Montreal Neurological Institute Research Articles

Electrical stimulation of the medial orbitofrontal cortex in humans elicits pleasant olfactory perceptions

BackgroundOlfactory hallucinations can be part of epileptic seizures of orbitofrontal origin. Olfactory hallucinations, however, are rare and therefore the semiology, localization and lateralization characteristics are underdetermined. In addition, many discrepancies are found in the literature regarding olfactory processing and orbitofrontal (OF) functions and olfactory function. Particularly, the questions of laterality and affective component in coding of odors in the OF cortex remain controversial. AimsThis study explored whether cortical electrical stimulation of the OF and mesiotemporal brain can trigger olfactory hallucinations with special focus on olfactory percepts in terms of laterality and hedonics. Materials and methodsEight patients with temporal lobe epilepsy participated in the study, at the time of invasive exploration of their epilepsy. The most distal contact of the OF and anterior hippocampus depth electrodes were stimulated (50 Hz, 0.2 ms biphasic pulse; maximal stimulation 4 mA). Patients were instructed to report any kind of sensation they might experience. Intracranial depth electrodes were localized (iElectrodes): subject-specific brain mask, subcortical segmentation and cortical parcellation based on the Destrieux atlas (FreeSurfer) were superposed to the coregistered T1-weighted MRI and CT images (SPM). The center of mass of each electrode-artifact cluster determined the electrode localization. The electrode labeling was done in patient space. To obtain the electrode coordinates in Montreal Neurological Institute (MNI) space, the images obtained previously in the patient space were first segmented and normalized (SPM). Then, the localization procedure (iElectrodes) was run again with these new normalized images in MNI space. ResultsNo hallucination was evoked by stimulation, neither of the right nor the left hippocampus (8/8 patients). Pleasant olfactory hallucinations were evoked by OF stimulation in 5/8 patients in either hemisphere. Patients named the percept as the smell of lemon or coffee for example. Among those 5 patients, electrodes were localized in the cortex of the olfactory sulcus, medial orbital sulcus or medial OF gyrus. Increasing stimulation amplitude changed the olfactory percept identification in 3 out of those 5 patients. No affective judgement or change in perceived odor intensity was reported by the patients. No hallucination was evoked by the stimulation of the white matter of the medial OF brain in 3/8 patients independently of the hemisphere stimulated. ConclusionsThis study demonstrated that stimulation of the cortex of the medial OF brain and not of its white matter elicits specific pleasant olfactory hallucinations independently of the hemisphere stimulated, supporting one symmetrical olfactory processing in human.

Lipid-suppressed and tissue-fraction corrected metabolic distributions in human central brain structures using 2D 1 H magnetic resonance spectroscopic imaging at 7 T.

IntroductionMagnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low signal‐to‐noise ratios data, signal variations due to partial‐volume effects, acquisition and extracranial lipid artifacts, along with clinically relevant aspects such as scan time constraints, are among the challenges associated with in vivo MRSI.MethodsThe aim of this work was to address some of these factors and to develop an acquisition, reconstruction, and postprocessing pipeline to derive lipid‐suppressed metabolite values of central brain structures based on free‐induction decay measurements made using a 7 T MR scanner. Anatomical images were used to perform high‐resolution (1 mm3) partial‐volume correction to account for gray matter, white matter (WM), and cerebral‐spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the Montreal Neurological Institute (MNI) standard atlas facilitated the creation of high‐resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions.Partial‐volume correction improved the delineation of deep brain nuclei. We report average metabolite values including glutamate + glutamine (Glx), glycerophosphocholine, choline and phosphocholine (tCho), (phospo)creatine, myo‐inositol and glycine (mI‐Gly), glutathione, N‐acetyl‐aspartyl glutamate(and glutamine), and N‐acetyl‐aspartate in the basal ganglia, central WM (thalamic radiation, corpus callosum) as well as insular cortex and intracalcarine sulcus.ConclusionMNI‐registered average metabolite maps facilitate group‐based analysis, thus offering the possibility to mitigate uncertainty in variable MRSI data.

Cortical Distribution of Fragile Periventricular Anastomotic Collateral Vessels in Moyamoya Disease: An Exploratory Cross-Sectional Study of Japanese Patients with Moyamoya Disease.

Collateral vessels in Moyamoya disease represent potential sources of bleeding. To test whether these cortical distributions vary among subtypes, we investigated cortical terminations using both standardized MR imaging and MRA. Patients with Moyamoya disease who underwent MR imaging with MRA in our institution were enrolled in this study. MRA was spatially normalized to the Montreal Neurological Institute space; then, collateral vessels were measured on MRA and classified into 3 types of anastomosis according to the parent artery: lenticulostriate, thalamic, and choroidal. We also obtained the coordinates of collateral vessel outflow to the cortex. Differences in cortical terminations were compared among the 3 types of anastomosis. We investigated 219 patients with Moyamoya disease, and a total of 190 collateral vessels (lenticulostriate anastomosis, n = 72; thalamic anastomosis, n = 21; choroidal anastomosis, n = 97) in 46 patients met the inclusion criteria. We classified the distribution patterns of collateral anastomosis as follows: lenticulostriate collaterals outflowing anteriorly (P < .001; 95% CI, 67.0-87.0) and medially (P < .001; 95% CI, 11.0-24.0) more frequently than choroidal collaterals; lenticulostriate collaterals outflowing anteriorly more frequently than thalamic collaterals (P < .001; 95% CI, 34.0-68.0); and choroidal collaterals outflowing posteriorly more frequently than thalamic collaterals (P < .001; 95% CI, 14.0-34.0). Lenticulostriate anastomoses outflowed to the superior or inferior frontal sulcus and interhemispheric fissure. Thalamic anastomoses outflowed to the insular cortex and cortex around the central sulcus. Choroidal anastomoses outflowed to the cortex posterior to the central sulcus and the insular cortex. Cortical distribution patterns appear to differ markedly among the 3 types of collaterals.

Martha Helson Wilson (1929-2020).

Memorializes Martha Helson Wilson (1929-2020), a physiological psychologist. Martha enrolled at Yale University for doctoral study in 1952, where she studied the physiological aspects of sensation with Burton Rosner. She also developed skills in electrophysiology under the direction of Karl Pribram, who became her career-long mentor, collaborator, and friend. In Pribram's Laboratory of Neurophysiology at the Institute of Living in Hartford, Connecticut, Martha met William A. Wilson, another lifelong collaborator as well as her husband for 62 years. Her behavioral investigations of intersensory learning were mainstream comparative psychology, as were her innovative studies of category learning that bridged animal research and human clinical neuropsychology, a field Wilson entered via her 1979 sabbatical with Brenda Milner at the Montreal Neurological Institute. Martha Wilson used this broad knowledge and experience to lead APA Division 6 (Physiological and Comparative Psychology)as its secretary-treasurer, executive committee member-at-large, representative to the Council of Representatives, president-elect, president (1986 -1987), and past president. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Preoperative Prognostic Stratification In GBM Patients Using Inverse Distance-Based Proximity To Stem Cell Niches

Glioblastoma multiforme (GBM) is the most lethal brain cancer in adults, with a high local recurrence rate despite surgery and chemoradiotherapy. Emerging evidence has linked tumor aggressiveness with the involvement of stem cell niches (SCN) that vary by patient. However, existing SCN research insufficiently quantifies the geometrical relationship between all SCN zones and the tumor for personalized risk assessment and potentially more effective therapy. This study aims to establish such relationship in brain GBM patients using MRI inverse distance map. Preoperative T1 MRI scans and pre-labeled tumor regions of 102 patients from the publicly available BRATS2017 dataset were used in this study. SCN segmentation, including bilateral subventricular zones and subgranular zones, were manually defined in the Montreal Neurological Institute (MNI) brain template. Based on the binary SCN segmentations, a proximity map was generated using the sum of the power 1 inverse distance weightings to all observations in SCNs, normalized between 0 and 1. All MR scans were transformed into the MNI space in Advanced Normalization Tools (ANTs) using affine alignment followed by symmetric normalization based lesion excluded deformable registration. The resulted transformations were propagated to each tumor segmentation to calculate the mean proximity score (PS), whose prognostic capacity was then evaluated using Cox proportional hazards regression with overall survival (OS) and Log-rank tests between sorted and evenly divided high-risk and low-risk groups. As a comparison, the same analyses were conducted on traditional stem cell niches related features, including tumor edge to the ventricle (EV) and center to the ventricle (CV). PS is correlated with OS with a hazardous ratio (HR) of 4.45 and a p-value of 0.0297, indicating a significant inverse relationship between SCN proximity and survival. In contrast, neither EV nor CV is significantly correlated with OS, with HR = 0.9676, p = 0.7483 and HR = 0.9884, p = 0.5660, respectively. Furthermore, the log-rank test for patients stratified by PS reveals a significant difference in survival risk (log-rank p = 0.0474), while stratification using either EV (log-rank p = 0.1486) or CV ((log-rank p = 0.5829) fails to result in significant differences. We introduced a novel inverse distance-based metric, proximity score, to more effectively characterize GBM tumor to SCN zones geometrical relationships. Proximity score outperformed traditional edge or center distance-based measurements in OS prediction and risk stratification. With the improved quantification, PS may be used for better personalized GBM risk assessment and therapy.

Commentary: Selective Posterior Callosotomy for Treatment of Epileptic Drop Attacks: Video Documentation of the Surgical Technique: 2-Dimensional Operative Video.

Commentary: Selective Posterior Callosotomy for Treatment of Epileptic Drop Attacks: Video Documentation of the Surgical Technique: 2-Dimensional Operative Video Farhan A Mirza, MD Farhan A Mirza, MD The Montreal Neurological Institute (MNI), Department of Neurosurgery, McGill University, Montreal, CanadaKentucky Neuroscience Institute (KNI), Department of Neurosurgery, University of Kentucky, Lexington, Kentucky Correspondence: Farhan A. Mirza, MD, Department of Neurosurgery, The Montreal Neurological Institute, 3801 Rue University, Montréal, QC H3A 2B4, Canada. Email: Farhan.amirza@gmail.com https://orcid.org/0000-0001-8203-8608 Search for other works by this author on: Oxford Academic Google Scholar Operative Neurosurgery, Volume 19, Issue 5, November 2020, Pages E516–E517, https://doi.org/10.1093/ons/opaa181 Published: 22 June 2020 Article history Received: 13 April 2020 Accepted: 15 April 2020 Published: 22 June 2020

A parcellation-based model of the auditory network

IntroductionThe auditory network plays an important role in interaction with the environment. Multiple cortical areas, such as the inferior frontal gyrus, superior temporal gyrus and adjacent insula have been implicated in this processing. However, understanding of this network's connectivity has been devoid of tractography specificity. MethodsUsing attention task-based functional magnetic resonance imaging (MRI) studies, an activation likelihood estimation (ALE) of the auditory network was generated. Regions of interest corresponding to the cortical parcellation scheme previously published under the Human Connectome Project were co-registered onto the ALE in the Montreal Neurological Institute coordinate space, and visually assessed for inclusion in the network. Diffusion spectrum MRI-based fiber tractography was performed to determine the structural connections between cortical parcellations comprising the network. ResultsFifteen cortical regions were found to be part of the auditory network: areas 44 and 8C, auditory area 1, 4, and 5, frontal operculum area 4, the lateral belt, medial belt and parabelt, parietal area F centromedian, perisylvian language area, retroinsular cortex, supplementary and cingulate eye field and the temporoparietal junction area 1. These regions showed consistent interconnections between adjacent parcellations. The frontal aslant tract was found to connect areas within the frontal lobe, while the arcuate fasciculus was found to connect the frontal and temporal lobe, and subcortical U-fibers were found to connect parcellations within the temporal area. Further studies may refine this model with the ultimate goal of clinical application.

Functional architecture of the motor homunculus detected by electrostimulation.

We performed a prospective electrostimulation study of the motor homunculus in 100 patients without motor deficit or brain lesion in the precentral gyrus in order to acquire accurate Montreal Neurological Institute (MNI) coordinates of the functional areas. The analysis of 248 body coordinates in the precentral gyrus showed rare inter-individual variations in the medial-to-lateral somatotopic movement organization with quite similar intensity thresholds. Electrostimulation only induced basic and stereotyped movements. We detected a relative medial-to-lateral somatotopy of the wrist/hand/global/individual fingers, with sometimes different sites for an individual muscle or movement. We found some similarities to, but also substantial differences from, the seminal work of Penfield and colleagues. We propose an updated version of the human motor homunculus and of its correlation with the somatosensory homunculus, previously defined in MNI space with a similar brain mapping technique. In this prospective electrostimulation study, based on 100 operated patients without motor deficit or brain lesion in the precentral gyrus, we acquired coordinates of the functional areas of the motor homunculus and normalized them to standard MNI space. Among 608 sites stimulated in the precentral gyrus (and 1937 in gyri nearby), 248 positive points (40%) for motor response were detected - 245 in the precentral gyrus. Positive stimulations were detected through the 'on/off' outbreak effect, and only basic movements were detected. We found no significant difference in mean intensity threshold between the motor representations of the fingers (1.94mA), tongue and lower limbs (both 2.0mA), or face (2.25mA). In the precentral gyrus, the evoked body movements displayed a medial-to-lateral somatotopy in very small (often <10mm2 ) areas. The hand region displayed multiple areas for a specific movement, with areas inducing either global or single-finger movement (with a relative medial-to-lateral somatotopy). Among these tested patients, the somatotopic organization of the intact motor cortex showed little inter-individual variations. Unlike Penfield and collaborators, we evoked no sensations such as sense of movement or desire to move, and only 2% of motor responses outside the precentral gyrus. We propose a rationalization of the standard drawing of the motor homunculus according to MNI space. We found a somatotopic correlation perpendicular to the central sulcus when matching our motor data to those previously obtained for the somatosensory homunculus.

A Quantitative EEG Toolbox for the MNI Neuroinformatics Ecosystem: Normative SPM of EEG Source Spectra.

The Tomographic Quantitative Electroencephalography (qEEGt) toolbox is integrated with the Montreal Neurological Institute (MNI) Neuroinformatics Ecosystem as a docker into the Canadian Brain Imaging Research Platform (CBRAIN). qEEGt produces age-corrected normative Statistical Parametric Maps of EEG log source spectra testing compliance to a normative database. This toolbox was developed at the Cuban Neuroscience Center as part of the first wave of the Cuban Human Brain Mapping Project (CHBMP) and has been validated and used in different health systems for several decades. Incorporation into the MNI ecosystem now provides CBRAIN registered users access to its full functionality and is accompanied by a public release of the source code on GitHub and Zenodo repositories. Among other features are the calculation of EEG scalp spectra, and the estimation of their source spectra using the Variable Resolution Electrical Tomography (VARETA) source imaging. Crucially, this is completed by the evaluation of z spectra by means of the built-in age regression equations obtained from the CHBMP database (ages 5–87) to provide normative Statistical Parametric Mapping of EEG log source spectra. Different scalp and source visualization tools are also provided for evaluation of individual subjects prior to further post-processing. Openly releasing this software in the CBRAIN platform will facilitate the use of standardized qEEGt methods in different research and clinical settings. An updated precis of the methods is provided in Appendix I as a reference for the toolbox. qEEGt/CBRAIN is the first installment of instruments developed by the neuroinformatic platform of the Cuba-Canada-China (CCC) project.

Investigation of networks underlying hyperkinetic seizures utilizing ictal SPECT.

To study neural networks involved in hyperkinetic seizures (HKS) using ictal SPECT. We retrospectively identified 18 patients with HKS evaluated at the Cleveland Clinic between 2005 and 2015 with video-EEG monitoring and ictal SPECT. Semiology was confirmed by the consensus of 2 epileptologists' independent reviews and classified as type 1, 2, or 3 HKS. SPECT data were analyzed by 2 independent physicians using a z score of 1.5. Ictal hyperperfusion patterns for each group were analyzed visually and with SPM. Spatial normalization to Montreal Neurological Institute space for each patient's data was performed, followed by flipping of data from patients with left-sided ictal onset to the right side. Finally, an average z score map for each group was calculated. Visual analysis and SPM identified different patterns of ictal hyperperfusion in the 3 subtypes of HKS. Type 1 seizures showed hyperperfusion in a more anteriorly located network involving the anterior insula, orbitofrontal cortex, cingulate, and anterior perisylvian region and rostral midbrain. Type 2 seizures were associated with hyperperfusion in a more caudally located network involving the orbitofrontal cortex, cingulate (middle and posterior), basal ganglia, thalami, and cerebellum. Type 3 seizures showed a mixed pattern of SPECT hyperperfusion involving the temporal pole and anterior perisylvian region. Each of the 3 different semiologic subtypes of HKS is associated with distinct patterns of hyperperfusion, providing further insight into the neural networks involved. This knowledge may inform placement of invasive EEG electrodes in patients with HKS semiology undergoing presurgical evaluation.

Characteristics Of Resting State Networks Of Elite Skating Athletes: An ICA Analysis

Long-term motor skill learning can lead neuro plasticity changes. Until now, this conclusion is mainly proved by task fMRI and spontaneous brain activity evidence. However, these methods heavily rely on prior knowledge and hypotheses, and exist algorithm limitations. PURPOSE: To investigate the differences of resting state networks (RSNs) between elite skating athletes and non-athlete controls by means of data-driven approach. METHODS: Resting state fMRI data were acquired by Philips Achieva 3.0T scanner with a standard 32 channel head coil from 15 Chinese national level skating athletes (all men, 20.87±1.78 years old, with an average training year of 9.67±3.50) and 15 demographically matched healthy controls (all men, 20.85±1.83 years old). Gift was used to perform ICA (independent component analysis) arithmetic calculations and identify RSNs, including default mode network, somatomotor network, dorsal attention network, left fronto-parietal network and visual network. A two-sample t-test was then conducted using SPM12 to investigate whether there were significant differences between two groups. Results were reported when voxel significant at a level of p < 0.01. Cluster-level whole-brain family wise error (FWE) was applied for multiple comparison correction (cluster p< 0.01). Coordinates are given in Montreal Neurological Institute(MNI) space. RESULTS: 1. Athletes showed higher spontaneous activity in postcentral gyrus (cluster size =230, peak coordinate =69, -12,18, peak t =11.88) and cingulate gyrus (cluster size =167, peak coordinate= 6, -3,39, peak t =6.65) in somatomotor network. 2. Athletes showed higher spontaneous activity in precuneus (cluster size =337, peak coordinate =30, -66,39, peak t =10.38) in dorsal attention network. CONCLUSIONS: Elite skating athletes showed better functional connectivity in somatomotor network and dorsal attention network, which may further indicate that long-term specialized motor training may promote functional network activation patterns.

Transcranial magnetic stimulation over the right temporoparietal junction influences the sense of agency in healthy humans.

The sense of agency is an important aspect of motor control. Impaired sense of agency has been linked to several medical conditions, including schizophrenia and functional neurological disorders. A complex brain network subserves the sense of agency, and the right temporoparietal junction is one of its main nodes. In this paper, we tested whether transcranial magnetic stimulation over the right temporoparietal junction elicited behavioural changes in the sense of agency. In experiment 1, 15 healthy participants performed a behavioural task during functional MRI, with the goal of localizing the area relevant for the sense of agency in the right temporoparietal junction. In the task, the movement of a cursor (controlled by the participants) was artificially manipulated, and the sense of agency was either diminished (turbulence) or enhanced (magic). In experiment 2, we applied transcranial magnetic stimulation in 20 healthy participants in a sham-controlled, crossover trial with excitatory, inhibitory or sham (vertex) stimulation. We measured the summary agency score, an indicator of the sense of agency (lower values correspond to diminished sense of agency). Experiment 1 revealed a peak of activation during agency manipulation in the right temporoparietal junction (Montreal Neurological Institute coordinates x, y, z: 68, -26, 34). Experiment 2 showed that inhibition of the right temporoparietal junction significantly reduced the summary agency score in both turbulence (from -14.4 ± 11.4% to -22.5 ± 8.9%), and magic (from -0.7 ± 5.8% to -4.4 ± 4.4%). We found no excitatory effects, possibly because of a ceiling effect (because healthy participants have a normal sense of agency) or noneffectiveness of the excitatory protocol. Our experiments showed that the network subserving the sense of agency was amenable to neuromodulation in healthy participants. This sets the ground for further research in patients with impaired sense of agency. Clinical trial identification: DRKS00012992 (German clinical trials registry).

The Relationship between Neuropsychiatric Symptoms and Default-Mode Network Connectivity in Alzheimer's Disease.

ObjectiveNeuropsychiatric symptoms of dementia are prevalent and extremely burdening for the patient and caregivers, but the underlying mechanism of these symptoms has not been investigated. This study aimed to investigate the relationship between neuropsychiatric symptoms and default-mode functional connectivity in Alzheimer’s disease. MethodsNeuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. Functional magnetic resonance imaging was conducted on seventy patients with Alzheimer’s disease during rest. We conducted a seed-based functional connectivity analysis to identify anterior and posterior default-mode networks (DMN). Seeds were the medial prefrontal cortex (Montreal Neurological Institute 12, 51, 36; seed radius=3 mm) for the anterior DMN and the precuneus (Montreal Neurological Institute -6, -63, 27; seed radius=3 mm) for the posterior DMN We then correlated the scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective, and psychosis syndrome) with maps of connectivity in the default-mode network. ResultsThere was a significant correlation between decreased connectivity in the medial prefrontal cortex of the anterior defaultmode network and hyperactivity (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) syndrome (p<0.05, family wise error cluster-level corrected). ConclusionOur study demonstrated that hyperactivity syndrome is related to hypoconnected default-mode network in Alzheimer’s disease. This finding suggests that specific network alterations are associated with certain neuropsychiatric syndromes.

Alterations in Functional Connectivity During Different Phases of the Triggered Migraine Attack.

To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. Randomized, double-blind, placebo-controlled, multi-visit experimental study. Subjects aged 18-50years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n=53). Consented subjects were randomized to a 0.5µg/kg/min nitroglycerin infusion or to placebo over 20minutes across different study visits, during the period February 2015-July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n=25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30-40minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin-triggered premonitory phase (T=3.23, peak connectivity change at [-6, -68, 40] for left thalamus, P=0.012 and [-4, -68, 40] for right thalamus, P=0.019). The nitroglycerin-triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T=3.47, peak connectivity change at [2, 8, 50], P<0.001). The headache phase of the nitroglycerin-triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T=3.47, peak connectivity change at [-8, -52, -58], P=0.007). Understanding the functional reorganization between subcortical and cortical brain areas in different phases of the migraine attack provides novel insights into the abnormal sensory processing and integration during migraine, as well as functional correlation with clinical symptoms displayed during each phase. [*Correction added on July 22, 2020 after first online publication: This sentence was revised from, "Consented subjects had a 0.5 μg/kg/min nitroglycerin infusion…".] [**Correction added on July 22, 2020 after first online publication: This sentence was revised from, "… at least on 1 occasion at screening."].

Differences in the preferential location and invasiveness of diffuse low‐grade gliomas and their impact on outcome

BackgroundLow‐grade gliomas (LGGs) are primary diffuse slow‐growing brain tumors derived from glial cells. The management of these tumors is dependent on their location, which often harbors eloquent areas. We retrospectively recorded the location of diffuse gliomas to identify whether specific differences exist between the histological types.MethodsWe analyzed 102 patients with previous histological diagnosis of WHO‐II astrocytomas (62) and WHO‐II oligodendrogliomas (40) according to WHO‐2016 classification. MRI sequences (T2‐FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations within the Montreal Neurological Institute (MNI) space. The Brain‐Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was created and merged with a tractography atlas for infiltration analysis.ResultsAstrocytomas frequently infiltrated association and projection white matter pathways within fronto‐temporo‐insular regions on the left side. Oligodendrogliomas infiltrated larger white matter networks (association‐commissural‐projection) of the frontal lobe bilaterally. A critical number of infiltrated BG voxels (7 for astrocytomas, 10 for oligodendrogliomas) significantly predicted shorter overall survival (OS) in both groups. Bilateral tumor extension in astrocytomas and preoperative tumor volume in oligodendrogliomas were independent prognostic factors for shorter OS.ConclusionsAstrocytomas and oligodendrogliomas differ in preferential location, and this has an impact on the type and the extent of white matter involvement. The number of BG voxels infiltrated reflected different tumor invasiveness and its impact on OS in both groups. All this new information may be valuable in neurosurgical oncology to classify and plan treatment for patients with diffuse gliomas.

Accurate MR Image Registration to Anatomical Reference Space for Diffuse Glioma.

To summarize the distribution of glioma location within a patient population, registration of individual MR images to anatomical reference space is required. In this study, we quantified the accuracy of MR image registration to anatomical reference space with linear and non-linear transformations using estimated tumor targets of glioblastoma and lower-grade glioma, and anatomical landmarks at pre- and post-operative time-points using six commonly used registration packages (FSL, SPM5, DARTEL, ANTs, Elastix, and NiftyReg). Routine clinical pre- and post-operative, post-contrast T1-weighted images of 20 patients with glioblastoma and 20 with lower-grade glioma were collected. The 2009a Montreal Neurological Institute brain template was used as anatomical reference space. Tumors were manually segmented in the patient space and corresponding healthy tissue was delineated as a target volume in the anatomical reference space. Accuracy of the tumor alignment was quantified using the Dice score and the Hausdorff distance. To measure the accuracy of general brain alignment, anatomical landmarks were placed in patient and in anatomical reference space, and the landmark distance after registration was quantified. Lower-grade gliomas were registered more accurately than glioblastoma. Registration accuracy for pre- and post-operative MR images did not differ. SPM5 and DARTEL registered tumors most accurate, and FSL least accurate. Non-linear transformations resulted in more accurate general brain alignment than linear transformations, but tumor alignment was similar between linear and non-linear transformation. We conclude that linear transformation suffices to summarize glioma locations in anatomical reference space.

Development of a quantitative statistical analysis system for double inversion recovery (DIR) MRI: A preliminary clinical study.

Gray matter (GM) imaging is important in the investigation of many neurological diseases, including schizophrenia, multiple sclerosis, stroke, Alzheimer's disease, tuberous sclerosis, and epilepsy, which are all associated with changes in cortical GM. The aim of this study was to develop a quantitative statistical analysis system for double inversion recovery (DIR) MRI and to evaluate the new system using preliminary clinical data. The study population comprised of 10 healthy volunteers and six patients with or without brain degeneration. A quantitative statistical analysis system for DIR images was developed using the following steps: 1) brain spatial normalization, 2) mean and standard deviation (SD) map creation, and 3) Z-score map creation. To evaluate the new voxel-based morphometry system, Z-scores of lesions in patients with brain degeneration were measured and then compared with Z-scores of normal regions. All DIR images were adequately spatially normalized to Montreal Neurological Institute MNI coordinate. Lesions in each patient were indicated by high Z-score values on a Z-score map, which were significantly higher than Z-scores of normal regions (p< 0.05). In this study, we developed a quantitative statistical analysis system for DIR MRI. Using our system, clinicians might accurately diagnose early brain degeneration.

Early Detection of Alzheimer's Disease Using Magnetic Resonance Imaging: A Novel Approach Combining Convolutional Neural Networks and Ensemble Learning.

Early detection is critical for effective management of Alzheimer’s disease (AD) and screening for mild cognitive impairment (MCI) is common practice. Among several deep-learning techniques that have been applied to assessing structural brain changes on magnetic resonance imaging (MRI), convolutional neural network (CNN) has gained popularity due to its superb efficiency in automated feature learning with the use of a variety of multilayer perceptrons. Meanwhile, ensemble learning (EL) has shown to be beneficial in the robustness of learning-system performance via integrating multiple models. Here, we proposed a classifier ensemble developed by combining CNN and EL, i.e., the CNN-EL approach, to identify subjects with MCI or AD using MRI: i.e., classification between (1) AD and healthy cognition (HC), (2) MCIc (MCI patients who will convert to AD) and HC, and (3) MCIc and MCInc (MCI patients who will not convert to AD). For each binary classification task, a large number of CNN models were trained applying a set of sagittal, coronal, or transverse MRI slices; these CNN models were then integrated into a single ensemble. Performance of the ensemble was evaluated using stratified fivefold cross-validation method for 10 times. The number of the intersection points determined by the most discriminable slices separating two classes in a binary classification task among the sagittal, coronal, and transverse slice sets, transformed into the standard Montreal Neurological Institute (MNI) space, acted as an indicator to assess the ability of a brain region in which the points were located to classify AD. Thus, the brain regions with most intersection points were considered as those mostly contributing to the early diagnosis of AD. The result revealed an accuracy rate of 0.84 ± 0.05, 0.79 ± 0.04, and 0.62 ± 0.06, respectively, for classifying AD vs. HC, MCIc vs. HC, and MCIc vs. MCInc, comparable to previous reports and a 3D deep learning approach (3D-SENet) based on a more state-of-the-art and popular Squeeze-and-Excitation Networks model using channel attention mechanism. Notably, the intersection points accurately located the medial temporal lobe and several other structures of the limbic system, i.e., brain regions known to be struck early in AD. More interestingly, the classifiers disclosed multiple patterned MRI changes in the brain in AD and MCIc, involving these key regions. These results suggest that as a data-driven method, the combined CNN and EL approach can locate the most discriminable brain regions indicated by the trained ensemble model while the generalization ability of the ensemble model was maximized to successfully capture AD-related brain variations early in the disease process; it can also provide new insights into understanding the complex heterogeneity of whole-brain MRI changes in AD. Further research is needed to examine the clinical implication of the finding, capability of the advocated CNN-EL approach to help understand and evaluate an individual subject’s disease status, symptom burden and progress, and the generalizability of the advocated CNN-EL approach to locate the most discriminable brain regions in the detection of other brain disorders such as schizophrenia, autism, and severe depression, in a data-driven way.

Individualized Anatomy-Based Targeting for VIM-cZI DBS in Essential Tremor

Deep brain stimulation of the ventral intermediate nucleus (VIM) or caudal zona incerta (cZI) is effective for refractory essential tremor (ET). To refine stereotactic planning for lead placement, we developed a unique individualized anatomy-based planning protocol that targets both the VIM and the cZI in patients with ET. 33 patients with ET underwent VIM-cZI lead implantation with targeting based on our protocol. Indirect targeting was adjusted based on anatomic landmarks as reference lines bisecting the red nuclei and ipsilateral subthalamus. Outcomes were evaluated through the follow-up of 31.1 ± 18.4 months. Active contact coordinates were obtained from reconstructed electrodes in the Montreal Neurological Institute space using the MATLAB Lead-DBS toolbox. Mean tremor improvement was 79.7% ±22.4% and remained stable throughout the follow-up period. Active contacts at last postoperative visit had mean Montreal Neurological Institute coordinates of 15.5 ± 1.6 mm lateral to the intercommissural line, 15.3± 1.8 mm posterior to the anterior commissure, and 1.4 ± 2.9 mm below the intercommissural plane. No hemorrhagic complications were observed in the analyzed group. Individualized anatomy-based VIM-cZI targeting is feasible and safe and is associated with favorable tremor outcomes.

Defining the optimal target for anterior thalamic deep brain stimulation in patients with drug-refractory epilepsy.

The anterior thalamic nucleus (ATN) is a common target for deep brain stimulation (DBS) for the treatment of drug-refractory epilepsy. However, no atlas-based optimal DBS (active contacts) target within the ATN has been definitively identified. The object of this retrospective study was to analyze the relationship between the active contact location and seizure reduction to establish an atlas-based optimal target for ATN DBS. From among 25 patients who had undergone ATN DBS surgery for drug-resistant epilepsy between 2016 and 2018, those who had follow-up evaluations for more than 1 year were eligible for study inclusion. After an initial stimulation period of 6 months, patients were classified as responsive (≥ 50% median decrease in seizure frequency) or nonresponsive (< 50% median decrease in seizure frequency) to treatment. Stimulation parameters and/or active contact positions were adjusted in nonresponsive patients, and their responsiveness was monitored for at least 1 year. Postoperative CT scans were coregistered nonlinearly with preoperative MR images to determine the center coordinate and atlas-based anatomical localizations of all active contacts in the Montreal Neurological Institute (MNI) 152 space. Nineteen patients with drug-resistant epilepsy were followed up for at least a year following bilateral DBS electrode implantation targeting the ATN. Active contacts located more adjacent to the center of gravity of the anterior half of the ATN volume, defined as the anterior center (AC), were associated with greater seizure reduction than those not in this location. Intriguingly, the initially nonresponsive patients could end up with much improved seizure reduction by adjusting the active contacts closer to the AC at the final postoperative follow-up. Patients with stimulation targeting the AC may have a favorable seizure reduction. Moreover, the authors were able to obtain additional good outcomes after electrode repositioning in the initially nonresponsive patients. Purposeful and strategic trajectory planning to target this optimal region may predict favorable outcomes of ATN DBS.