The bacterial exoenzyme C3 transferase (C3) irreversibly inhibits RhoA GTPase leading to stimulation of axonal outgrowth in injured neurons. C3 has been used successfully in models of neurotrauma and shows promise as an option to support cell survival and axonal growth of dopaminergic (DA) neurons in Parkinson's disease (PD) cell therapy. Whether the continuous expression of C3 in DA neurons is well-tolerated is unknown. To assess the potential neurotoxicity of sustained expression of C3 in DA neurons, we generated Cre recombinase-dependent adeno-associated viral vectors (AAV) for targeted C3 delivery to DA neurons of the mouse substantia nigra pars compacta (SNc). The effect of continuous expression of C3 on DA neurons was assessed by immunohistochemistry and compared to that of Enhanced Yellow Fluorescent Protein (EYFP) as negative controls. We did not find significant reduction of tyrosine hydroxylase (TH) expression levels nor the presence of cleaved activated caspase 3. Astrocytic activation as determined by GFAP expression was comparable to EYFP controls. To evaluate the impact of C3 expression on striatal terminals of the nigrostriatal pathway, we compared the rotational behavior of wildtype mice injected unilaterally with either C3 or 6-hydroxydopamine (6-OHDA). Mice injected with C3 exhibited similar ipsiversive rotations to the site of injection in comparison to control mice injected with EYFP and significantly fewer ipsiversive rotations compared to 6-OHDA lesioned mice. Non-significant difference between C3 and EYFP controls in behavioral and histological analyses demonstrate that transduced DA neurons express C3 continuously without apparent adverse effects, supporting the use of C3 in efficacy studies targeting DA neurons.

RATIONALE: Temporal lobe (TL) epilepsy is the most common form of drug-resistant epilepsy. While the limbic circuit and the structures composing the TL have been a major focus of human and animal studies on TL seizures, there is also evidence suggesting that the basal ganglia have an active role in the propagation and control of TL seizures. Studies in patients have shown that TL seizures can cause changes in the oscillatory activity of the basal ganglia when the seizures spread to extratemporal structures. Preclinical studies have found that inhibition of the substantia nigra pars reticulata (SN), a major output structure of the basal ganglia, can reduce the duration and severity of TL seizures in animal models. These findings suggest the SN plays a role critical in the maintenance or propagation of TL seizures. Two stereotyped onset patterns commonly observed in TL seizures are low-amplitude fast (LAF) and high-amplitude slow (HAS). Both onset patterns can arise from the same ictogenic circuit, however seizures with LAF onset pattern typically spread farther and have a larger onset zone than HAS. Therefore, we would expect LAF seizures to entrain the SN more so than HAS seizures. Here, we use a nonhuman primate (NHP) model of TL seizures to confirm the implication of the SN in TL seizure and to characterize the relationship between TL seizure onset pattern and the entrainment of the SN. METHODS: Recording electrodes were implanted in the hippocampus (HPC) and SN in 2 NHPs. One subject was also implanted with extradural screws for recording activity in the somatosensory cortex (SI). Neural activity from both structures was recorded at a 2 kHz sampling rate. Seizures were induced by intrahippocampal injection of penicillin, which produced multiple spontaneous, nonconvulsive seizures over 3-5 hours. The seizure onset patterns were manually classified as LAF, HAS or other/undetermined. Across all seizures, spectral power and coherence were calculated for the frequency bands 1-7 Hz, 8-12 Hz and 13-25 Hz from/between both structures and compared between the 3 seconds before the seizure, the first 3 seconds of the seizure, and the 3 seconds before seizure offset. These changes were then compared between the LAF and HAS onset patterns. RESULTS: During temporal lobe seizures, the 8-12 Hz and 13-25 Hz power in the SN along with the 1-7 Hz and 13-15 Hz power in the SI was significantly higher during onset than before the seizure. Both the SN and SI had an increase in coherence with the HPC in the 13-25 Hz and 1- 7 Hz frequency ranges, respectively. Comparing these differences between LAF and HAS, both were associated with the increase in the HPC/SI coherence, while the increase in HPC/SN increase was specific to LAF. CONCLUSION: Our findings suggest that the SN may be entrained by temporal lobe seizures secondary to the SI during the farther spreading of LAF seizures, which supports the theory that the SN plays a role in the generalization and/or maintenance of temporal lobe seizures and helps explains the anti-ictogenic effect of SN inhibition.

Most medical centers are postponing elective procedures and deferring non-urgent clinic visits to conserve hospital resources and prevent spread of COVID-19. The pandemic crisis presents some unique challenges for patients currently being treated with deep brain stimulation (DBS). Movement disorder (Parkinson's disease, essential tremor, dystonia), neuropsychiatric disorder (obsessive compulsive disorder, Tourette syndrome, depression), and epilepsy patients can develop varying degrees of symptom worsening from interruption of therapy due to neurostimulator battery reaching end of life, device malfunction or infection. Urgent intervention to maintain or restore stimulation may be required for patients with Parkinson's disease who can develop a rare but potentially life-threatening complication known as DBS-withdrawal syndrome. Similarly, patients with generalized dystonia can develop status dystonicus, patients with obsessive compulsive disorder can become suicidal, and epilepsy patients can experience potentially life-threatening worsening of seizures as a result of therapy cessation. DBS system infection can require urgent, and rarely emergent surgery. Elective interventions including new implantations and initial programming should be postponed. For patients with existing DBS systems, the battery status and electrical integrity interrogation can now be performed using patient programmers, and employed through telemedicine visits or by phone consultations. The decision for replacement of the implantable pulse generator to prevent interruption of DBS therapy should be made on a case-by-case basis taking into consideration battery status and a patient's tolerance to potential therapy disruption. Scheduling of the procedures, however, depends heavily on the hospital system regulations and on triage procedures with respect to safety and resource utilization during the health crisis.

Outcomes of treating low-grade epilepsy-associated tumors (LEATs) in the temporal lobe with MRI-guided laser interstitial thermal therapy (MRgLITT) remain poorly characterized. This study aimed to compare the safety and effectiveness of treating temporal lobe LEATs with MRgLITT versus open resection in a consecutive single-institution series. We reviewed all adult patients with epilepsy that underwent surgery for temporal lobe LEATs at our institution between 2002 and 2019, during which time we switched from open surgery to MRgLITT. Surgical outcome was categorized by Engel classification at >12mo follow-up and Kaplan–Meir analysis of seizure freedom. We recorded hospital length of stay, adverse events, and available neuropsychological results. Of 14 total patients, 7 underwent 9 open resections, 6 patients underwent MRgLITT alone, and 1 patient underwent an open resection followed by MRgLITT. Baseline group demographics differed and were notable for preoperative duration of epilepsy of 9.0 years (range 1–36) for open resection versus 14.0 years (range 2–34) for MRgLITT. Median length of stay was one day shorter for MRgLITT compared to open resection (p=<.0001). There were no major adverse events in the series, but there were fewer minor adverse events following MRgLITT. At 12mo follow-up, 50% (5/10) of patients undergoing open resection and 57% (4/7) of patients undergoing MRgLITT were free of disabling seizures (Engel I). When comparing patients who underwent similar procedures in the dominant temporal lobe, patients undergoing MRgLITT had fewer and milder material-specific neuropsychological declines than patients undergoing open resections. In this small series, MRgLITT was comparably safe and effective relative to open resection of temporal lobe LEATs.

Modulating brain oscillations has strong therapeutic potential. However, commonly used non-invasive interventions such as transcranial magnetic or direct current stimulation have limited effects on deeper cortical structures like the medial temporal lobe. Repetitive audio-visual stimulation, or sensory flicker, modulates such structures in mice but little is known about its effects in humans. Using high spatiotemporal resolution, we mapped and quantified the neurophysiological effects of sensory flicker in human subjects undergoing presurgical intracranial seizure monitoring. We found that flicker modulates both local field potential and single neurons in higher cognitive regions, including the medial temporal lobe and prefrontal cortex, and that local field potential modulation is likely mediated via resonance of involved circuits. We then assessed how flicker affects pathological neural activity, specifically interictal epileptiform discharges, a biomarker of epilepsy also implicated in Alzheimer’s and other diseases. In our patient population with focal seizure onsets, sensory flicker decreased the rate interictal epileptiform discharges. Our findings support the use of sensory flicker to modulate deeper cortical structures and mitigate pathological activity in humans.

Background Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. Objective The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain. Methods To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. Results Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. Conclusion By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

BACKGROUND: Radiological identification of temporal lobe epilepsy (TLE) is crucial for diagnosis and treatment planning. TLE neuroimaging abnormalities are pervasive at the group level, but they can be subtle and difficult to identify by visual inspection of individual scans, prompting applications of artificial intelligence (AI) assisted technologies. METHOD: We assessed the ability of a convolutional neural network (CNN) algorithm to classify TLE vs. patients with AD vs. healthy controls using T1-weighted magnetic resonance imaging (MRI) scans. We used feature visualization techniques to identify regions the CNN employed to differentiate disease types. RESULTS: We show the following classification results: healthy control accuracy = 81.54% (SD = 1.77%), precision = 0.81 (SD = 0.02), recall = 0.85 (SD = 0.03), and F1-score = 0.83 (SD = 0.02); TLE accuracy = 90.45% (SD = 1.59%), precision = 0.86 (SD = 0.03), recall = 0.86 (SD = 0.04), and F1-score = 0.85 (SD = 0.04); and AD accuracy = 88.52% (SD = 1.27%), precision = 0.64 (SD = 0.05), recall = 0.53 (SD = 0.07), and F1 score = 0.58 (0.05). The high accuracy in identification of TLE was remarkable, considering that only 47% of the cohort had deemed to be lesional based on MRI alone. Model predictions were also considerably better than random permutation classifications (p < 0.01) and were independent of age effects. CONCLUSIONS: AI (CNN deep learning) can classify and distinguish TLE, underscoring its potential utility for future computer-aided radiological assessments of epilepsy, especially for patients who do not exhibit easily identifiable TLE associated MRI features (e.g., hippocampal sclerosis).

Brain stimulation is a promising therapy for several neurological disorders, including Parkinson's disease. Stimulation parameters are selected empirically and are limited to the frequency and intensity of stimulation. We varied the temporal pattern of deep brain stimulation to ameliorate symptoms in a parkinsonian animal model and in humans with Parkinson's disease. We used model-based computational evolution to optimize the stimulation pattern. The optimized pattern produced symptom relief comparable to that from standard high-frequency stimulation (a constant rate of 130 or 185 Hz) and outperformed frequency-matched standard stimulation in a parkinsonian rat model and in patients. Both optimized and standard high-frequency stimulation suppressed abnormal oscillatory activity in the basal ganglia of rats and humans. The results illustrate the utility of model-based computational evolution of temporal patterns to increase the efficiency of brain stimulation in treating Parkinson's disease and thereby reduce the energy required for successful treatment below that of current brain stimulation paradigms.

Objective. Patients with medically refractory epilepsy often undergo intracranial electroencephalography (iEEG) monitoring to identify a seizure focus and determine their candidacy for surgical intervention. This clinically necessary monitoring period provides an increasingly utilized research opportunity to study human neurophysiology, however ethical concerns demand a thorough appreciation of the associated risks. We measured the incidence of research stimulation-Associated seizures in a large multi-institutional dataset in order to determine whether brain stimulation was statistically associated with seizure incidence and identify potential risk factors for stimulation-Associated seizures. Approach. 188 subjects undergoing iEEG monitoring across ten institutions participated in 770 research stimulation sessions over 3.5 yr. Seizures within 30 min of a stimulation session were included in our retrospective analysis. We analyzed stimulation parameters, seizure incidence, and typical seizure patterns, to assess the likelihood that recorded seizures were stimulation-induced, rather than events that occurred by chance in epilepsy patients prone to seizing. Main results. In total, 14 seizures were included in our analysis. All events were single seizures, and no adverse events occurred. The mean amplitude of seizure-Associated stimulation did not differ significantly from the mean amplitude delivered in sessions without seizures. In order to determine the likelihood that seizures were stimulation induced, we used three sets of analyses: visual iEEG analysis, statistical frequency, and power analyses. We determined that three of the 14 seizures were likely stimulation-induced, five were possibly stimulation-induced, and six were unlikely stimulation-induced. Overall, we estimate a rate of stimulation-induced seizures between 0.39% and 1.82% of sessions. Significance. The rarity of stimulation-Associated seizures and the fact that none added morbidity or affected the clinical course of any patient are important findings for understanding the feasibility and safety of intracranial stimulation for research purposes.

Objective: Magnetic resonance imaging (MRI)–guided laser interstitial thermal therapy (MRg-LITT) is an alternative to open epilepsy surgery. We assess safety and effectiveness of MRg-LITT for extratemporal lobe epilepsy (ETLE) in patients who are considered less favorable for open resection. Methods: We retrospectively reviewed sequential cases of patients with focal ETLE who underwent MRg-LITT between 2012 and 2019. Epileptogenic zones were determined from standard clinical and imaging data ± stereoelectroencephalography (SEEG). Standard stereotactic techniques, MRI thermometry, and a commercial laser thermal therapy system were used for ablations. Anatomic MRI was used to calculate ablation volumes. Clinical outcomes were determined longitudinally. Results: Thirty-five patients with mean epilepsy duration of 21.3 ± 12.2 years underwent MRg-LITT for focal ETLE at a mean age 36.4 ± 12.7 years. A mean 2.59 ± 1.45 trajectories per patient were used to obtain ablation volumes of 8.8 ± 7.5 cm3. Mean follow-up was 27.3 ± 19.5 months. Of 32 patients with >12 months of follow-up, 17 (53%) achieved good outcomes (Engel class I + II) of whom 14 (44%) were Engel class I. Subgroup analysis revealed better outcomes for patients with lesional ETLE than for those who were nonlesional, multifocal, or who had failed prior interventions (P =.02). Of 13 patients showing favorable seizure-onset patterns (localized low voltage fast activity or rhythmic spiking on SEEG) prior to ablation, 9 (69%) achieved good outcomes, whereas only 3 of 11 (27%) who show other slower onset patterns achieved good outcomes. Minor adverse events included six patients with transient sensorimotor neurologic deficits and four patients with asymptomatic hemorrhages along the fiber tract. Major adverse events included one patient with a brain abscess that required stereotactic drainage and one patient with persistent hypothalamic obesity. Three deaths—two seizure-associated and one suicide—were unrelated to surgical procedures. Significance: MRI-guided laser interstitial thermal therapy (or MRg-LITT) was well-tolerated and yielded good outcomes in a heterogeneous group of ETLE patients. Lesional epilepsy and favorable seizure-onset patterns on SEEG predicted higher likelihoods of success.