scholarly journals More than just summed neuronal activity: how multiple cell types shape the BOLD response

2020 ◽  
Vol 376 (1815) ◽  
pp. 20190630 ◽  
Author(s):  
Clare Howarth ◽  
Anusha Mishra ◽  
Catherine N. Hall
Keyword(s):  
Neuronal Activity ◽  
Functional Neuroimaging ◽  
Cell Types ◽  
Blood Oxygen Level Dependent ◽  
Inhibitory Neurons ◽  
Human Cognition ◽  
Projection Neurons ◽  
Bold Signal ◽  
Bold Response ◽  
Biological Phenomena

Functional neuroimaging techniques are widely applied to investigations of human cognition and disease. The most commonly used among these is blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The BOLD signal occurs because neural activity induces an increase in local blood supply to support the increased metabolism that occurs during activity. This supply usually outmatches demand, resulting in an increase in oxygenated blood in an active brain region, and a corresponding decrease in deoxygenated blood, which generates the BOLD signal. Hence, the BOLD response is shaped by an integration of local oxygen use, through metabolism, and supply, in the blood. To understand what information is carried in BOLD signals, we must understand how several cell types in the brain—local excitatory neurons, inhibitory neurons, astrocytes and vascular cells (pericytes, vascular smooth muscle and endothelial cells), and their modulation by ascending projection neurons—contribute to both metabolism and haemodynamic changes. Here, we review the contributions of each cell type to the regulation of cerebral blood flow and metabolism, and discuss situations where a simplified interpretation of the BOLD response as reporting local excitatory activity may misrepresent important biological phenomena, for example with regards to arousal states, ageing and neurological disease. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

scholarly journals Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity

2020 ◽  
Vol 376 (1815) ◽  
pp. 20190622
Author(s):  
Anusha Mishra ◽  
Catherine N. Hall ◽  
Clare Howarth ◽  
Ralph D. Freeman
Keyword(s):  
Blood Flow ◽  
Neuronal Activity ◽  
Vascular Function ◽  
Functional Neuroimaging ◽  
Cell Types ◽  
Human Cognition ◽  
Measured Signal ◽  
Bold Signal ◽  
Theme Issue ◽  
Non Invasive

Functional neuroimaging using MRI relies on measurements of blood oxygen level-dependent (BOLD) signals from which inferences are made about the underlying neuronal activity. This is possible because neuronal activity elicits increases in blood flow via neurovascular coupling, which gives rise to the BOLD signal. Hence, an accurate interpretation of what BOLD signals mean in terms of neural activity depends on a full understanding of the mechanisms that underlie the measured signal, including neurovascular and neurometabolic coupling, the contribution of different cell types to local signalling, and regional differences in these mechanisms. Furthermore, the contributions of systemic functions to cerebral blood flow may vary with ageing, disease and arousal states, with regard to both neuronal and vascular function. In addition, recent developments in non-invasive imaging technology, such as high-field fMRI, and comparative inter-species analysis, allow connections between non-invasive data and mechanistic knowledge gained from invasive cellular-level studies. Considered together, these factors have immense potential to improve BOLD signal interpretation and bring us closer to the ultimate purpose of decoding the mechanisms of human cognition. This theme issue covers a range of recent advances in these topics, providing a multidisciplinary scientific and technical framework for future work in the neurovascular and cognitive sciences. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.

scholarly journals Single-cell dissection of schizophrenia reveals neurodevelopmental-synaptic axis and transcriptional resilience

2020 ◽  
Author(s):  
W. Brad Ruzicka ◽  
Shahin Mohammadi ◽  
Jose Davila-Velderrain ◽  
Sivan Subburaju ◽  
Daniel Reed Tso ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Types ◽  
Synaptic Function ◽  
Inhibitory Neurons ◽  
Projection Neurons ◽  
Cell Type ◽  
Cortical Projection ◽  
Human Neurons ◽  
Small Effect Size ◽  
Therapeutic Development

AbstractSchizophrenia is a devastating mental disorder with a high societal burden, complex pathophysiology, and diverse genetic and environmental risk factors. Its complexity, polygenicity, and small-effect-size and cell-type-specific contributors have hindered mechanistic elucidation and the search for new therapeutics. Here, we present the first single-cell dissection of schizophrenia, across 500,000+ cells from 48 postmortem human prefrontal cortex samples, including 24 schizophrenia cases and 24 controls. We annotate 20 cell types/states, providing a high-resolution atlas of schizophrenia-altered genes and pathways in each. We find neurons are the most affected cell type, with deep-layer cortico-cortical projection neurons and parvalbumin-expressing inhibitory neurons showing significant transcriptional changes converging on genetically-implicated regions. We discover a novel excitatory-neuron cell-state indicative of transcriptional resilience and enriched in schizophrenia subjects with less-perturbed transcriptional signatures. We identify key trans-acting factors as candidate drivers of observed transcriptional perturbations, including MEF2C, TCF4, SOX5, and SATB2, and map their binding patterns in postmortem human neurons. These factors regulate distinct gene sets underlying fetal neurodevelopment and adult synaptic function, bridging two leading models of schizophrenia pathogenesis. Our results provide the most detailed map to date for mechanistic understanding and therapeutic development in neuropsychiatric disorders.

scholarly journals A novel population of long-range inhibitory neurons

2019 ◽  
Author(s):  
Zoé Christenson Wick ◽  
Madison R. Tetzlaff ◽  
Esther Krook-Magnuson
Keyword(s):  
Long Range ◽  
Viral Vector ◽  
Neuronal Cell ◽  
Building Blocks ◽  
Cell Types ◽  
Neuronal Population ◽  
Inhibitory Neurons ◽  
Projection Neurons ◽  
Neuronal Diversity ◽  
Rich Diversity

AbstractThe hippocampus, a brain region important for spatial navigation and episodic memory, benefits from a rich diversity of neuronal cell-types. Recent work suggests fundamental gaps in our knowledge of these basic building blocks (i.e., neuronal types) in the hippocampal circuit, despite extensive prior examination. Through the use of an intersectional genetic viral vector approach, we report a novel hippocampal neuronal population, which has not previously been characterized, and which we refer to as LINCs. LINCs are GABAergic, but, in addition to broadly targeting local CA1 cells, also have long-range axons. LINCs are thus both interneurons and projection neurons. We demonstrate that LINCs, despite being relatively few in number, can have a strong influence on both hippocampal and extrahippocampal network synchrony and function. Identification and characterization of this novel cell population advances our basic understanding of both hippocampal circuitry and neuronal diversity.

scholarly journals Quantitative relations between transient BOLD responses, cortical energetics, and impulse firing in different cortical regions

2019 ◽  
Vol 122 (3) ◽  
pp. 1226-1237 ◽  
Author(s):  
M. R. Bennett ◽  
L. Farnell ◽  
W. G. Gibson
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Neuronal Activity ◽  
Blood Oxygen Level Dependent ◽  
Blood Oxygen ◽  
Bold Signal ◽  
Oxygen Level ◽  
Blood Oxygen Level ◽  
Baseline Activity ◽  
Input Activity

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow (cerebral blood flow) and oxygen usage (cerebral metabolic rate of oxygen) that in turn are modulated by changes in neuronal activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neuronal activity. Here we use our previous theory relating the steady-state BOLD signal to neuronal activity and amalgamate it with the standard dynamic causal model (DCM, Friston) theory to produce a quantitative model relating the time-dependent BOLD signal to the underlying neuronal activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both positive and negative BOLD signals. It can reproduce a wide variety of experimental BOLD signals reported in the literature solely by adjusting the neuronal input activity. In this way it provides support for the claim that the main features of the signals, including poststimulus undershoot and overshoot, are principally a result of changes in neuronal activity. NEW & NOTEWORTHY A previous model relating the steady-state blood oxygen level-dependent (BOLD) signal to neuronal activity, both above and below baseline, is extended to account for transient BOLD signals. This allows for a detailed investigation of the role neuronal activity can play in such signals and also encompasses poststimulus undershoot and overshoot. A wide variety of experimental BOLD signals are reproduced solely by adjusting the neuronal input activity, including recent results regarding the BOLD signal in patients with schizophrenia.

scholarly journals A dynamical model of the laminar BOLD response

2019 ◽  
Author(s):  
Martin Havlicek ◽  
Kamil Uludag
Keyword(s):  
High Resolution ◽  
Blood Volume ◽  
Neuronal Activity ◽  
Cerebral Blood Volume ◽  
Local Maximum ◽  
Mass Conservation ◽  
Physiological Parameters ◽  
Blood Oxygenation ◽  
Bold Signal ◽  
Bold Response

AbstractHigh-resolution functional magnetic resonance imaging (fMRI) using blood oxygenation dependent level-dependent (BOLD) signal is an increasingly popular tool to non-invasively examine neuronal processes at the mesoscopic level. However, as the BOLD signal stems from hemodynamic changes, its temporal and spatial properties do not match those of the underlying neuronal activity. In particular, the laminar BOLD response (LBR), commonly measured with gradient-echo (GE) MRI sequence, is confounded by non-local changes in deoxygenated hemoglobin and cerebral blood volume propagated within intracortical ascending veins, leading to a unidirectional blurring of the neuronal activity distribution towards the cortical surface. Here, we present a new cortical depth-dependent model of the BOLD response based on the principle of mass conservation, which takes the effect of ascending (and pial) veins on the cortical BOLD responses explicitly into account. It can be used to dynamically model cortical depth profiles of the BOLD signal as a function of various baseline- and activity-related physiological parameters for any spatiotemporal distribution of neuronal changes. We demonstrate that the commonly observed spatial increase of LBR is mainly due to baseline blood volume increase towards the surface. In contrast, an occasionally observed local maximum in the LBR (i.e. the so-called “bump”) is mainly due to spatially inhomogeneous neuronal changes rather than locally higher baseline blood volume. In addition, we show that the GE-BOLD signal laminar point-spread functions, representing the signal leakage towards the surface, depend on several physiological parameters and on the level of neuronal activity. Furthermore, even in the case of simultaneous neuronal changes at each depth, inter-laminar delays of LBR transients are present due to the ascending vein. In summary, the model provides a conceptual framework for the biophysical interpretation of common experimental observations in high-resolution fMRI data. In the future, the model will allow for deconvolution of the spatiotemporal hemodynamic bias of the LBR and provide an estimate of the underlying laminar excitatory and inhibitory neuronal activity.

scholarly journals Connectivity characterization of the mouse basolateral amygdalar complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Houri Hintiryan ◽  
Ian Bowman ◽  
David L. Johnson ◽  
Laura Korobkova ◽  
Muye Zhu ◽  
...  
Keyword(s):  
Granular Cell ◽  
Cell Types ◽  
Projection Neurons ◽  
Cell Type ◽  
Connectivity Map ◽  
Analysis Techniques ◽  
Domain Specific ◽  
Cell Type Specific ◽  
Unique Domain

AbstractThe basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks.

scholarly journals A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI

2021 ◽  
pp. 0271678X2097858
Author(s):  
Jinxia (Fiona) Yao ◽  
Ho-Ching (Shawn) Yang ◽  
James H Wang ◽  
Zhenhu Liang ◽  
Thomas M Talavage ◽  
...  
Keyword(s):  
Arrival Time ◽  
Stress Test ◽  
Low Frequency ◽  
Hemodynamic Response ◽  
Blood Oxygen Level Dependent ◽  
Cerebrovascular Reactivity ◽  
Bold Signal ◽  
Hemodynamic Response Function ◽  
Carbon Dioxide Co2 ◽  
Co2 Challenge

Elevated carbon dioxide (CO2) in breathing air is widely used as a vasoactive stimulus to assess cerebrovascular functions under hypercapnia (i.e., “stress test” for the brain). Blood-oxygen-level-dependent (BOLD) is a contrast mechanism used in functional magnetic resonance imaging (fMRI). BOLD is used to study CO2-induced cerebrovascular reactivity (CVR), which is defined as the voxel-wise percentage BOLD signal change per mmHg change in the arterial partial pressure of CO2 (PaCO2). Besides the CVR, two additional important parameters reflecting the cerebrovascular functions are the arrival time of arterial CO2 at each voxel, and the waveform of the local BOLD signal. In this study, we developed a novel analytical method to accurately calculate the arrival time of elevated CO2 at each voxel using the systemic low frequency oscillations (sLFO: 0.01-0.1 Hz) extracted from the CO2 challenge data. In addition, 26 candidate hemodynamic response functions (HRF) were used to quantitatively describe the temporal brain reactions to a CO2 stimulus. We demonstrated that our approach improved the traditional method by allowing us to accurately map three perfusion-related parameters: the relative arrival time of blood, the hemodynamic response function, and CVR during a CO2 challenge.

scholarly journals Brain reactivity using fMRI to insomnia stimuli in insomnia patients with discrepancy between subjective and objective sleep

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Young-Bo Kim ◽  
Nambeom Kim ◽  
Jae Jun Lee ◽  
Seo-Eun Cho ◽  
Kyoung-Sae Na ◽  
...  
Keyword(s):  
Brain Activity ◽  
Blood Oxygen Level Dependent ◽  
Brain Regions ◽  
Cognitive Distortion ◽  
Sleep Diary ◽  
Bold Signal ◽  
Blood Oxygen Level ◽  
General Anxiety ◽  
Sleep Deficit ◽  
Perception Of Sleep

AbstractSubjective–objective discrepancy of sleep (SODS) might be related to the distorted perception of sleep deficit and hypersensitivity to insomnia-related stimuli. We investigated differences in brain activation to insomnia-related stimuli among insomnia patients with SODS (SODS group), insomnia patients without SODS (NOSODS group), and healthy controls (HC). Participants were evaluated for subjective and objective sleep using sleep diary and polysomnography. Functional magnetic resonance imaging was conducted during the presentation of insomnia-related (Ins), general anxiety-inducing (Gen), and neutral (Neu) stimuli. Brain reactivity to the contrast of Ins vs. Neu and Gen vs. Neu was compared among the SODS (n = 13), NOSODS (n = 15), and HC (n = 16) groups. In the SODS group compared to other groups, brain areas including the left fusiform, bilateral precuneus, right superior frontal gyrus, genu of corpus callosum, and bilateral anterior corona radiata showed significantly increased blood oxygen level dependent (BOLD) signal in the contrast of Ins vs. Neu. There was no brain region with significantly increased BOLD signal in the Gen vs. Neu contrast in the group comparisons. Increased brain activity to insomnia-related stimuli in several brain regions of the SODS group is likely due to these individuals being more sensitive to sleep-related threat and negative cognitive distortion toward insomnia.

scholarly journals A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

2020 ◽  
Author(s):  
Krishnakanth Kondabolu ◽  
Natalie M. Doig ◽  
Olaoluwa Ayeko ◽  
Bakhtawer Khan ◽  
Alexandra Torres ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Subthalamic Nucleus ◽  
Ex Vivo ◽  
Cell Types ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Primary Input ◽  
Cholinergic Interneurons ◽  
Axonal Connections ◽  
Excitatory Responses

AbstractThe striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

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