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1.
Neuroimage Clin ; 30: 102565, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33556791

RESUMO

OBJECTIVE: Focal cortical dysplasias (FCDs) are a common cause of apparently non-lesional drug-resistant focal epilepsy. Visual detection of subtle FCDs on MRI is clinically important and often challenging. In this study, we implement a set of 3D local image filters adapted from computer vision applications to characterize the appearance of normal cortex surrounding the gray-white junction. We create a normative model to serve as the basis for a novel multivariate constrained outlier approach to automated FCD detection. METHODS: Standardized MPRAGE, T2 and FLAIR MR images were obtained in 15 patients with radiologically or histologically diagnosed FCDs and 30 healthy volunteers. Multiscale 3D local image filters were computed for each MR contrast then sampled onto the gray-white junction surface. Using an iterative Gaussianization procedure, we created a normative model of cortical variability in healthy volunteers, allowing for identification of outlier regions and estimates of similarity in normal cortex and FCD lesions. We used a constrained outlier approach following local normalization to automatically detect FCD lesions based on projection onto the mean FCD feature vector. RESULTS: FCDs as well as some normal cortical regions such as primary sensorimotor and paralimbic regions appear as outliers. Regions such as the paralimbic regions and the anterior insula have similar features to FCDs. Our constrained outlier approach allows for automated FCD detection with 80% sensitivity and 70% specificity. SIGNIFICANCE: A normative model using multiscale local image filters can be used to describe the normal cortical variability. Although FCDs appear similar to some cortical regions such as the anterior insula and paralimbic cortices, they can be identified using a constrained outlier detection approach. Our method for detecting outliers and estimating similarity is generic and could be extended to identification of other types of lesions or atypical cortical areas.

2.
Trends Cogn Sci ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33549494

RESUMO

Liu et al. recently demonstrated novel neural evidence for visual and semantic contributions to the encoding and maintenance of object information in a delayed match-to-sample task. Their data highlight the close interaction between sensory experience and prior semantic knowledge in human visual short-term memory for naturalistic stimuli.

3.
Nat Commun ; 11(1): 6075, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247100

RESUMO

Our memories enable us to form expectations for our future experiences, yet the precise neural mechanisms underlying how we compare any experience to our memory remain unknown. Here, using intracranial EEG recordings, we show that episodic memories formed after a single visual experience establish expectations for future experience within neocortical-medial temporal lobe circuits. When subsequent experiences violate these expectations, we find a 80-120 Hz prediction error signal that emerges in both visual association areas and the medial temporal lobe. Critically, this error signal emerges in visual association areas first and then propagates to the medial temporal lobe. This error signal is accompanied by alpha coherence between the two regions. Our data therefore suggest that internal models formed from episodic memories are generated throughout the visual hierarchy after just a single exposure, and that these internal models are then used for comparison with future experiences.

4.
Biomedicines ; 8(9)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825279

RESUMO

Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas. IDH mutants confer a neomorphic enzyme activity that converts α-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism. IDH mutation establishes distinctive patterns in metabolism, cancer biology, and the therapeutic sensitivity of glioma. Thus, a deeper understanding of the roles of IDH mutations is of great value to improve the therapeutic efficacy of glioma and other malignancies that share similar genetic characteristics. In this review, we focused on the genetics, biochemistry, and clinical impacts of IDH mutations in glioma.

5.
Nat Neurosci ; 23(12): 1629-1636, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32807948

RESUMO

Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

6.
Nat Hum Behav ; 4(9): 937-948, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32601459

RESUMO

Despite large individual differences in memory performance, people remember certain stimuli with overwhelming consistency. This phenomenon is referred to as the memorability of an individual item. However, it remains unknown whether memorability also affects our ability to retrieve associations between items. Here, using a paired-associates verbal memory task, we combine behavioural data, computational modelling and direct recordings from the human brain to examine how memorability influences associative memory retrieval. We find that certain words are correctly retrieved across participants irrespective of the cues used to initiate memory retrieval. These words, which share greater semantic similarity with other words, are more readily available during retrieval and lead to more intrusions when retrieval fails. Successful retrieval of these memorable items, relative to less memorable ones, results in faster reinstatement of neural activity in the anterior temporal lobe. Collectively, our data reveal how the brain prioritizes certain information to facilitate memory retrieval.


Assuntos
Associação , Rememoração Mental/fisiologia , Lobo Temporal/fisiologia , Adulto , Mapeamento Encefálico , Eletroencefalografia , Feminino , Humanos , Masculino , Testes Neuropsicológicos
7.
Elife ; 92020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32496194

RESUMO

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance in human circuit function. In this study, we focus on neurogliaform cells, that possess specialized physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms underlying human cognitive processing and behavior.

8.
Brain Stimul ; 13(5): 1218-1225, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526475

RESUMO

BACKGROUND: Direct electrical stimulation of the human brain has been used to successfully treat several neurological disorders, but the precise effects of stimulation on neural activity are poorly understood. Characterizing the neural response to stimulation, however, could allow clinicians and researchers to more accurately predict neural responses, which could in turn lead to more effective stimulation for treatment and to fundamental knowledge regarding neural function. OBJECTIVE: Here we use a linear systems approach in order to characterize the response to electrical stimulation across cortical locations and then to predict the responses to novel inputs. METHODS: We use intracranial electrodes to directly stimulate the human brain with single pulses of stimulation using amplitudes drawn from a random distribution. Based on the evoked responses, we generate a simple model capturing the characteristic response to stimulation at each cortical site. RESULTS: We find that the variable dynamics of the evoked response across cortical locations can be captured using the same simple architecture, a linear time-invariant system that operates separately on positive and negative input pulses of stimulation. We demonstrate that characterizing the response to stimulation using this simple and tractable model of evoked responses enables us to predict the responses to subsequent stimulation with single pulses with novel amplitudes, and the compound response to stimulation with multiple pulses. CONCLUSION: Our data suggest that characterizing the response to stimulation in an approximately linear manner can provide a powerful and principled approach for predicting the response to direct electrical stimulation.

9.
Brain Stimul ; 13(5): 1183-1195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32446925

RESUMO

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

10.
Neuron ; 106(5): 759-768.e7, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32243781

RESUMO

Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing ∼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Neurônios/metabolismo , Transtorno do Espectro Autista/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual/genética , Masculino , Mutação , Transporte Proteico/genética
11.
Science ; 367(6482): 1131-1134, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32139543

RESUMO

Episodic memory retrieval is thought to rely on the replay of past experiences, yet it remains unknown how human single-unit activity is temporally organized during episodic memory encoding and retrieval. We found that ripple oscillations in the human cortex reflect underlying bursts of single-unit spiking activity that are organized into memory-specific sequences. Spiking sequences occurred repeatedly during memory formation and were replayed during successful memory retrieval, and this replay was associated with ripples in the medial temporal lobe. Together, these data demonstrate that human episodic memory is encoded by specific sequences of neural activity and that memory recall involves reinstating this temporal order of activity.


Assuntos
Memória Episódica , Rememoração Mental/fisiologia , Lobo Temporal/fisiologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino
13.
PLoS One ; 15(1): e0216185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929531

RESUMO

The ability to interpret transcranial magnetic stimulation (TMS)-evoked electroencephalography (EEG) potentials (TEPs) is limited by artifacts, such as auditory evoked responses produced by discharge of the TMS coil. TEPs generated from direct cortical stimulation should vary in their topographical activity pattern according to stimulation site and differ from responses to sham stimulation. Responses that do not show these effects are likely to be artifactual. In 20 healthy volunteers, we delivered active and sham TMS to the right prefrontal, left primary motor, and left posterior parietal cortex and compared the waveform similarity of TEPs between stimulation sites and active and sham TMS using a cosine similarity-based analysis method. We identified epochs after the stimulus when the spatial pattern of TMS-evoked activation showed greater than random similarity between stimulation sites and sham vs. active TMS, indicating the presence of a dominant artifact. To do this, we binarized the derivatives of the TEPs recorded from 30 EEG channels and calculated cosine similarity between conditions at each time point with millisecond resolution. Only TEP components occurring before approximately 80 ms differed across stimulation sites and between active and sham, indicating site and condition-specific responses. We therefore conclude that, in the absence of noise masking or other measures to decrease neural artifact, TEP components before about 80 ms can be safely interpreted as stimulation location-specific responses to TMS, but components beyond this latency should be interpreted with caution due to high similarity in their topographical activity pattern.


Assuntos
Potenciais Evocados Auditivos/fisiologia , Córtex Motor/fisiologia , Lobo Parietal/fisiologia , Estimulação Magnética Transcraniana , Adulto , Mapeamento Encefálico , Eletroencefalografia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Adulto Jovem
14.
Behav Brain Sci ; 42: e298, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31896383

RESUMO

Bastin et al. present a framework that draws heavily on existing ideas of dual processes in memory in order to make predictions about memory deficits in clinical populations. It has been difficult to find behavioral evidence for multiple memory processes but we offer some evidence for dual processes in a related domain: memory for the time-of-occurrence of events.


Assuntos
Memória , Rememoração Mental , Humanos , Transtornos da Memória
15.
J Neural Eng ; 16(6): 066039, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509808

RESUMO

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


Assuntos
Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrocorticografia/métodos , Convulsões/fisiopatologia , Epilepsia Resistente a Medicamentos/diagnóstico , Estimulação Elétrica/efeitos adversos , Eletrocorticografia/efeitos adversos , Eletrocorticografia/instrumentação , Feminino , Humanos , Masculino , Fatores de Risco , Convulsões/etiologia
16.
Netw Neurosci ; 3(3): 848-877, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410383

RESUMO

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

17.
Curr Biol ; 29(17): 2801-2811.e5, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31422882

RESUMO

Recent evidence has suggested that coherent neuronal oscillations may serve as a gating mechanism for flexibly modulating communication between brain regions. For this to occur, such oscillations should be robust and coherent between brain regions that also demonstrate time-locked correlations, with time delays that match the phase delays of the coherent oscillations. Here, by analyzing functional connectivity in both the time and frequency domains, we demonstrate that alpha oscillations satisfy these constraints and are well suited for modulating communication over large spatial scales in the human brain. We examine intracranial EEG in the human temporal lobe and find robust alpha oscillations that are coherent between brain regions with center frequencies that are consistent within each individual participant. Regions demonstrating coherent narrowband oscillations also exhibit time-locked broadband correlations with a consistent time delay, a requirement for an efficient communication channel. The phase delays of the coherent alpha oscillations match the time delays of the correlated components, and importantly, both broadband correlations and neuronal spiking activity are modulated by the phase of the oscillations. These results are specific to the alpha band and build upon emerging evidence suggesting that alpha oscillations may play an active role in cortical function. Our data therefore provide evidence that large-scale communication in the human brain may be rhythmically modulated by alpha oscillations.


Assuntos
Ondas Encefálicas/fisiologia , Vias Neurais/fisiologia , Lobo Temporal/fisiologia , Adulto , Eletroencefalografia , Epilepsia/cirurgia , Feminino , Humanos , Masculino
18.
Clin Neurophysiol ; 130(9): 1628-1641, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31325676

RESUMO

OBJECTIVE: Due to variability in the patterns of propagation of interictal epileptiform discharges (IEDs), qualitative definition of the irritative zone has been challenging. Here, we introduce a quantitative approach toward exploration of the dynamics of IED propagation within the irritative zone. METHODS: We examined intracranial EEG (iEEG) in nine participants undergoing invasive monitoring for seizure localization. We used an automated IED detector and a community detection algorithm to identify populations of electrodes exhibiting IED activity that co-occur in time, and to group these electrodes into communities. RESULTS: Within our algorithmically-identified communities, IED activity in the seizure onset zone (SOZ) tended to lead IED activity in other functionally coupled brain regions. The tendency of pathological activity to arise in the SOZ, and to spread to non-SOZ tissues, was greater in the asleep state. CONCLUSIONS: IED activity, and, by extension, the variability observed between the asleep and awake states, is propagated from a core seizure focus to nearby less pathological brain regions. SIGNIFICANCE: Using an unsupervised, computational approach, we show that the spread of IED activity through the epilepsy network varies with physiologic state.


Assuntos
Eletroencefalografia/métodos , Epilepsia/fisiopatologia , Convulsões/fisiopatologia , Adolescente , Adulto , Algoritmos , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Eletrodos Implantados/normas , Eletroencefalografia/instrumentação , Epilepsia/diagnóstico , Feminino , Humanos , Masculino , Convulsões/diagnóstico , Sono
19.
Mov Disord ; 34(7): 1073-1078, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31145831

RESUMO

OBJECTIVE: To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients. METHODS: Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 µL/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18 F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively. RESULTS: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P < 0.0002). CONCLUSION: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased [18 F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Dependovirus/genética , Terapia Genética , Doença de Parkinson/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , Adulto , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Doença de Parkinson/genética , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/terapia , Putamen/efeitos dos fármacos
20.
Science ; 363(6430): 975-978, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819961

RESUMO

Episodic memory retrieval relies on the recovery of neural representations of waking experience. This process is thought to involve a communication dynamic between the medial temporal lobe memory system and the neocortex. How this occurs is largely unknown, however, especially as it pertains to awake human memory retrieval. Using intracranial electroencephalographic recordings, we found that ripple oscillations were dynamically coupled between the human medial temporal lobe (MTL) and temporal association cortex. Coupled ripples were more pronounced during successful verbal memory retrieval and recover the cortical neural representations of remembered items. Together, these data provide direct evidence that coupled ripples between the MTL and association cortex may underlie successful memory retrieval in the human brain.


Assuntos
Memória Episódica , Rememoração Mental , Neocórtex/fisiologia , Lobo Temporal/fisiologia , Adulto , Mapeamento Encefálico , Epilepsia Resistente a Medicamentos , Eletrocorticografia , Eletrodos , Feminino , Humanos , Masculino , Testes de Memória e Aprendizagem
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