Targeted stimulation of human orbitofrontal networks disrupts outcome-guided behavior

ABSTRACTOutcome-guided behavior requires knowledge about the current value of expected outcomes. Such behavior can be isolated in the reinforcer devaluation task, which assesses the ability to infer the current value of rewards after devaluation. Animal lesion studies demonstrate that orbitofrontal cortex (OFC) is necessary for normal behavior in this task, but a causal role for human OFC in outcome-guided behavior has not been established. Here we used sham-controlled non-invasive continuous theta-burst stimulation (cTBS) to temporarily disrupt human OFC network activity prior to devaluation of food odor rewards in a between-subjects design. Subjects in the sham group appropriately avoided Pavlovian cues associated with devalued food odors. However, subjects in the stimulation group persistently chose those cues, even though devaluation of food odors themselves was unaffected by cTBS. This behavioral impairment was mirrored in changes in resting-stated functional magnetic resonance imaging (rs-fMRI) activity, such that subjects in the stimulation group exhibited reduced global OFC network connectivity after cTBS, and the magnitude of this reduction was correlated with choices after devaluation. These findings demonstrate the feasibility of indirectly targeting the human OFC with non-invasive cTBS, and indicate that OFC is specifically required for inferring the value of expected outcomes.

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The brain timewise: how timing shapes and supports brain function

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0170 ◽

2015 ◽

Vol 370 (1668) ◽

pp. 20140170 ◽

Cited By ~ 39

Author(s):

Riitta Hari ◽

Lauri Parkkonen

Keyword(s):

Human Brain ◽

Brain Imaging ◽

Brain Function ◽

Temporal Dynamics ◽

Generative Models ◽

Network Activity ◽

Brain Diseases ◽

Specific Information ◽

Non Invasive ◽

The Brain

We discuss the importance of timing in brain function: how temporal dynamics of the world has left its traces in the brain during evolution and how we can monitor the dynamics of the human brain with non-invasive measurements. Accurate timing is important for the interplay of neurons, neuronal circuitries, brain areas and human individuals. In the human brain, multiple temporal integration windows are hierarchically organized, with temporal scales ranging from microseconds to tens and hundreds of milliseconds for perceptual, motor and cognitive functions, and up to minutes, hours and even months for hormonal and mood changes. Accurate timing is impaired in several brain diseases. From the current repertoire of non-invasive brain imaging methods, only magnetoencephalography (MEG) and scalp electroencephalography (EEG) provide millisecond time-resolution; our focus in this paper is on MEG. Since the introduction of high-density whole-scalp MEG/EEG coverage in the 1990s, the instrumentation has not changed drastically; yet, novel data analyses are advancing the field rapidly by shifting the focus from the mere pinpointing of activity hotspots to seeking stimulus- or task-specific information and to characterizing functional networks. During the next decades, we can expect increased spatial resolution and accuracy of the time-resolved brain imaging and better understanding of brain function, especially its temporal constraints, with the development of novel instrumentation and finer-grained, physiologically inspired generative models of local and network activity. Merging both spatial and temporal information with increasing accuracy and carrying out recordings in naturalistic conditions, including social interaction, will bring much new information about human brain function.

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Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation

Molecular Autism ◽

10.1186/s13229-020-00391-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Mouhamed Alsaqati ◽

Vivi M. Heine ◽

Adrian J. Harwood

Keyword(s):

Neuronal Network ◽

Electrode Array ◽

Network Connectivity ◽

Autism Spectrum ◽

Network Activity ◽

Inhibitory Synapses ◽

Pharmacological Intervention ◽

Spatial Connectivity ◽

Neuronal Network Activity

Abstract Background Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. Methods Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. Results We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory–excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. Limitations Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. Conclusions Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.

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Disruptions of network connectivity predict impairment in multiple behavioral domains after stroke

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521083113 ◽

2016 ◽

Vol 113 (30) ◽

pp. E4367-E4376 ◽

Cited By ~ 193

Author(s):

Joshua Sarfaty Siegel ◽

Lenny E. Ramsey ◽

Abraham Z. Snyder ◽

Nicholas V. Metcalf ◽

Ravi V. Chacko ◽

...

Keyword(s):

Verbal Memory ◽

Visual Memory ◽

General Pattern ◽

Network Connectivity ◽

Neurological Impairment ◽

Brain Network ◽

Behavioral Impairment ◽

Lesion Topography ◽

Multiple Domains ◽

Behavioral Domains

Deficits following stroke are classically attributed to focal damage, but recent evidence suggests a key role of distributed brain network disruption. We measured resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual) in a cohort of 132 stroke patients, and used machine-learning models to predict neurological impairment in individual subjects. We found that visual memory and verbal memory were better predicted by FC, whereas visual and motor impairments were better predicted by lesion topography. Attention and language deficits were well predicted by both. Next, we identified a general pattern of physiological network dysfunction consisting of decrease of interhemispheric integration and intrahemispheric segregation, which strongly related to behavioral impairment in multiple domains. Network-specific patterns of dysfunction predicted specific behavioral deficits, and loss of interhemispheric communication across a set of regions was associated with impairment across multiple behavioral domains. These results link key organizational features of brain networks to brain–behavior relationships in stroke.

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Non-invasive electrical stimulation of the brain (ESB) modifies the resting-state network connectivity of the primary motor cortex: A proof of concept fMRI study

Brain Research ◽

10.1016/j.brainres.2011.06.013 ◽

2011 ◽

Vol 1403 ◽

pp. 37-44 ◽

Cited By ~ 21

Author(s):

G. Alon ◽

S.R. Roys ◽

R.P. Gullapalli ◽

J.D. Greenspan

Keyword(s):

Electrical Stimulation ◽

Resting State ◽

Primary Motor Cortex ◽

Network Connectivity ◽

Proof Of Concept ◽

Non Invasive ◽

Resting State Network ◽

Fmri Study ◽

The Brain ◽

Stimulation Of

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Internally generated population activity in cortical networks hinders information transmission

10.1101/2020.02.03.932723 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chengcheng Huang ◽

Alexandre Pouget ◽

Brent Doiron

Keyword(s):

Information Transfer ◽

Network Connectivity ◽

Network Activity ◽

Population Code ◽

Neuron Models ◽

Population Activity ◽

Variable Activity ◽

Code Performance ◽

Wide Variability ◽

Pattern Forming

AbstractHow neuronal variability impacts neuronal codes is a central question in systems neuroscience, often with complex and model dependent answers. Most population models are parametric, with a tacitly assumed structure of neuronal tuning and population-wide variability. While these models provide key insights, they purposely divorce any mechanistic relationship between trial average and trial variable neuronal activity. By contrast, circuit based models produce activity with response statistics that are reflection of the underlying circuit structure, and thus any relations between trial averaged and trial variable activity are emergent rather than assumed. In this work, we study information transfer in networks of spatially ordered spiking neuron models with strong excitatory and inhibitory interactions, capable of producing rich population-wide neuronal variability. Motivated by work in the visual system we embed a columnar stimulus orientation map in the network and measure the population estimation of an orientated input. We show that the spatial structure of feedforward and recurrent connectivity are critical determinants for population code performance. In particular, when network wiring supports stable firing rate activity then with a sufficiently large number of decoded neurons all available stimulus information is transmitted. However, if the inhibitory projections place network activity in a pattern forming regime then the population-wide dynamics compromise information flow. In total, network connectivity determines both the stimulus tuning as well as internally generated population-wide fluctuations and thereby dictates population code performance in complicated ways where modeling efforts provide essential understanding.

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Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSCs with a TSC2 mutation

10.21203/rs.3.rs-35221/v2 ◽

2020 ◽

Author(s):

Mouhamed Alsaqati ◽

Vivi M Heine ◽

Adrian J. Harwood

Keyword(s):

Neuronal Network ◽

Electrode Array ◽

Network Connectivity ◽

Autism Spectrum ◽

Network Activity ◽

Inhibitory Synapses ◽

Pharmacological Intervention ◽

Spatial Connectivity ◽

Neuronal Network Activity

Abstract Background Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system is currently unclear.MethodsHere we apply Multi-electrode array (MEA)-based assays to study the effects of TSC2 loss on neuronal network activity using Autism Spectrum Disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting, and spatial connectivity between electrodes across the network. Results We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory-excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK), and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604 increases the network behaviour, shortens the network burst lengths, and reduces the number of uncorrelated spikes.LimitationsAlthough a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients.ConclusionsOur observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.

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Spatiospectral brain networks reflective of improvisational experience

10.1101/2021.02.25.432633 ◽

2021 ◽

Author(s):

Josef Faller ◽

Andrew Goldman ◽

Yida Lin ◽

James R. McIntosh ◽

Paul Sajda

Keyword(s):

Large Scale ◽

Time Window ◽

Network Connectivity ◽

Functional Class ◽

Network Activity ◽

Oddball Paradigm ◽

Auditory Oddball ◽

Scalp Eeg ◽

Musical Structures ◽

Functional Classes

AbstractMusical improvisers are trained to categorize certain musical structures into functional classes, which is thought to facilitate improvisation. Using a novel auditory oddball paradigm (Goldman et al., 2020) which enables us to disassociate a deviant (i.e. musical cord inversion) from a consistent functional class, we recorded scalp EEG from a group of musicians who spanned a range of improvisational and classically trained experience. Using a spatiospectral based inter and intra network connectivity analysis, we found that improvisers showed a variety of differences in connectivity within and between large-scale cortical networks compared to classically trained musicians, as a function of deviant type. Inter-network connectivity in the alpha band, for a time window leading up to the behavioural response, was strongly linked to improvisation experience, with the default mode network acting as a hub. Spatiospectral networks post response were substantially different between improvisers and classically trained musicians, with greater inter-network connectivity (specific to the alpha and beta bands) seen in improvisers whereas those with more classical training had largely reduced inter-network activity (mostly in the gamma band). More generally, we interpret our findings in the context of network-level correlates of expectation violation as a function of subject expertise, and we discuss how these may generalize to other and more ecologically valid scenarios.

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Heterogeneous side-effects of cortical inactivation in behaving animals

eLife ◽

10.7554/elife.66400 ◽

2021 ◽

Vol 10 ◽

Author(s):

Ariana R Andrei ◽

Samantha Debes ◽

Mircea Chelaru ◽

Xiaoqin Liu ◽

Elsa Rodarte ◽

...

Keyword(s):

Side Effects ◽

Full Range ◽

Network Connectivity ◽

Careful Consideration ◽

Network Activity ◽

Cortical Region ◽

Target Area ◽

Response Modulation ◽

Cortical Column ◽

Local Circuits

Cortical inactivation represents a key causal manipulation that allows the study of cortical circuits and their impact on behavior. A key assumption in these studies is that the neurons in the target area become silent while the surrounding cortical tissue is only negligibly impacted. However, individual neurons are embedded in complex local circuits comprised of excitatory and inhibitory cells with connections extending hundreds of microns. This raises the possibility that silencing one part of the network could induce complex, unpredictable activity changes in neurons outside the targeted inactivation zone. These off-target side effects can potentially complicate interpretations of inactivation manipulations, especially when they are related to changes in behavior. Here, we demonstrate that optogenetic inactivation of glutamatergic neurons in the superficial layers of monkey V1 induces robust suppression at the light-targeted site, but destabilizes stimulus responses in the neighboring, untargeted network. We identified 4 types of stimulus-evoked neuronal responses within a cortical column, ranging from full suppression to facilitation, and a mixture of both. Mixed responses were most prominent in middle and deep cortical layers. Importantly, these results demonstrate that response modulation driven by lateral network connectivity is diversely implemented throughout a cortical column. Furthermore, consistent behavioral changes induced by optogenetic inactivation were only achieved when cumulative network activity was homogeneously suppressed. Therefore, careful consideration of the full range of network changes outside the inactivated cortical region is required, as heterogeneous side-effects can confound interpretation of inactivation experiments.

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Behavioral Responses to 'Alarm Odors' In Potentially Invasive and Non-invasive Crayfish Species from Aquaculture Ponds

Behaviour ◽

10.1163/1568539042245204 ◽

2004 ◽

Vol 141 (6) ◽

pp. 691-702 ◽

Cited By ~ 11

Author(s):

William Daniels ◽

Francesca Gherardi ◽

Patrizia Acquistapace

Keyword(s):

The Other ◽

Control Phase ◽

Food Odor ◽

Non Invasive ◽

Aquaculture Ponds ◽

Invasive Crayfish ◽

Food Odors ◽

Conspecific Odors ◽

Procambarus Acutus ◽

Crayfish Species

AbstractTwo North American crayfish species, the Eastern white river crayfish, Procambarus acutus acutus, and the red swamp crayfish, P. clarkii, were studied in the laboratory for their responses to food odors and to cues released by injured conspecifics and heterospecifics. The two species differ in that only P. clarkii is known to behave as an invasive species. All the test individuals were collected from aquaculture research ponds, in which they had had no prior contact with the other species and predation risks, excluding cannibalism, were reduced. The experimental design consisted in subjecting 20 crayfish per species to (1) a 3-min control phase after the injection of 20 ml of water and (2) a 3-min test phase after the injection of 20 ml of one of three test solutions (food odor, conspecific odor plus food odor, heterospecific odor plus food odor). We found that the two species differ on one hand for their background behavior and on the other for the intensity and quality of their responses to the three types of cues. Firstly, P. clarkii appeared more active than P. acutus acutus during the control phase and responded in a stronger fashion to the injection of the solutions. Secondly, we recorded an increased locomotion in P. acutus acutus with food and heterospecific cues (by moving crayfish maximize the chance of finding food), but not with conspecific odors (by not moving, crayfish reduce their exposure to visual predators). To the contrary, at the injection of the three test solutions P. clarkii displayed clear feeding-related activities (although less intense with conspecific odors) as opposed to the danger reactions shown in a previous study on individuals from a naturalized population of the same species. This result suggests that crayfish reared in an environment where predation risks are reduced (e. g. in aquaculture ponds) may respond differently to cues that in other, more risky habitats inform of a danger.

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