OBJECTIVE:Depression is common in mesial temporal lobe epilepsy (mTLE), but its neuroanatomical basis-and overlap with major depressive disorder (MDD)-remains poorly defined. We investigated whether the cortical and subcortical alterations reported in MDD are also present in mTLE and leveraged the frequent occurrence of depression after epilepsy surgery to test whether such changes predate the onset of post-surgical depression. METHODS:Eighty-nine mTLE patients scheduled for anterior temporal lobectomy were classified as never depressed (NoD, n = 42), depressed before surgical evaluation (PreD, n = 23), or developing de-novo depression after surgery (PostD, n = 22). Pre-operative 3 T MRI (1 mm T1, T2, FLAIR) was processed with FreeSurfer v6.3. Six frontotemporal-limbic regions showing the largest MDD effects in ENIGMA studies-orbitofrontal cortex, rostral anterior cingulate, insula, fusiform gyrus, hippocampus, posterior cingulate-were analyzed using a latent variable model. RESULTS:Depression status significantly influenced combined morphology in both hemispheres (p < 0.05). Relative to NoD, both PreD and PostD groups showed reduced cortical thickness in the orbitofrontal cortex, fusiform gyrus, insula, and rostral anterior cingulate (Cohen's d = -0.04 to -0.14). Hippocampal volume and posterior cingulate thickness did not differ between groups. SIGNIFICANCE:Four of the six frontotemporal regions showing the largest morphometric alterations in MDD also exhibit reduced cortical thickness in mTLE patients with past or future depression. This shared frontotemporal thinning pattern supports depression in mTLE as an expression of network pathology common to MDD, while residual regional differences may help explain the distinct phenotypic presentations of depression in these neuropsychiatric disorders. In PostD patients, these abnormalities were already present pre-operatively, consistent with a pre-existing vulnerability rather than a purely psychosocial reaction to surgery or epilepsy per se.

INTRODUCTION:Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an efficient treatment for advanced Parkinson's disease (PD), when oral medication no longer provides satisfactory symptom control or causes disabling side effects. However, long-term outcomes vary considerably, and reliable preoperative biomarkers remain lacking. Dopamine transporter single-photon emission computed tomography (DAT SPECT) provides an indirect in vivo measure of presynaptic striatal dopaminergic degeneration in the basal ganglia. In patients evaluated for STN-DBS, DAT SPECT with [123I]FP-CIT supported the clinical diagnosis. This study aimed to examine whether preoperative DAT SPECT predicts the long-term outcome after STN-DBS surgery. METHODS:Fifty-five patients with PD underwent DAT SPECT before STN-DBS surgery. Motor symptoms were assessed in ON and OFF medication states before surgery, and at long-term follow-up, 8-14 years after surgery. Cognition was assessed before surgery and at the long-term follow-up, and clinical data were curated retrospectively from medical records. RESULTS:Lower DAT striatal specific binding ratio (SBR) significantly correlated with longer disease duration, indicating greater dopaminergic loss. Reduced striatal SBR predicted increased mortality during the long-term follow-up. Regional analyses revealed that this association was driven by the caudate nucleus. Furthermore, greater caudate compared to putaminal involvement, reflected by a higher putaminal/caudate uptake ratio, was related to longer disease duration and increased mortality. Preoperative DAT SPECT measures were not associated with DBS effect, cognitive function, or depression. CONCLUSION:Dopamine transporter imaging provides valuable insight into the pathophysiology and disease progression of PD. Although DAT SPECT did not predict the therapeutic effect of STN-DBS, this study demonstrates that DAT SPECT captures aspects of disease progression and survival in PD. These results highlight the value of assessing the dopaminergic system before advanced treatment, as DAT SPECT may provide prognostic indicators that could complement the preoperative evaluation.

Background Cognitive impairment and dementia are common findings in patients with Parkinson's disease (PD). However, the long-term effects of subthalamic deep brain stimulation (STN-DBS) on cognition remain unclear. Objective We report short- and long-term effects of STN-DBS on cognition in PD. Methods We analyzed neuropsychological data before STN-DBS surgery, 3-month post-surgery, 1-year post-surgery and in a long-term follow-up (8–15 years post-surgery) to examine the effects of STN-DBS on cognition. Results 81 patients with a mean disease duration of 13.0 years were examined before surgery. 50.6% were identified with mild cognitive impairment (MCI), having a mean disease duration of 14.2 years. Pre-surgical PD-MCI was not associated with clinically diagnosed dementia (PD-D) before death or before long-term follow-up (OR 0.8, 95% CI 0.3–2.2, p = 0.714), but disease duration at the time of surgery was associated with development of PD-D (OR 1.2, 95% CI 1.1–1.3, p = 0.005). Verbal fluency declined significantly 3 months after surgery, while other domains remained unaffected. In neuropsychological testing at long-term follow-up (N = 29), global cognitive impairment or dementia was found in 19 patients. The presence of depressive symptoms before surgery was associated to PD-D at long-term follow-up. Death before long-term follow-up was more common in patients with pre-surgical MCI than in patients with normal cognition. Conclusions Influence on cognition was described in a short- and long-term follow-up study up to 15 years after STN-DBS surgery in PD. Disease duration, but not pre-surgical MCI was associated with development of dementia. Impaired verbal fluency was observed both in a short- and long-term follow-up.

Introduction Vasopressor support is often preferred as an efficient and convenient way to raise the blood pressure during surgery and intensive care therapy. However, the optimal vasopressor for ensuring organ blood flow and tissue oxygen delivery during surgery remains undetermined. This study aims to assess the impact of norepinephrine versus phenylephrine on cerebral and non-cerebral organ perfusion and oxygenation during anaesthesia in neurosurgical patients with brain tumours. The study also explores the impact of the vasopressor agents on the distribution of cardiac output between various organs.Methods and analysis This is an investigator-initiated, double-blinded, randomised clinical trial including 32 patients scheduled for supratentorial brain tumour surgery. The patients are randomised to receive a phenylephrine or norepinephrine infusion during preoperative positron emission tomography (PET) examinations and the following neurosurgical procedure. PET measurements of blood flow and oxygen metabolism in the brain and other organs are performed on the awake subject during anaesthesia, following a 10% and 20% gradual increase in blood pressure from the baseline value. The primary endpoint is the between-group difference in cerebral blood flow. Secondary endpoints include detection of ischaemic brain lesions possibly associated with vasopressor treatment, changes in cerebral oxygen metabolism, non-cerebral organ blood flow and oxygen metabolism, cardiac output, regional cerebral oxygen saturation, autoregulation and distribution of cardiac output between organs.Ethics and dissemination This study was approved by the Danish National Medical Ethics Committee (20 May 2022; 2203674). Results will be disseminated via peer-reviewed publication and presentation at international conferences.Trial registration number EudraCT no: 2021-006168-26. ClinicalTrials.gov: NCT06083948.

BACKGROUND:Essential tremor is the most common hyperkinetic movement disorder. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) has emerged as second-line therapy. OBJECTIVE:The aim was to obtain the results of the first 108 patients treated with MRgFUS in Denmark. METHODS:Data were entered in a quality assurance database at baseline and 3, 6, and 12 months. Clinician- and patient-rated treatment efficacy was evaluated using the Fahn-Marin-Tolosa (FMT) scale and the Patient Global Impression of Change. RESULTS:A total of 108 persons have currently been treated. Tremor improved by a total mean 6.39 points (95% confidence interval [CI]: 5.01;7.76, P < 0.00001) and 9.63 points (95% CI: 7.60;11.66, P < 0.00001), 10.42 (95% CI: 9.06;11.79, P < 0.00001), and 26.45 (95% CI: 22.46;30.43, P < 0.00001) for FMT parts A, B, and C, respectively, at 3 months. Side effects occurred in 65.7% of patients at 3 months and 33.7% at 12 months. CONCLUSION:Our findings are in line with existing evidence. Questions regarding persistence of gait- and balance-related side effects remain.

Amyotrophic lateral sclerosis (ALS) affects the cerebral cortex layer-dependently, most notably by the foremost targeting of upper motor neurons (UMNs) sited in layer Vb. Previous studies have shown a retained ability of paralysed patients to activate cortical motor networks, even in late-stage ALS. However, it is currently unknown whether such activation reflects a retained capacity to process sensorimotor inputs or if it is a result of actual motor output. Given the distinct function of individual cortical layers, layer-specific functional measurements may provide insight to this question. In this study, using submillimetre resolution laminar fMRI, we assessed the layer-dependent activation associated with attempted (motor) and passive (somatosensory) movements in a locked-in stage ALS patient. We found robust activation in both superficial and deep layers of primary motor cortex (M1). The peak activation in deep layers was localised to layer Vb. These findings demonstrate preserved activity in deep output layers of M1, possibly reflecting a retained ability to engage surviving UMNs despite years of paralysis. Our study underscores the capacity of laminar fMRI to discern subtle cortical activity and elucidates a promising pathway for probing in vivo human ALS pathology with unprecedented resolution.

Objective. Histopathological examinations will diminish as minimally invasive epilepsy surgery increasingly replaces open surgery. The objective of this study was to test if visual and computer-aided quantitative analyses of presurgical high-quality 3 Tesla MRIs complying with the International League Against Epilepsy (ILAE) Neuroimaging Task Force recommendations can inform on histopathological diagnosis. Methods. Ninety-two patients from Copenhagen and Oslo University Hospitals fulfilled patient-, imaging-, and histopathological inclusion criteria: 69 patients were diagnosed with hippocampal sclerosis (HS) ILAE type 1 or 2, and 23 patients had normal appearing hippocampi or other histopathology than HS (no-HS). MRIs from 52 healthy controls (HC) were included. Image processing was performed in FreeSurfer v.6.0 with the built-in cross-sectional hippocampal subfield segmentation tool and multimodal MRI input. Volume outputs were used to calculate volume asymmetry ratios (VARs) for whole hippocampus (WH) and subfields. Results. HS patients had significantly larger WH VARs compared to no-HS patients and HC, with a sensitivity=0.93 and specificity=1.0 for histopathological HS diagnosis. Visual MRI assessment yielded a sensitivity=0.90 and specificity=0.96 for histopathological HS diagnosis. CA1 and CA4 VARs and the number of seizure-free patients were not significantly different in HS ILAE type 1 compared to type 2 patients. Significance. FreeSurfer analyses of presurgical MRIs are excellent at separating patients histopathologically diagnosed with HS from patients with other pathology or normal appearing hippocampi. Using the FreeSurfer hippocampal subfield segmentation tool did not allow for separating HS ILAE subtypes.

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.

Abstract 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.

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.

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.

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.

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.

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.

To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. 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. 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. 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.

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.

We lack viable explanations of how brain functions emerge from collective activities of neurons in networks. We recorded field potentials from many local networks in the human cerebral cortex during a wide variety of brain functions. The network dynamics showed that each local cortical network produced fluctuating attractor states. The state trajectories continuously stretched and contracted during all brain functions, leaving no stable patterns. Different local networks all produced this dynamic, despite different architectures. Single trial stimuli and tasks modified the stretching and contractions. These modified fluctuations cross-correlated among particular networks during specific brain functions. Spontaneous states, rest, sensory, motor and cognitive states all emerged from this dynamic. Its mathematical structure provides a general explanation of cortical dynamics that can be tested experimentally. This universal dynamic is a simple functional organizing principle for brain functions at the mm3 scale that is distinct from existing frameworks. ### Competing Interest Statement The authors have declared no competing interest.