outpatient local field potential (LFP) recordings. Whereas beta oscillations have been demonstrated to be a useful biomarker in movement disorders, the clinical utility of DBS sensing in epilepsy remains unclear. Our aim was to determine LFP features that distinguish ictal from inter-ictal states, which may aid in tracking seizure outcomes with DBS. METHODS: Electrophysiology data were obtained from DBS devices implanted in the anterior nucleus (N = 12) or centromedian nucleus (N = 2) of the thalamus. Power spectra recorded during patient/caregiver-marked seizure events were analyzed with a method that quantitatively separates the oscillatory and non-oscillatory/aperiodic components of the LFP using non-parametric statistics, without the need for pre-specification of the frequency bands of interest. Features of the LFP parameterized using this algorithm were compared with those from inter-ictal power spectra recorded in clinic. RESULTS: Oscillatory activity in multiple canonical frequency bands was identified from the power spectra in 86.48% of patient-marked seizure events. Delta oscillations were present in all patients, followed by theta (N = 10) and beta (N = 9). Although there were no differences in oscillatory LFP features between the ictal and inter-ictal states, there was a steeper decline in the 1/f slope of the aperiodic component of the LFP during seizures. SIGNIFICANCE: Our work highlights the potential and shortcomings of chronic LFP recordings in thalamic DBS for epilepsy. Findings suggest that no single frequency band in isolation clearly differentiates seizures, and that features of aperiodic LFP activity may be clinically-relevant biomarkers of seizures.

Ambulatory Local Field Potential Recordings from the Thalamus in Epilepsy: A Feasibility Study.

INTRODUCTION: Stimulation of the thalamus is gaining favor in the treatment of medically refractory multifocal and generalized epilepsy. Implanted brain stimulators capable of recording ambulatory local field potentials (LFPs) have recently been introduced, but there is little information to guide their use in thalamic stimulation for epilepsy. This study sought to assess the feasibility of chronically recording ambulatory interictal LFP from the thalamus in patients with epilepsy. METHODS: In this pilot study, ambulatory LFP was recorded from patients who underwent sensing-enabled deep brain stimulation (DBS, 2 participants) or responsive neurostimulation (RNS, 3 participants) targeting the anterior nucleus of the thalamus (ANT, 2 electrodes), centromedian nucleus (CM, 7 electrodes), or medial pulvinar (PuM, 1 electrode) for multifocal or generalized epilepsy. Time-domain and frequency-domain LFP was investigated for epileptiform discharges, spectral peaks, circadian variation, and peri-ictal patterns. RESULTS: Thalamic interictal discharges were visible on ambulatory recordings from both DBS and RNS. At-home interictal frequency-domain data could be extracted from both devices. Spectral peaks were noted at 10-15 Hz in CM, 6-11 Hz in ANT, and 19-24 Hz in PuM but varied in prominence and were not visible in all electrodes. In CM, 10-15 Hz power exhibited circadian variation and was attenuated by eye opening. CONCLUSION: Chronic ambulatory recording of thalamic LFP is feasible. Common spectral peaks can be observed but vary between electrodes and across neural states. DBS and RNS devices provide a wealth of complementary data that have the potential to better inform thalamic stimulation for epilepsy.

Evidence for Thalamic Responsive Neurostimulation in Treatment of Adult and Pediatric Epilepsy.

Responsive neurostimulation (RNS) has well-established efficacy in patients with identifiable seizure foci. Emerging evidence suggests the feasibility of expanding this treatment to patients with nonfocal or multifocal epileptic profiles with thalamic targeting. Our institution performed two successful implantations of thalamic RNS (tRNS) targeting the centromedian nucleus of the thalamus (CMT), and 1-year postoperative outcomes are provided. Additionally, a literature review of all reported tRNS was conducted. Publications were excluded if they did not include demographic data and/or epilepsy outcomes at follow-up. In the literature, 19 adult and 3 pediatric cases were identified. These cases were analyzed for outcome, indications, previous operations, and surgical practice variations. Both of our patients had failed multiple previous pharmacological and neurosurgical interventions for epilepsy. Case #1 underwent tRNS with bilateral CMT stimulation. Case #2 underwent tRNS with simultaneous right CMT and right insular stimulation, although an additional lead was placed in the left CMT and left capped for potential future use. Each has achieved ≥90% reduction in seizure burden and approach seizure freedom. 71% of patients in the literature review had multifocal, bilateral, or cryptogenic seizure onset. Three patients were implanted for Lennox Gastaut (2 of 3 are pediatric). 16 patients underwent an average of 1.6 failed procedures prior to successful tRNS implantation. Taken together, the 21 adult patients reviewed have experienced an average seizure reduction of 77% at the latest follow-up. 95% of the adult patients reported in the literature experienced >50% reduction in seizure activity following tRNS and 52% experienced ≥90% reduction in seizure burden following tRNS. Pediatric patients have experienced 70-100% improvement.

Neural correlates of multidimensional motor outputs in an excitatory parafascicular-zona incerta circuit.

The parafascicular nucleus (Pf) in medial thalamus is interconnected with prefrontal cortex and basal ganglia. Though much research has determined its importance in cognitive regulation of behaviour, its projections to regions in subthalamus remain less known. Such connections include those to zona incerta (ZI), located immediately dorsal to subthalamic nuclei (STN) regulating motor output, and whose role in a motor context is only beginning to be investigated. We thus examined circuits from parafascicular (Pf) thalamus to ZI, and its activity during locomotion and spontaneous behaviours in mice. We found that a distinct group of CaMKIIα-positive excitatory parafascicular neurons, separated from VGLUT2-positive excitatory neurons, project widely into ZI, more than adjacent STN. Our results from fibre photometry and decoding with general linear model (GLM) indicate that PF-ZI pathways do not specifically correlate with amount of locomotion or movement velocity, but instead show more specified activity during relative directional changes of movements observed in turning, sniffing behaviours. These results hint at the PF-ZI pathway having a distinct role in directing action specificity and have implications for subcortical bases in dimensional control of behaviours.

Processing of information from the parafascicular nucleus of the thalamus through the basal ganglia.

Accumulating evidence implicates the parafascicular nucleus of the thalamus (Pf) in basal ganglia (BG)-related functions and pathologies. Despite Pf connectivity with all BG components, most attention is focused on the thalamostriatal system and an integrated view of thalamic information processing in this network is still lacking. Here, we addressed this question by recording the responses elicited by Pf activation in single neurons of the substantia nigra pars reticulata (SNr), the main BG output structure in rodents, in anesthetized mice. We performed optogenetic activation of Pf neurons innervating the striatum, the subthalamic nucleus (STN), or the SNr using virally mediated transcellular delivery of Cre from injection in either target in Rosa26-LoxP-stop-ChR2-EYFP mice to drive channelrhodopsin expression. Photoactivation of Pf neurons connecting the striatum evoked an inhibition often followed by an excitation, likely resulting from the activation of the trans-striatal direct and indirect pathways, respectively. Photoactivation of Pf neurons connecting the SNr or the STN triggered one or two early excitations, suggesting partial functional overlap of trans-subthalamic and direct thalamonigral projections. Excitations were followed in about half of the cases by an inhibition that might reflect recruitment of intranigral inhibitory loops. Finally, global Pf stimulation, electrical or optogenetic, elicited similar complex responses comprising up to four components: one or two short-latency excitations, an inhibition, and a late excitation. These data provide evidence for functional connections between the Pf and different BG components and for convergence of the information processed through these pathways in single SNr neurons, stressing their importance in regulating BG outflow.

Responsive neurostimulation of the thalamus improves seizure control in idiopathic generalised epilepsy: initial case series.

OBJECTIVES: Up to 40% of patients with idiopathic generalised epilepsy (IGE) are drug resistant and potentially could benefit from intracranial neuromodulation of the seizure circuit. We present outcomes following 2 years of thalamic-responsive neurostimulation for IGE. METHODS: Four patients with pharmacoresistant epilepsy underwent RNS System implantation in the bilateral centromedian (CM) nucleus region. Electrophysiological data were extracted from the clinical patient data management system and analysed using a specialised platform (BRAINStim). Postoperative visualisation of electrode locations was performed using Lead-DBS. Seizure outcomes were reported using the Engel scale. RESULTS: Patients experienced a 75%-99% reduction in seizure frequency with decreased seizure duration and severity (Engel class IB, IC, IIA and IIIA), as well as significant improvements in quality of life. Outcomes were durable through at least 2 years of therapy. Detection accuracy for all patients overall decreased over successive programming epochs from a mean of 96.5% to 88.3%. Most electrodes used to deliver stimulation were located in the CM (7/10) followed by the posterior dorsal ventral lateral (2/2), posterior ventral posterior lateral (3/4) and posterior ventral ventral lateral (2/3). In all patients, stimulation varied from 0.2 to 2.0 mA and amplitude only increased over successive epochs. The raw percentage of intracranial electroencephalography recordings with stimulations delivered to electrographic seizures was 24.8%, 1.2%, 7.6% and 8.8%. CONCLUSION: Closed-loop stimulation of the CM region may provide significant improvement in seizure control and quality of life for patients with drug-resistant IGE. Optimal detection and stimulation locations and parameters remain an active area of investigation for accelerating and fine-tuning clinical responses.

Pathway-Specific Remodeling of Thalamostriatal Synapses in a Mouse Model of Parkinson's Disease.

BACKGROUND: The network pathophysiology underlying the motor symptoms of Parkinson's disease (PD) is poorly understood. In models of late-stage PD, there is significant cell-specific remodeling of corticostriatal, axospinous glutamatergic synapses on principal spiny projection neurons (SPNs). Neurons in the centrolateral nucleus (CLN) of the thalamus that relay cerebellar activity to the striatum also make axospinous synapses on SPNs, but the extent to which they are affected in PD has not been definitively characterized. OBJECTIVE: To fill this gap, transgenic mice in which CLN neurons express Cre recombinase were used in conjunction with optogenetic and circuit mapping approaches to determine changes in the CLN projection to SPNs in a unilateral 6-hydroxydopamine (6-OHDA) model of late-stage PD. METHODS: Adeno-associated virus vectors carrying Cre-dependent opsin expression constructs were stereotaxically injected into the CLN of Grp-KH288 mice in which CLN, but not parafascicular nucleus neurons, expressed Cre recombinase. The properties of this projection to identify direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) were then studied in ex vivo brain slices of the dorsolateral striatum from control and 6-OHDA lesioned mice using anatomic, optogenetic, and electrophysiological approaches. RESULTS: Optogenetically evoked excitatory synaptic currents in both iSPNs and dSPNs were reduced in lesioned mice; however, the reduction was significantly greater in dSPNs. In iSPNs, the reduction in evoked responses was attributable to synaptic pruning, because synaptic channelrhodopsin assisted circuit mapping (sCRACm) revealed fewer synapses per cell after lesioning. In contrast, sCRACm mapping of CLN inputs to dSPNs failed to detect any change in synapse abundance in lesioned mice. However, the ratio of currents through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors to those through N-methyl-D-aspartate receptors was significantly reduced in dSPNs. Moreover, the distribution of currents evoked by optical stimulation of individual synapses shifted toward smaller amplitudes by lesioning, suggesting that they had undergone long-term depression. CONCLUSIONS: Taken together, our results demonstrate that the CLN projection to the striatum undergoes a pathway-specific remodeling that could contribute to the circuit imbalance thought to drive the hypokinetic features of PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation targets in epilepsy: Systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus.

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and meta-analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

Novel targets in deep brain stimulation for movement disorders.

The neurosurgical treatment of movement disorders, primarily via deep brain stimulation (DBS), is a rapidly expanding and evolving field. Although conventional targets including the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) for Parkinson's disease and ventral intermediate nucleus of the thalams (VIM) for tremor provide substantial benefit in terms of both motor symptoms and quality of life, other targets for DBS have been explored in an effort to maximize clinical benefit and also avoid undesired adverse effects associated with stimulation. These novel targets primarily include the rostral zona incerta (rZI), caudal zona incerta (cZI)/posterior subthalamic area (PSA), prelemniscal radiation (Raprl), pedunculopontine nucleus (PPN), substantia nigra pars reticulata (SNr), centromedian/parafascicular (CM/PF) nucleus of the thalamus, nucleus basalis of Meynert (NBM), dentato-rubro-thalamic tract (DRTT), dentate nucleus of the cerebellum, external segment of the globus pallidus (GPe), and ventral oralis (VO) complex of the thalamus. However, reports of outcomes utilizing these targets are scattered and disparate. In order to provide a comprehensive resource for researchers and clinicians alike, we have summarized the existing literature surrounding these novel targets, including rationale for their use, neurosurgical techniques where relevant, outcomes and adverse effects of stimulation, and future directions for research.

Management of Lennox-Gastaut syndrome with deep brain stimulation: A systematic literature review.

OBJECTIVES: To review the current literature regarding the efficacy and safety of deep brain stimulation (DBS) in Lennox-Gastaut syndrome (LGS). METHODS: The authors conducted a systematic review of PubMed databases using keywords relevant to the objective of this research. Titles and abstracts were reviewed, after which studies that met the inclusion criteria were selected. Findings were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Thirteen studies were identified, and only 3 studies that reported 50 patients (age range from 3 to 65 years) met the inclusion criteria of DBS for LGS. Radiological imaging findings and neurophysiological findings were described in all studies. The thalamus nuclei, particularly the centromedian thalamic nucleus (CMN), were found to be highly active in LGS. By targeting this brain region, patients showed favorable outcomes. Overall, the mean seizure reduction was more than 50% in all patients (among whom 2 were seizure free) at a mean follow-up of 15 (12-18) months. CONCLUSION: According to this systemic review, DBS for LGS showed satisfactory outcomes, indicating that DBS should be considered a valid treatment option. However, more studies are needed to ensure the role of DBS in LGS by establishing accurate targeting of the CMN using proper lead positioning and radiological imaging, a standard DBS intervention, and long-term outcomes.

TRPM4 Conductances in Thalamic Reticular Nucleus Neurons Generate Persistent Firing during Slow Oscillations.

During sleep, neurons in the thalamic reticular nucleus (TRN) participate in distinct types of oscillatory activity. While the reciprocal synaptic circuits between TRN and sensory relay nuclei are known to underlie the generation of sleep spindles, the mechanisms regulating slow (<1 Hz) forms of thalamic oscillations are not well understood. Under in vitro conditions, TRN neurons can generate slow oscillations in a cell-intrinsic manner, with postsynaptic Group 1 metabotropic glutamate receptor activation triggering long-lasting plateau potentials thought to be mediated by both T-type Ca2+ currents and Ca2+-activated nonselective cation currents (ICAN). However, the identity of ICAN and the possible contribution of thalamic circuits to slow rhythmic activity remain unclear. Using thalamic slices derived from adult mice of either sex, we recorded slow forms of rhythmic activity in TRN neurons, which were driven by fast glutamatergic thalamoreticular inputs but did not require postsynaptic Group 1 metabotropic glutamate receptor activation. For a significant fraction of TRN neurons, synaptic inputs or brief depolarizing current steps led to long-lasting plateau potentials and persistent firing (PF), and in turn, resulted in sustained synaptic inhibition in postsynaptic relay neurons of the ventrobasal thalamus (VB). Pharmacological approachesindicated that plateau potentials were triggered by Ca2+ influx through T-type Ca2+ channels and mediated by Ca2+- and voltage-dependent transient receptor potential melastatin 4 (TRPM4) channels. Together, our results suggest that thalamic circuits can generate slow oscillatory activity, mediated by an interplay of TRN-VB synaptic circuits that generate rhythmicity and TRN cell-intrinsic mechanisms that control PF and oscillation frequency.SIGNIFICANCE STATEMENT Slow forms of thalamocortical rhythmic activity are thought to be essential for memory consolidation during sleep and the efficient removal of potentially toxic metabolites. In vivo, thalamic slow oscillations are regulated by strong bidirectional synaptic pathways linking neocortex and thalamus. Therefore, in vitro studies in the isolated thalamus offer important insights about the ability of individual neurons and local circuits to generate different forms of rhythmic activity. We found that circuits formed by GABAergic neurons in the thalamic reticular nucleus and glutamatergic relay neurons in the ventrobasal thalamus generated slow oscillatory activity, which was accompanied by persistent firing in thalamic reticular nucleus neurons. Our results identify both cell-intrinsic and synaptic mechanisms that mediate slow forms of rhythmic activity in thalamic circuits.

Morphological Study of the Cortical and Thalamic Glutamatergic Synaptic Inputs of Striatal Parvalbumin Interneurons in Rats.

Parvalbumin-immunoreactive (Parv+) interneurons is an important component of striatal GABAergic microcircuits, which receive excitatory inputs from the cortex and thalamus, and then target striatal projection neurons. The present study aimed to examine ultrastructural synaptic connection features of Parv+ neruons with cortical and thalamic input, and striatal projection neurons by using immuno-electron microscopy (immuno-EM) and immunofluorescence techniques. Our results showed that both Parv+ somas and dendrites received numerous asymmetric synaptic inputs, and Parv+ terminals formed symmetric synapses with Parv- somas, dendrites and spine bases. Most interestingly, spine bases targeted by Parv+ terminals simultaneously received excitatory inputs at their heads. Electrical stimulation of the motor cortex (M1) induced higher proportion of striatal Parv+ neurons express c-Jun than stimulation of the parafascicular nucleus (PFN), and indicated that cortical- and thalamic-inputs differentially modulate Parv+ neurons. Consistent with that, both Parv + soma and dendrites received more VGlut1+ than VGlut2+ terminals. However, the proportion of VGlut1+ terminal targeting onto Parv+ proximal and distal dendrites was not different, but VGlut2+ terminals tended to target Parv+ somas and proximal dendrites than distal dendrites. These functional and morphological results suggested excitatory cortical and thalamic glutamatergic inputs differently modulate Parv+ interneurons, which provided inhibition inputs onto striatal projection neurons. To maintain the balance between the cortex and thalamus onto Parv+ interneurons may be an important therapeutic target for neurological disorders.

Radiofrequency ablation of the centromedian thalamic nucleus in the treatment of drug-resistant epilepsy.

OBJECTIVE: To determine the usefulness and efficacy of radiofrequency ablations (RFA) of the Centromedian thalamic nucleus (CMN) to control primarily generalized or multifocal seizures in refractory epilepsy. METHODS: Six patients with clinical diagnosis of multifocal or primarily generalized drug-resistant epilepsy were included. Bilateral RFA of the CMN was performed through a monopolar 1.8 mm. tip electrode with a temperature of 80 °C during 90 seconds. Patients were followed in every 3 months visit for 20 to 36 months and kept a monthly seizure count calendar. We also compared maximal paroxysmal electroencephalogram (EEG) activity and neuropsychological evaluation pre and 6 months postoperatively. RESULTS: A significant reduction in the number of generalized seizures was observed in all subjects in the range of 79-98%, starting the first post-operative month. Although focal aware seizures remained unchanged throughout follow-up, there was an important reduction on paroxysmal activity between the pre and postoperative EEG. No major changes on cognitive status were detected. There was post-operative dysphagia and odynophagia lasting one week and there was no mortality in this group of patients. CONCLUSION: Preliminary results of CMN RFA suggest safety and a trend toward reduction of some seizure types, it may reduce the seizure frequency like other palliative procedures since the first post-operative month, but a larger, controlled study would be needed to establish the value of this therapy.

Minimally invasive trans-sulcal parafascicular surgical resection of cerebral tumors: translating anatomy to early clinical experience.

The minimally invasive port-based trans-sulcal parafascicular surgical corridor (TPSC) has incrementally evolved to provide a safe, feasible, and effective alternative to access subcortical and intraventricular pathologies. A detailed anatomical foundation is important in mitigating cortical and white matter tract injury with this corridor. Thus, the aims of this study are (1) to provide a detailed anatomical construct and overview of TPSCs and (2) to translate an anatomical framework to early clinical experience. Based on regional anatomical constraints, suitable parafascicular entry points were identified and described. Fiber tracts at both minimal and increased risks for each corridor were analyzed. TPSC-managed cases for metastatic or primary brain tumors were retrospectively reviewed. Adult patients 18 years or older with Karnofsky Performance Status (KPS) ≥ 70 were included. Subcortical brain metastases between 2 and 6 cm or primary brain tumors between 2 and 5 cm were included. Patient-specific corridors and trajectories were determined using MRI-tractography. Anatomy: The following TPSCs were described and translated to clinical practice: superior frontal, inferior frontal, inferior temporal, intraparietal, and postcentral sulci. Clinical: Eleven patients (5 males, 6 females) were included (mean age = 52 years). Seven tumors were metastatic, and 4 were primary. Gross total, near total, and subtotal resection was achieved in 7, 3, and 1 patient(s), respectively. Three patients developed intraoperative complications; all recovered from their intraoperative deficits and returned to baseline in 30 days. A detailed TPSC anatomical framework is critical in conducting safe and effective port-based surgical access. This review may represent one of the few early translational TPSC studies bridging anatomical data to clinical subcortical and intraventricular surgical practice.

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.

Thalamic anterior part of the ventral posterolateral nucleus and central lateral nucleus in the genesis of central post-stroke pain.

BACKGROUND: The genesis of central post-stroke pain (CPSP) is important but difficult to understand. We evaluated the involvement of the thalamic anterior part of the ventral posterolateral nucleus (VPLa) and central lateral nucleus (CL) in the occurrence of CPSP. METHOD: Stereotactic thalamotomy was performed on the posterior part of the ventral lateral nucleus (VLp)-VPLa and CL in 9 patients with CPSP caused by deep-seated intracerebral hemorrhage. Computed tomography (CT) did not reveal definite thalamic lesion in 5 patients but did in 4 patients. Electrophysiological studies of these thalamic nuclei were carried out during the surgery. Anatomical studies using CT were performed in another 20 patients with thalamic hemorrhage who had clear consciousness but had sensory disturbance at onset. RESULTS: Neural activities were preserved and hyperactive and unstable discharges (HUDs) were often recognized along the trajectory in the thalamic VLp-VPLa in 5 patients without thalamic lesion. Surgical modification of this area ameliorated pain, particularly movement-related pain. Neural activities were hypoactive in the other 4 patients with thalamic lesion. However, neural activities were preserved and HUDs were sometimes recognized in the CL. Sensory responses were seen, but at low rate, in the sensory thalamus. Anatomical study showed that the thalamic lesion was obviously smaller in the patients with developing pain in the chronic stage. CONCLUSIONS: Change in neural activities around the cerebrovascular disease lesion in the thalamic VPLa or CL might affect the perception of sensory impulses or sensory processing in those thalamic nuclei, resulting in the genesis of CPSP.