Targeting thalamocortical circuits for closed-loop stimulation in Lennox-Gastaut syndrome.

This paper outlines the therapeutic rationale and neurosurgical targeting technique for bilateral, closed-loop, thalamocortical stimulation in Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy. Thalamic stimulation can be an effective treatment for Lennox-Gastaut syndrome, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. We aimed to identify a cortical target by synthesizing prior neuroimaging studies, and to use this knowledge to advance a dual thalamic (centromedian) and cortical (frontal) approach for closed-loop stimulation. Multi-modal brain network maps from three group-level studies of Lennox-Gastaut syndrome were averaged to define the area of peak overlap: simultaneous EEG-functional MRI of generalized paroxysmal fast activity, [18F]fluorodeoxyglucose PET of cortical hypometabolism and diffusion MRI structural connectivity associated with clinical efficacy in a previous trial of thalamic deep brain stimulation. The resulting 'hotspot' was used as a seed in a normative functional MRI connectivity analysis to identify connected networks. Intracranial electrophysiology was reviewed in the first two trial patients undergoing bilateral implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analysed for presence and synchrony of epileptiform activity. The peak overlap was in bilateral premotor cortex/caudal middle frontal gyrus. Functional connectivity of this hotspot revealed a distributed network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-functional MRI and PET. Intracranial electrophysiology showed characteristic epileptiform activity of Lennox-Gastaut syndrome in both the cortical hotspot and thalamus; most detected events occurred first in the cortex before appearing in the thalamus. Premotor frontal cortex shows peak involvement in Lennox-Gastaut syndrome and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for a range of neuromodulation therapies, including thalamocortical stimulation and emerging non-invasive treatments like focused ultrasound or transcranial magnetic stimulation. Compared to thalamus-only approaches, the addition of this cortical target may allow more rapid detections of seizures, more diverse stimulation paradigms and broader modulation of the epileptic network. A prospective, multi-centre trial of closed-loop thalamocortical stimulation for Lennox-Gastaut syndrome is currently underway.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

Preclinical assessment of a noncooled MR thermometry-based neurosurgical laser therapy system.

OBJECTIVE: MRI-guided laser interstitial thermal therapy (MRgLITT) has recently gained interest as an ablative stereotactic procedure for intractable epilepsy, movement disorders, and brain tumors. Conventionally, a LITT system consists of a laser generator and cooled laser applicator, which is a fiber optic core surrounded by a sheath through which cooled fluid is pumped. However, this footprint can make the system bulky and nonmobile, limit the maximum depth of targeting, and increase the chances of breakdown. Herein, the authors conduct a preclinical assessment of a noncooled MRgLITT system in a porcine model. METHODS: Three-tesla MRI was used to guide the in vivo placement of noncooled laser applicators in the porcine brain. The study consisted of a survival arm and terminal arm. The laser was activated at a power of 4-7 W for ≤ 180 seconds. Temperature changes were monitored using the MR thermometry software ThermoGuide in the survival arm (n = 5) or both ThermoGuide software and adjacently inserted thermal probes in the terminal arm (n = 3). Thermal damage was determined by the software using the temperature-time relationship of cumulative equivalent minutes at 43°C (CEM43). Temperatures calculated by the software were compared with those recorded by the temperature probes. The dimensions of thermal damage thresholds (TDTs; 2-9, 10-59, 60-239, ≥ 240 CEM43 isolines) given by MR thermometry were compared with the dimensions of irreversible damage on histopathological analysis. RESULTS: There was a strong correlation between temperature recordings by ThermoGuide and those by thermal probes at both 4 mm (r = 0.96) and 8 mm (r = 0.80), with a mean absolute error of 0.76°C ± 2.13°C and 0.17°C ± 1.65°C at 4 and 8 mm, respectively. The area of 2-9 CEM43 was larger than the area of irreversible damage seen on histopathological analysis. The dimensions of the 10 and 60 CEM43 correlated well with dimensions of the lesion on histopathological analysis. A well-defined border (≤ 1 mm) was observed between the area of irreversible damage and healthy brain tissue. CONCLUSIONS: This preclinical assessment showed that the noncooled LITT system was able to precisely reach the target and create well-defined lesions within a margin of safety, without any adverse effects. MR thermometry software provided an accurate near-real-time temperature of the brain tissue, and dimensions of the lesion as visualized by the software correlated well with histopathological findings. Further studies to test the system's efficacy and safety in human subjects are in progress.

Increased electrode impedance as an indicator for early detection of deep brain stimulation (DBS) hardware Infection: Clinical experience and in vitro study.

BACKGROUND: When deep brain stimulation (DBS) infections are identified, they are often too advanced to treat without complete hardware removal. New objective markers to promptly identify DBS infections are needed. We present a patient with GPi (globus pallidus interna) DBS for dystonia, where the electrode impedance unexpectedly increased 3-months post-operatively, followed by serologic and hematologic markers of inflammation at 6-months, prompting explantation surgery. We recreated these conditions in a laboratory environment to analyze the pattern of changing of electrical impedance across the contacts of a DBS lead following Staphylococcus biofilm formation. METHODS: A stainless-steel culture chamber containing 1 % brain heart infusion agar was used. A DBS electrode was dipped in peptone water containing a strain of S. aureus and subsequently introduced into the chamber. The apparatus was incubated at 37 °C for 6 days. Impedance was measured at 24hr intervals. A control experiment without S. Aureus inoculation was used to determine changes in impedance over a period of 6-days. RESULTS: The mean monopolar impedance on day-1 was 751.8 ± 23.8 Ω and on day-3 was 1004.8 ± 68.7 Ω, a 33.7 % rise (p = 0.007). A faint biofilm formation could be seen around the DBS lead by day-2 and florid growth by day-3. After addition of the linezolid solution, a 15.9 % decrease in monopolar impedance was observed from day 3-6 (p = 0.003). CONCLUSION: This study gives insight into impedance trends following a hardware infection in DBS. Increased impedance outside expected norms may be valuable for early prediction of infection. Furthermore, timely management using antibiotics might reduce the frequency of infection-related explant surgeries.

The RIGHT Scoring System for the Medicolegal Classification of Head Injury.

Background: In India, in case of an allegation of assault, the medical officer is required to classify the nature of injury into simple, grievous, and dangerous based upon the Indian Penal Code, which is outdated and has numerous gray areas. Objective: The aim of this study is twofold: first, to formulate an objective scoring system for the medicolegal classification of head injuries and Second to validate the proposed scoring system on patients with head injury. Methods and Material: A panel of experts consisting of neurosurgeons, radiologists, and forensic specialists came up with an objective scoring system, coined as the RIGHT (radiological-intervention-Glasgow Coma Scale (GCS)-based head trauma) scoring system consisting of three parameters, namely, the motor subscore of the GCS, computerized tomography image findings, and management of the patient. This was used to classify head injuries-into simple, grievous, and dangerous. A single-centre pilot study was planned-including patients with head trauma reporting to the emergency department. Medicolegal nature of the head injury was classified according to the proposed RIGHT score. A 6-month follow-up was performed using the Glasgow Outcome Score (GOS). Results: In total, 130 patients with head injury reported to the emergency department. There was a significant correlation between the RIGHT score assigned upon admission and the GOS at 6 months (P < 0.001). Conclusions: As the scoring system could be applied objectively and a significant correlation between nature of injury given by RIGHT score and 6-month outcome was present; therefore, the RIGHT scoring system proved to be an effective method in unambiguously classifying the nature of head injury for medicolegal opinions.

Characterization of spatiotemporal dynamics of binary and graded tonic pain in humans using intracranial recordings.

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks' relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded "yes" or "no" to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions, including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus.

Characterization of spatiotemporal dynamics of binary and graded tonic pain in humans using intracranial recordings.

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks' relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded "yes" or "no" to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus.

Psychophysical pain encoding in the cingulate cortex predicts responsiveness of electrical stimulation.

Background: The anterior cingulate cortex (ACC) plays an important role in the cognitive and emotional processing of pain. Prior studies have used deep brain stimulation (DBS) to treat chronic pain, but results have been inconsistent. This may be due to network adaptation over time and variable causes of chronic pain. Identifying patient-specific pain network features may be necessary to determine patient candidacy for DBS. Hypothesis: Cingulate stimulation would increase patients' hot pain thresholds if non-stimulation 70-150 Hz activity encoded psychophysical pain responses. Methods: In this study, four patients who underwent intracranial monitoring for epilepsy monitoring participated in a pain task. They placed their hand on a device capable of eliciting thermal pain for five seconds and rated their pain. We used these results to determine the individual's thermal pain threshold with and without electrical stimulation. Two different types of generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. Results: The pain threshold for each patient was determined from the psychometric probability density function. Two patients had a higher pain threshold with stimulation than without, while the other two patients had no difference. We also evaluated the relationship between neural activity and pain responses. We found that patients who responded to stimulation had specific time windows where high-frequency activity was associated with increased pain ratings. Conclusion: Stimulation of cingulate regions with increased pain-related neural activity was more effective at modulating pain perception than stimulating non-responsive areas. Personalized evaluation of neural activity biomarkers could help identify the best target for stimulation and predict its effectiveness in future studies evaluating DBS.