GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABAA receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach.

Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus.

Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene therapy is an evolving innovative approach that may prove useful for clinical applications. In animal models of temporal lobe epilepsy (TLE), gene therapy treatments based on viral vectors encoding NPY or galanin have been shown to effectively suppress seizures. However, how this translates to human TLE remains unknown. A unique possibility to validate these animal studies is provided by a surgical therapeutic approach, whereby resected epileptic tissue from temporal lobes of pharmacoresistant patients are available for neurophysiological studies in vitro. To test whether NPY and galanin have antiepileptic actions in human epileptic tissue as well, we applied these neuropeptides directly to human hippocampal slices in vitro. NPY strongly decreased stimulation-induced EPSPs in dentate gyrus and CA1 (up to 30 and 55%, respectively) via Y2 receptors, while galanin had no significant effect. Receptor autoradiographic binding revealed the presence of both NPY and galanin receptors, while functional receptor binding was only detected for NPY, suggesting that galanin receptor signaling may be impaired. These results underline the importance of validating findings from animal studies in human brain tissue, and advocate for NPY as a more appropriate candidate than galanin for future gene therapy trials in pharmacoresistant TLE patients.

The use of Brainsuite iCT for frame-based stereotactic procedures.

BACKGROUND: Frame-based stereotactic procedures are the gold standard because of their superior stereotactic accuracy. The procedure used to be in multiple steps and was especially cumbersome and hazardous in intubated patients. A single-step procedure using intraoperative CT was created to optimize the procedures. METHODS: A combined fixation and low profile frame holder was designed for the operating table, allowing positioning for the scanning procedure immediately followed by the surgical biopsy procedure with the same positioning and head fixation. For placement of depth electrodes immediate CT control of positioning was feasible. RESULTS: In the first 8 months the procedure was successfully used 65 times including 8 times in pediatric cases. The procedure duration in awake patients was on average 81 min (range 33 to 202) and in intubated patients (children) on average 89 min (median 89, 78-100). DISCUSSION: This study demonstrates that frame-based stereotactic procedures in all brain locations are a feasible and practical technique with improved workflow and added patient safety and comfort.

Source localization of rhythmic ictal EEG activity: a study of diagnostic accuracy following STARD criteria.

PURPOSE: Although precise identification of the seizure-onset zone is an essential element of presurgical evaluation, source localization of ictal electroencephalography (EEG) signals has received little attention. The aim of our study was to estimate the accuracy of source localization of rhythmic ictal EEG activity using a distributed source model. METHODS: Source localization of rhythmic ictal scalp EEG activity was performed in 42 consecutive cases fulfilling inclusion criteria. The study was designed according to recommendations for studies on diagnostic accuracy (STARD). The initial ictal EEG signals were selected using a standardized method, based on frequency analysis and voltage distribution of the ictal activity. A distributed source model-local autoregressive average (LAURA)-was used for the source localization. Sensitivity, specificity, and measurement of agreement (kappa) were determined based on the reference standard-the consensus conclusion of the multidisciplinary epilepsy surgery team. Predictive values were calculated from the surgical outcome of the operated patients. To estimate the clinical value of the ictal source analysis, we compared the likelihood ratios of concordant and discordant results. Source localization was performed blinded to the clinical data, and before the surgical decision. KEY FINDINGS: Reference standard was available for 33 patients. The ictal source localization had a sensitivity of 70% and a specificity of 76%. The mean measurement of agreement (kappa) was 0.61, corresponding to substantial agreement (95% confidence interval (CI) 0.38-0.84). Twenty patients underwent resective surgery. The positive predictive value (PPV) for seizure freedom was 92% and the negative predictive value (NPV) was 43%. The likelihood ratio was nine times higher for the concordant results, as compared with the discordant ones. SIGNIFICANCE: Source localization of rhythmic ictal activity using a distributed source model (LAURA) for the ictal EEG signals selected with a standardized method is feasible in clinical practice and has a good diagnostic accuracy. Our findings encourage clinical neurophysiologists assessing ictal EEGs to include this method in their armamentarium.

Awake Laser Ablation with Continuous Neuropsychological Testing During Treatment of Brain Tumors and Epilepsy.

MR-guided laser interstitial thermal therapy (LITT) is feasible and safe in the awake patient. Awake LITT may be performed with analgesics for head fixation in a head-ring, no sedation during laser ablation, and with continuous neurological testing in patients with brain tumors and epilepsy. In the LITT treatment of lesions near eloquent areas and subcortical fiber tracts, neurological function can potentially be preserved by monitoring the patient during laser ablation.

Hot and Cold Cognitive Disturbances in Parkinson Patients Treated with DBS-STN: A Combined PET and Neuropsychological Study.

Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how the cerebral 5-HT system associates to disturbances in cognition and mood in PD patients with DBS-STN turned on and off. We used psychological tests and questionnaires to evaluate cognitive function and the effects on mood from turning DBS-STN off. We applied a novel PET neuroimaging methodology to evaluate the integrity of the cerebral serotonin system. We measured 5-HT1BR binding in 13 DBS-STN-treated PD patients, at baseline and after turning DBS off. Thirteen age-matched volunteers served as controls. The measures for cognition and mood were correlated to the 5-HT1BR availability in temporal limbic cortex. 5-HT1BR binding was proportional to working memory performance and inverse proportional to affective bias for face recognition. When DBS is turned off, patients feel less vigorous; the higher the limbic and temporal 5-HT1BR binding, the more they are affected by DBS being turned off. Our study suggests that cerebral 5-HTR binding is associated with non-motor symptoms, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

A randomised double-blind controlled study of Deep Brain Stimulation for dystonia in STN or GPi - A long term follow-up after up to 15 years.

AIM: This is a long-term open follow-up of a prospective double-blind crossover study, where electrodes were bilaterally implanted in both the Subthalamic nucleus (STN) and internal pallidum (GPi) in patients with isolated dystonia. METHODS: Patients with isolated dystonia were included to undergo surgery with Deep Brain stimulation (DBS) and after randomization, in a double-blind cross-over study, receiving bilateral stimulation of either STN or GPi for 6 months in each target. Preoperative and postoperative assessments with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the 36-item Short Form Health Survey (SF-36) were performed. In this long-term follow-up (LFU), these ratings were repeated, and patients were evaluated with cognitive tests. RESULTS: 21 patients were included in the protocol, 9 patients with generalized dystonia, 12 with a diagnosis of cervical dystonia. The mean duration of disease was 19.3 years, age at time of surgery 50.1 years. Fourteen patients participated in the LFU. At a mean follow-up of 10.2 years (range 4.8-15.4), BFMDRS movement score was improved with a mean of 36% (p < 0.05) compared with baseline. At LFU both a statistically significant improvement of stimulation in STN on BFMDRS movement score (p = 0.029) and Gpi (p = 0.008) was demonstrated, no significant difference was found between the two targets (p = 0.076). SF-36 improved for both targets. CONCLUSION: In this study we performed a long-term follow-up in 14 patients with cervical or generalized dystonia, who received stimulation in GPi, STN or both. The mean follow-up time was more than 10 years. Our data support a long-term effect of both STN-DBS and GPi-DBS in dystonia with equal effect and safety for up to 15 years. STN has been proven a viable safe and effective target and may be used as an alternative to GPi in both adult-onset cervical dystonia and generalized dystonia.

An fMRI-compatible system for targeted electrical stimulation.

BACKGROUND: Neuromodulation is a rapidly expanding therapeutic option considered within neuropsychiatry, pain and rehabilitation therapy. Combining electrostimulation with feedback from fMRI can provide information about the mechanisms underlying the therapeutic effects, but so far, such studies have been hampered by the lack of technology to conduct safe and accurate experiments. Here we present a system for fMRI compatible electrical stimulation, and the first proof-of-concept neuroimaging data with deep brain stimulation (DBS) in pigs obtained with the device. NEW METHOD: The system consists of two modules, placed in the control and scanner room, connected by optical fiber. The system also connects to the MRI scanner to timely initiate the stimulation sequence at start of scan. We evaluated the system in four pigs with DBS in the subthalamic nucleus (STN) while we acquired BOLD responses in the STN and neocortex. RESULTS: We found that the system delivered robust electrical stimuli to the implanted electrode in sync with the preprogrammed fMRI sequence. All pigs displayed a DBS-STN induced neocortical BOLD response, but none in the STN. COMPARISONS WITH EXISTING METHOD: The system solves three major problems related to electric stimuli and fMRI examinations, namely preventing distortion of the fMRI signal, enabling communication that synchronize the experimental conditions, and surmounting the safety hazards caused by interference with the MRI scanner. CONCLUSIONS: The fMRI compatible electrical stimulator circumvents previous problems related to electroceuticals and fMRI. The system allows flexible modifications for fMRI designs and stimulation parameters, and can be customized to electroceutical applications beyond DBS.

Local networks from different parts of the human cerebral cortex generate and share the same population dynamic.

A major goal of neuroscience is to reveal mechanisms supporting collaborative actions of neurons in local and larger-scale networks. However, no clear overall principle of operation has emerged despite decades-long experimental efforts. Here, we used an unbiased method to extract and identify the dynamics of local postsynaptic network states contained in the cortical field potential. Field potentials were recorded by depth electrodes targeting a wide selection of cortical regions during spontaneous activities, and sensory, motor, and cognitive experimental tasks. Despite different architectures and different activities, all local cortical networks generated the same type of dynamic confined to one region only of state space. Surprisingly, within this region, state trajectories expanded and contracted continuously during all brain activities and generated a single expansion followed by a contraction in a single trial. This behavior deviates from known attractors and attractor networks. The state-space contractions of particular subsets of brain regions cross-correlated during perceptive, motor, and cognitive tasks. Our results imply that the cortex does not need to change its dynamic to shift between different activities, making task-switching inherent in the dynamic of collective cortical operations. Our results provide a mathematically described general explanation of local and larger scale cortical dynamic.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study.

OBJECTIVE: EEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. METHODS: We have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. RESULTS: We analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66-85.37%). CONCLUSIONS: Automated ictal ESI has a high accuracy for localizing the seizure onset zone. SIGNIFICANCE: Automating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Parkinson patients have a presynaptic serotonergic deficit: A dynamic deep brain stimulation PET study.

Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Apart from alleviating the motor symptoms, Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how turning DBS off affects the serotonergic system. We here exploit a novel functional PET neuroimaging methodology to evaluate the preservation of serotonergic neurons and capacity to release serotonin. We measured cerebral 5-HT1BR binding in 13 DBS-STN treated PD patients, at baseline and after turning DBS off. Ten age-matched volunteers served as controls. Clinical measures of motor symptoms were assessed under the two conditions and correlated to the PET measures of the static and dynamic integrity of the serotonergic system. PD patients exhibited a significant loss of frontal and parietal 5-HT1BR, and the loss was significantly correlated to motor symptom severity. We saw a corresponding release of serotonin, but only in brain regions with preserved 5-HT1BR, suggesting the presence of a presynaptic serotonergic deficit. Our study demonstrates that DBS-STN dynamically regulates the serotonin system in PD, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

[MR-guided laser interstitial thermal therapy in the treatment of brain tumours and epilepsy].

MR-guided laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical procedure, which in the last decade has gained significant momentum of the treatment of intracranial tumours and epileptic foci. In brief, LITT utilises the heat from a stereotactically placed laser catheter to selectively ablate a lesion or a structure under real-time MRI guidance, which is summarised and discussed in this review. The first LITT system gained FDA approval in 2007 and was CE-marked in 2018. In December 2020, the first patient with recurrent glioblastoma was treated at the Department of Neurosurgery at Rigshospitalet, Copenhagen.

Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up.

OBJECTIVE: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. METHODS: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. RESULTS: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. CONCLUSION: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

Somatosensory phenomena elicited by electrical stimulation of hippocampus: Insight into the ictal network.

Up to 11% of patients with mesial temporal lobe epilepsy experience somatosensory auras, although these structures do not have any somatosensory physiological representation. We present the case of a patient with left mesial temporal lobe epilepsy who had somatosensory auras on the right side of the body. Stereo-EEG recording demonstrated seizure onset in the left mesial temporal structures, with propagation to the sensory cortices, when the patient experienced the somatosensory aura. Direct electrical stimulation of both the left amygdala and the hippocampus elicited the patient's habitual, somatosensory aura, with afterdischarges propagating to sensory cortices. These unusual responses to cortical stimulation suggest that in patients with epilepsy, aberrant neural networks are established, which have an essential role in ictogenesis.

Deep Brain Stimulation in Parkinson's Disease: Still Effective After More Than 8 Years.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is well established and the most effective treatment for advanced Parkinson's disease (PD). However, little is known of the long-term effects. OBJECTIVES: The aim of this study was to examine the long-term effects of STN-DBS in PD and evaluate the effect of reprogramming after more than 8 years of treatment. METHODS: A total of 82 patients underwent surgery in Copenhagen between 2001 and 2008. Before surgery and at 8 to 15 years follow-up, the patients were rated with the Unified Parkinson's Disease Rating Scale (UPDRS) with and without stimulation and medicine. Furthermore, at long-term follow-up, the patients were offered a systemic reprogramming of the stimulation settings. Data from patients' medical records were collected. The mean (range) age at surgery was 60 (42-78) years, and the duration of disease was 13 (5-25) years. A total of 30 patients completed the long-term follow-up. RESULTS: The mean reduction of the motor UPDRS by medication before surgery was 52%. The improvement of motor UPDRS with stimulation alone compared with motor UPDRS with neither stimulation nor medication was 61% at 1 year and 39% at 8 to 15 years after surgery (before reprogramming). Compared with before surgery, medication was reduced by 55% after 1 year and 44% after 8 to 15 years. After reprogramming, most patients improved. CONCLUSIONS: STN-DBS remains effective in the long run, with a sustained reduction of medication in the 30 of 82 patients available for long-term follow-up. Reprogramming is effective even in the late stages of PD and after many years of treatment.

Increase in cognitive function is seen in many single-operated pediatric patients after epilepsy surgery.

PURPOSE: The recurrent seizures of pediatric drug-resistant epilepsy (DRE) are known to impair brain development and can lead to a loss in cognitive functioning. Surgery is increasingly being used to treat children with DRE. This study investigates the pre- and postoperative cognitive function in a pediatric epilepsy surgery cohort as well as predictive determinants of change in intelligence quotient (IQ) following surgery. METHODS: A consecutive series of 91 Danish children who underwent focal resective epilepsy surgery between January 1996 and December 2016 were included. All underwent preoperative cognitive evaluation and were reevaluated at 1-year and/or 2-year follow-up. Single-operated and multi-operated patients were examined separately. RESULTS: 79 of 91 patients were single-operated. Single-operated patients received less anti-epileptic drugs (AED) and experienced a decrease in seizure frequency postoperatively, p < 0.001. IQ increased postoperatively (IQ change ± standard deviation: 3.3 ± 14.0), p < 0.05. High preoperative seizure frequency was a significant predictor for decreased IQ, p < 0.01. Multi-operated patients did not experience a reduction in AED treatment. Surgery and continued AED treatment did, however, result in significantly better seizure control, p < 0.01. IQ remained unchanged in multi-operated patients. CONCLUSION: Epilepsy surgery allowed for IQ gains in single-operated patients. Preoperative seizure frequency was a significant predictor of IQ change following surgery. Interactions between other, not included, possible predictors remain to be examined. Single-operated patients had the best cognitive outcome. The inclusion of a non-surgical control group is needed to assess the extent of the beneficial effects of surgery on cognitive ability.

Diagnostic added value of electrical source imaging in presurgical evaluation of patients with epilepsy: A prospective study.

OBJECTIVE: To investigate the diagnostic added value of electrical source imaging (ESI) in presurgical evaluation of patients with drug resistant focal epilepsy. METHODS: Eighty-two consecutive patients were included. We analyzed both low density (LD) and high density (HD) EEG recordings. LD ESI was done on interictal and ictal signals recorded during long-term video-EEG monitoring (LTM), with standard 25 electrodes and age-matched template head models. HD ESI was done on shorter recordings (90-120 min), with 256 electrodes, using individual head model. The multidisciplinary team made decisions first blinded to ESI (based on all other modalities) and then discussed the results of the ESI. We considered that ESI had diagnostic added value, when it provided non-redundant information that changed the patients management plan. RESULTS: ESI had diagnostic added value in 28 patients (34%). In most cases (85.7%), these changes were related to planning of the invasive recordings. In nine out of 13 patients, invasive recordings confirmed the localization. Out of eight patients in whom the ESI source was resected, six became seizure-free. CONCLUSIONS: ESI provides non-redundant information in one third of the patients undergoing presurgical evaluation. SIGNIFICANCE: This study provides evidence for the diagnostic added value of ESI in presurgical evaluation.

[Gene therapy for central nervous system disorders].

In recent years, gene therapy has resurged as a potential treatment for an increasing number of medical diseases including those affecting the central nervous system (CNS), which is discussed in this review. Clinical trials have revealed promising results particularly in gene therapy for Parkinson's disease with upregulation of dopamine synthesis or downregulation of huntingtin synthesis in Huntington's disease. Gene therapy for spinal motor atrophy has received FDA approval this year. The biggest success is seen in ophthalmology, where gene therapy has been FDA/EU-approved for retinitis pigmentosa, sparking further hope of use for other CNS diseases in a near future.

[Neurosurgical treatment of dystonia].

In this review, we present evidence of treatment effect with deep brain stimulation (DBS) in patients with isolated forms of dystonia with generalised-, segmental- and focal phenotypes as well as tardive dystonia and dyskinetic cerebral palsy. Dystonia is a heterogeneous movement disorder, which can be disabling and difficult to treat. Patients with dystonia, who do not experience relief with medication and botulinum toxin, may be candidates for DBS.

Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients.

In epilepsy patients, drug-resistant seizures often originate in one of the temporal lobes. In selected cases, when certain requirements are met, this area is surgically resected for therapeutic reasons. We kept the resected tissue slices alive in vitro for 48 h to create a platform for testing a novel treatment strategy based on neuropeptide Y (NPY) against drug-resistant epilepsy. We demonstrate that NPY exerts a significant inhibitory effect on epileptiform activity, recorded with whole-cell patch-clamp, in human hippocampal dentate gyrus. Application of NPY reduced overall number of paroxysmal depolarising shifts and action potentials. This effect was mediated by Y2 receptors, since application of selective Y2-receptor antagonist blocked the effect of NPY. This proof-of-concept finding is an important translational milestone for validating NPY-based gene therapy for targeting focal drug-resistant epilepsies, and increasing the prospects for positive outcome in potential clinical trials.