SCIENCE TIMES
Figure. Glioma system xc2 (SXC) expression predicts patient survival and peritumoral glutamate response. A, Kaplan-Meier survival plot of patients in the REMBRANDT database comparing gliomas with high SLC7A11 ($150%) and low SLC7A11 (#66%) expression with nonneoplastic brain (n ¼ 120 glioma [all grades] patients; Kaplan-Meier analyzed with the log-rank test, P ¼ .02). B through E, detection of peritumoral glutamate (Glx) measured by magnetic resonance spectroscopy in glioma patients before and after an acute SAS dose (1 g). B, representative images showing voxel placement. C, peritumoral glutamate, detected as a peak composed of glutamate 1 glutamine (Glx), which is predominantly glutamate (27), and quantified with respect to creatine (Cr). Intracranial Glx/Cr changes after SAS administration (Post-SAS) are graphed (bottom) and compared with SLC7A11 expression in patient glioma tissue (top) quantified by staining intensity (n ¼ 3 tissue samples per patient; total n ¼ 27; glioma types include glioblastoma [GBM], astrocytoma [Astro], and oligodendroglioma/oligoastrocytoma [Oligo]; mean6 SEM; analysis of variance, P , .001). D, examples of high and low SLC7A11 staining of patient glioma tissue. Scale bars ¼ 100 mmol/L. E, linear correlation between maximum Glx/Cr decrease and GBM tissue SLC7A11 expression (linear regression; *P ¼ .0134; R2 ¼ 0.9996). Reprinted with permission from Robert SM, Buckingham SC, Campbell SL, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015;7(289):289ra76.
These findings establish high SLC7A11 expression as a poor prognostic marker for GBM owing to its role in promoting growth and peritumoral excitotoxicity. This study also identified SXC inhibition and candidate drugs that may effectively treat SLC7A11-expressing GBM patients. Further work should develop, optimize, and clinically evaluate SXC inhibitors as GBM therapies and for managing tumorassociated seizures. In addition, more studies should explore the expression of SLC7A11 and its role in lower-grade gliomas.
NEUROSURGERY
Ray R. Zhang, BS Kelli B. Pointer, BS John S. Kuo, MD, PhD University of Wisconsin Madison, Wisconsin
REFERENCE 1. Robert SM, Buckingham SC, Campbell SL, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015;7(289): 289ra76.
The Future of Neural Recording Devices: Nanoscale, Flexible, and Injectable
I
n recent years, research efforts toward the development of flexible electronics for interfacing with nonplanar biological substrates have increased dramatically. Traditional, relatively rigid electronic devices
VOLUME 77 | NUMBER 6 | DECEMBER 2015 | N17
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
SCIENCE TIMES
Figure. A and B, in vivo stereotaxic injection of mesh electronics into a mouse brain. C and D, coronal slice schematics illustrating brain targets where electronics were injected: through the cerebral cortex (CTX) to the lateral ventricle (LV) adjacent to the caudoputamen (CPu) and lateral septal nucleus (LSD; C) or to the hippocampus (HIP D). Red lines indicate the mesh; dark blue circles, recording devices; yellow circles, input/output pads; and blue dashed lines, the direction of horizontal slicing for imaging. E, confocal image from a 100-mm-thick horizontal slice 5 weeks after injection at the position indicated by the blue dashed line in C. The red dashed line highlights the boundary of the mesh inside the LV, and the solid red circle indicates the size of the needle used for injection. F, reconstructed confocal image of the interface between the mesh electronics and subventricular zone (SVZ). G, reconstructed confocal image of the approximate middle (in the x-y plane) of the LV in the slice. H, bright-field microscopy image of a coronal slice of the HIP region 5 weeks after injection. Red dashed lines indicate the boundary of the glass needle. White arrows indicate longitudinal elements that were broken during tissue slicing. I, overlaid bright-field and epifluorescence images (blue shows DAPI staining of cell nuclei) from the region indicated by the white dashed box in H. CA1 and the dentate gyrus (DG) are marked with arrows. J, confocal image from a 30-mmthick slice from the zoomed-in region highlighted by the black dashed box in I. K, acute in vivo recording using mesh electronics (Pt-metal electrodes) injected into a mouse brain with their relative positions marked by red spots in the schematic (left). The dashed red rectangle indicates the section used for spatiotemporal mapping of multichannel local field potential recordings. L, superimposed single-unit neural recordings from 1 channel. The red line represents the mean waveform. Reprinted with permission from Liu J, Fu TM, Cheng Z, et al. Syringe-injectable electronics. Nat Nanotechnol. 2015;10(7):629-636.
conform poorly to curved biological tissues and resist their natural dynamic motion, leading to suboptimal electric contact and exacerbation of the immune response to foreign bodies. Flexible electronics
N18 | VOLUME 77 | NUMBER 6 | DECEMBER 2015
promise to attenuate these notable obstacles, offering new applications for devices implanted short term and, in particular, long term. These soft devices have already been used in a host of biomedical and
neuroscientific applications, ranging from direct brain recordings to skin-like scalp electroencephalogram electrode arrays.1 Liu et al2 have recently contributed an exciting advancement to this field by developing a flexible electronic mesh capable of being delivered into the brain parenchyma via syringe injection. The 2-dimensional grid-like, macroporous mesh Liu et al developed is made up of longitudinal polymer/metal/polymer elements held together by transverse polymer elements that connect exposed electrical contacts at one end of the device with input/output pads at the other. To facilitate syringe-mediated delivery, the group experimented with different mesh geometries to minimize stiffness in the transverse direction, allowing it to easily fold on itself to pass through the narrow bore of a needle while maximizing stiffness in the longitudinal direction, thus preventing buckling in the direction of the needle during injection. To test the viability of this delivery system, the group first injected various mesh sizes and geometries through syringes of various inner diameters into a solution of phosphate-buffered saline. Encouragingly, postinjection device yields typically averaged .90% and demonstrated that meshes with a native width of 1.5 cm could be successfully delivered through a syringe with an inner diameter as small as 450 mm (a size ratio of approximately 33 times). Additional validation of this system before in vivo testing included mesh injection into 3-dimensional Matrigel constructs. These experiments again yielded viable meshes after injection, which gradually unrolled toward their native 2-dimensional shape, over the course of 3 weeks in a Matrigel concentration–dependent manner (90% and 30% unfolding for 25% and 100% Matrigel, respectively). Testing their device directly in neuroscientific applications, Liu et al stereotactically injected electronic mesh into the lateral ventricle and hippocampus of live rodents and conducted microscopy studies 5 weeks after injection (summarized in the Figure). In accordance with the Matrigel concentration studies, the 2 injection locations yielded different results in regard to mesh unfolding after injection: The mesh exhibited considerable re-expansion in the free space of the lateral ventricle but remained narrow in the densely cellular hippocampus. Interestingly, no appreciable immune response to the mesh was found; instead, confocal imaging suggested that the electronics exhibited neurotrophic properties. NeuN and DAPI staining was tightly associated with the mesh with some cells migrating hundreds of microns along the construct. The authors attributed the striking biocompatibility of the mesh to a range of properties, including its low bending stiffness and small feature sizes, which are
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
SCIENCE TIMES
similar to the size of single cells. Finally, the authors investigated the ability of the mesh to reliably record neurophysiological signals and found that they were able to record not only local-field potentials but also single neurons. These findings suggest that advances in flexible electronics exhibit a biocompatibility that will allow the recording of neuronal activity at a very high level of spatial and functional resolution, ultimately improving the efficacy of neural implants. Furthermore, the ability to compress these devices to such small spatial scales that they may easily pass through the bore of a syringe enables minimally invasive delivery of these devices. It is likely that these devices will interact with advances in neurophysiology to contribute to novel applications of direct neural recording and stimulation-based therapies along the entire length of the neuroaxis. Thomas A. Wozny, BS R. Mark Richardson, MD, PhD University of Pittsburgh Pittsburgh, Pennsylvania
REFERENCES 1. Jeong JW, Shin G, Park SI, Yu KJ, Xu L, Rogers JA. Soft materials in neuroengineering for
hard problems in neuroscience. Neuron. 2015;86 (1):175-186. 2. Liu J, Fu TM, Cheng Z, et al. Syringe-njectable electronics. Nat Nanotechnol. 2015;10(7):629-636.
Single Neuron Markers of Memory Retrieval Confidence
I
nformation about previous experiences, stored as memories, is an essential factor in decision making. The perceived confidence in the validity of a memory, and ultimately a decision, is as important as the recall of information. It is unclear whether metacognitive and decision-making processes occur within overlapping or distinct neural systems. A recent finding from Rutishauser et al1 demonstrates neural correlates of an uncertaintyprocessing mechanism in the human medial temporal lobe. Subjects provided subjective confidence ratings of their choices during a memory recognition task to identify neurons that encoded memory strength in addition to memory itself.
Twenty-eight patients undergoing intracranial epilepsy monitoring performed a recognition memory test of 100 images (with the categories of cars, foods, people, landscapes, or animals) in which they made a binary decision of whether or not they had seen an image before. Half of the images were presented to subjects 30 minutes before the task; these were considered familiar. Half of the images were novel. Images were each presented for 1 second, and after a brief delay, the subject was asked both to indicate whether he or she had seen the image previously and to rate his or her confidence in that decision (Figure, A). The responses of 1065 individual neurons recorded from amygdala and hippocampus revealed a subpopulation of memory-selective (MS) neurons that encoded both stimulus familiarity and confidence in their firing rates. Some of these MS neurons increased their rate of firing in response to familiar images, whereas others increased their firing rate in response to novel images, representing memory related to that stimulus (Figure, B). The average area under the curve (AUC) of the receiver-operating characteristic curve for each MS neuron was used to measure the ability to predict the
Figure. A, recognition memory task. B, mean normalized firing rates across neurons that selectively respond to familiar images (FS) or novel images (NS) during correct trials. True positive (TP) describes trials in which subjects correctly recognized familiar images, and true negative (TN) describes trials in which subjects correctly indicated an image as novel. High and low refer to the rated confidence level. C, higher areas under the curve (AUCs) for receiver-operating characteristic analyses of individual memory-selective (MS) neurons that responded during correct trials with a higher confidence rating compared with that of MS neurons responding during correct trials with a lower confidence rating. D, the AUCs of receiver-operating characteristic analyses of individual visually selective neurons did not differ between high or low confidence trials, nor did they differ between familiar or novel stimulus trials.
NEUROSURGERY
VOLUME 77 | NUMBER 6 | DECEMBER 2015 | N19
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
Figure. Glioma system xc2 (SXC) expression predicts patient survival and peritumoral glutamate response. A, Kaplan-Meier survival plot of patients in the REMBRANDT database comparing gliomas with high SLC7A11 ($150%) and low SLC7A11 (#66%) expression with nonneoplastic brain (n ¼ 120 glioma [all grades] patients; Kaplan-Meier analyzed with the log-rank test, P ¼ .02). B through E, detection of peritumoral glutamate (Glx) measured by magnetic resonance spectroscopy in glioma patients before and after an acute SAS dose (1 g). B, representative images showing voxel placement. C, peritumoral glutamate, detected as a peak composed of glutamate 1 glutamine (Glx), which is predominantly glutamate (27), and quantified with respect to creatine (Cr). Intracranial Glx/Cr changes after SAS administration (Post-SAS) are graphed (bottom) and compared with SLC7A11 expression in patient glioma tissue (top) quantified by staining intensity (n ¼ 3 tissue samples per patient; total n ¼ 27; glioma types include glioblastoma [GBM], astrocytoma [Astro], and oligodendroglioma/oligoastrocytoma [Oligo]; mean6 SEM; analysis of variance, P , .001). D, examples of high and low SLC7A11 staining of patient glioma tissue. Scale bars ¼ 100 mmol/L. E, linear correlation between maximum Glx/Cr decrease and GBM tissue SLC7A11 expression (linear regression; *P ¼ .0134; R2 ¼ 0.9996). Reprinted with permission from Robert SM, Buckingham SC, Campbell SL, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015;7(289):289ra76.
These findings establish high SLC7A11 expression as a poor prognostic marker for GBM owing to its role in promoting growth and peritumoral excitotoxicity. This study also identified SXC inhibition and candidate drugs that may effectively treat SLC7A11-expressing GBM patients. Further work should develop, optimize, and clinically evaluate SXC inhibitors as GBM therapies and for managing tumorassociated seizures. In addition, more studies should explore the expression of SLC7A11 and its role in lower-grade gliomas.
NEUROSURGERY
Ray R. Zhang, BS Kelli B. Pointer, BS John S. Kuo, MD, PhD University of Wisconsin Madison, Wisconsin
REFERENCE 1. Robert SM, Buckingham SC, Campbell SL, et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med. 2015;7(289): 289ra76.
The Future of Neural Recording Devices: Nanoscale, Flexible, and Injectable
I
n recent years, research efforts toward the development of flexible electronics for interfacing with nonplanar biological substrates have increased dramatically. Traditional, relatively rigid electronic devices
VOLUME 77 | NUMBER 6 | DECEMBER 2015 | N17
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
SCIENCE TIMES
Figure. A and B, in vivo stereotaxic injection of mesh electronics into a mouse brain. C and D, coronal slice schematics illustrating brain targets where electronics were injected: through the cerebral cortex (CTX) to the lateral ventricle (LV) adjacent to the caudoputamen (CPu) and lateral septal nucleus (LSD; C) or to the hippocampus (HIP D). Red lines indicate the mesh; dark blue circles, recording devices; yellow circles, input/output pads; and blue dashed lines, the direction of horizontal slicing for imaging. E, confocal image from a 100-mm-thick horizontal slice 5 weeks after injection at the position indicated by the blue dashed line in C. The red dashed line highlights the boundary of the mesh inside the LV, and the solid red circle indicates the size of the needle used for injection. F, reconstructed confocal image of the interface between the mesh electronics and subventricular zone (SVZ). G, reconstructed confocal image of the approximate middle (in the x-y plane) of the LV in the slice. H, bright-field microscopy image of a coronal slice of the HIP region 5 weeks after injection. Red dashed lines indicate the boundary of the glass needle. White arrows indicate longitudinal elements that were broken during tissue slicing. I, overlaid bright-field and epifluorescence images (blue shows DAPI staining of cell nuclei) from the region indicated by the white dashed box in H. CA1 and the dentate gyrus (DG) are marked with arrows. J, confocal image from a 30-mmthick slice from the zoomed-in region highlighted by the black dashed box in I. K, acute in vivo recording using mesh electronics (Pt-metal electrodes) injected into a mouse brain with their relative positions marked by red spots in the schematic (left). The dashed red rectangle indicates the section used for spatiotemporal mapping of multichannel local field potential recordings. L, superimposed single-unit neural recordings from 1 channel. The red line represents the mean waveform. Reprinted with permission from Liu J, Fu TM, Cheng Z, et al. Syringe-injectable electronics. Nat Nanotechnol. 2015;10(7):629-636.
conform poorly to curved biological tissues and resist their natural dynamic motion, leading to suboptimal electric contact and exacerbation of the immune response to foreign bodies. Flexible electronics
N18 | VOLUME 77 | NUMBER 6 | DECEMBER 2015
promise to attenuate these notable obstacles, offering new applications for devices implanted short term and, in particular, long term. These soft devices have already been used in a host of biomedical and
neuroscientific applications, ranging from direct brain recordings to skin-like scalp electroencephalogram electrode arrays.1 Liu et al2 have recently contributed an exciting advancement to this field by developing a flexible electronic mesh capable of being delivered into the brain parenchyma via syringe injection. The 2-dimensional grid-like, macroporous mesh Liu et al developed is made up of longitudinal polymer/metal/polymer elements held together by transverse polymer elements that connect exposed electrical contacts at one end of the device with input/output pads at the other. To facilitate syringe-mediated delivery, the group experimented with different mesh geometries to minimize stiffness in the transverse direction, allowing it to easily fold on itself to pass through the narrow bore of a needle while maximizing stiffness in the longitudinal direction, thus preventing buckling in the direction of the needle during injection. To test the viability of this delivery system, the group first injected various mesh sizes and geometries through syringes of various inner diameters into a solution of phosphate-buffered saline. Encouragingly, postinjection device yields typically averaged .90% and demonstrated that meshes with a native width of 1.5 cm could be successfully delivered through a syringe with an inner diameter as small as 450 mm (a size ratio of approximately 33 times). Additional validation of this system before in vivo testing included mesh injection into 3-dimensional Matrigel constructs. These experiments again yielded viable meshes after injection, which gradually unrolled toward their native 2-dimensional shape, over the course of 3 weeks in a Matrigel concentration–dependent manner (90% and 30% unfolding for 25% and 100% Matrigel, respectively). Testing their device directly in neuroscientific applications, Liu et al stereotactically injected electronic mesh into the lateral ventricle and hippocampus of live rodents and conducted microscopy studies 5 weeks after injection (summarized in the Figure). In accordance with the Matrigel concentration studies, the 2 injection locations yielded different results in regard to mesh unfolding after injection: The mesh exhibited considerable re-expansion in the free space of the lateral ventricle but remained narrow in the densely cellular hippocampus. Interestingly, no appreciable immune response to the mesh was found; instead, confocal imaging suggested that the electronics exhibited neurotrophic properties. NeuN and DAPI staining was tightly associated with the mesh with some cells migrating hundreds of microns along the construct. The authors attributed the striking biocompatibility of the mesh to a range of properties, including its low bending stiffness and small feature sizes, which are
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
SCIENCE TIMES
similar to the size of single cells. Finally, the authors investigated the ability of the mesh to reliably record neurophysiological signals and found that they were able to record not only local-field potentials but also single neurons. These findings suggest that advances in flexible electronics exhibit a biocompatibility that will allow the recording of neuronal activity at a very high level of spatial and functional resolution, ultimately improving the efficacy of neural implants. Furthermore, the ability to compress these devices to such small spatial scales that they may easily pass through the bore of a syringe enables minimally invasive delivery of these devices. It is likely that these devices will interact with advances in neurophysiology to contribute to novel applications of direct neural recording and stimulation-based therapies along the entire length of the neuroaxis. Thomas A. Wozny, BS R. Mark Richardson, MD, PhD University of Pittsburgh Pittsburgh, Pennsylvania
REFERENCES 1. Jeong JW, Shin G, Park SI, Yu KJ, Xu L, Rogers JA. Soft materials in neuroengineering for
hard problems in neuroscience. Neuron. 2015;86 (1):175-186. 2. Liu J, Fu TM, Cheng Z, et al. Syringe-njectable electronics. Nat Nanotechnol. 2015;10(7):629-636.
Single Neuron Markers of Memory Retrieval Confidence
I
nformation about previous experiences, stored as memories, is an essential factor in decision making. The perceived confidence in the validity of a memory, and ultimately a decision, is as important as the recall of information. It is unclear whether metacognitive and decision-making processes occur within overlapping or distinct neural systems. A recent finding from Rutishauser et al1 demonstrates neural correlates of an uncertaintyprocessing mechanism in the human medial temporal lobe. Subjects provided subjective confidence ratings of their choices during a memory recognition task to identify neurons that encoded memory strength in addition to memory itself.
Twenty-eight patients undergoing intracranial epilepsy monitoring performed a recognition memory test of 100 images (with the categories of cars, foods, people, landscapes, or animals) in which they made a binary decision of whether or not they had seen an image before. Half of the images were presented to subjects 30 minutes before the task; these were considered familiar. Half of the images were novel. Images were each presented for 1 second, and after a brief delay, the subject was asked both to indicate whether he or she had seen the image previously and to rate his or her confidence in that decision (Figure, A). The responses of 1065 individual neurons recorded from amygdala and hippocampus revealed a subpopulation of memory-selective (MS) neurons that encoded both stimulus familiarity and confidence in their firing rates. Some of these MS neurons increased their rate of firing in response to familiar images, whereas others increased their firing rate in response to novel images, representing memory related to that stimulus (Figure, B). The average area under the curve (AUC) of the receiver-operating characteristic curve for each MS neuron was used to measure the ability to predict the
Figure. A, recognition memory task. B, mean normalized firing rates across neurons that selectively respond to familiar images (FS) or novel images (NS) during correct trials. True positive (TP) describes trials in which subjects correctly recognized familiar images, and true negative (TN) describes trials in which subjects correctly indicated an image as novel. High and low refer to the rated confidence level. C, higher areas under the curve (AUCs) for receiver-operating characteristic analyses of individual memory-selective (MS) neurons that responded during correct trials with a higher confidence rating compared with that of MS neurons responding during correct trials with a lower confidence rating. D, the AUCs of receiver-operating characteristic analyses of individual visually selective neurons did not differ between high or low confidence trials, nor did they differ between familiar or novel stimulus trials.
NEUROSURGERY
VOLUME 77 | NUMBER 6 | DECEMBER 2015 | N19
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited
