Default-Mode Network Changes in Huntington’s Disease: An Integrated MRI Study of Functional Connectivity and Morphometry

Previous MRI studies of functional connectivity in pre-symptomatic mutation carriers of Huntington’s disease (HD) have shown dysfunction of the Default-Mode Network (DMN). No data however are currently available on the DMN alterations in the symptomatic stages of the disease, which are characterized by cortical atrophy involving several DMN nodes. We assessed DMN integrity and its possible correlations with motor and cognitive symptoms in 26 symptomatic HD patients as compared to 22 normal volunteers, by analyzing resting state functional MRI data, using the Precuneal Cortex/Posterior Cingulate Cortices (PC/PCC) as seed, controlling at voxel level for the effect of atrophy by co-varying for gray matter volume. Direct correlation with PC/PCC was decreased, without correlation with atrophy, in the ventral medial prefrontal cortex (including anterior cingulate and subgenual cortex), right dorso-medial prefrontal cortex, and in the right inferior parietal cortex (mainly involving the angular gyrus). Negative correlations with PC/PCC were decreased bilaterally in the inferior parietal cortices, while a cluster in the right middle occipital gyrus presented increased correlation with PC/PCC. DMN changes in the ventral medial prefrontal cortex significantly correlated with the performance at the Stroop test (p = .0002). Widespread DMN changes, not correlating with the atrophy of the involved nodes, are present in symptomatic HD patients, and correlate with cognitive disturbances.     

Neural circuit mechanisms for pattern detection and feature combination in olfactory cortex

Odors are initially encoded in the brain as a set of distinct physicochemical characteristics but are ultimately perceived as a unified sensory object--a "smell." It remains unclear how chemical features encoded by diverse odorant receptors and segregated glomeruli in the main olfactory bulb (MOB) are assembled into integrated cortical representations. Combining patterned optical microstimulation of MOB with in vivo electrophysiological recordings in anterior piriform cortex (PCx), we assessed how cortical neurons decode complex activity patterns distributed across MOB glomeruli. PCx firing was insensitive to single-glomerulus photostimulation. Instead, individual cells reported higher-order combinations of coactive glomeruli resembling odor-evoked sensory maps. Intracellular recordings revealed a corresponding circuit architecture providing each cortical neuron with weak synaptic input from a distinct subpopulation of MOB glomeruli. PCx neurons thus detect specific glomerular ensembles, providing an explicit neural representation of chemical feature combinations that are the hallmark of complex odor stimuli.     

Investigating the neural basis for functional and effective connectivity. Application to fMRI

Viewing cognitive functions as mediated by networks has begun to play a central role in interpreting neuroscientific data, and studies evaluating interregional functional and effective connectivity have become staples of the neuroimaging literature. The neurobiological substrates of functional and effective connectivity are, however, uncertain. We have constructed neurobiologically realistic models for visual and auditory object processing with multiple interconnected brain regions that perform delayed match-to-sample (DMS) tasks. We used these models to investigate how neurobiological parameters affect the interregional functional connectivity between functional magnetic resonance imaging (fMRI) time-series. Variability is included in the models as subject-to-subject differences in the strengths of anatomical connections, scan-to-scan changes in the level of attention, and trial-to-trial interactions with non-specific neurons processing noise stimuli. We find that time-series correlations between integrated synaptic activities between the anterior temporal and the prefrontal cortex were larger during the DMS task than during a control task. These results were less clear when the integrated synaptic activity was haemodynamically convolved to generate simulated fMRI activity. As the strength of the model anatomical connectivity between temporal and frontal cortex was weakened, so too was the strength of the corresponding functional connectivity. These results provide a partial validation for using fMRI functional connectivity to assess brain interregional relations.     

Dissociable codes of odor quality and odorant structure in human piriform cortex

The relationship between odorant structure and odor quality has been a focus of olfactory research for 100 years, although no systematic correlations are yet apparent. Animal studies suggest that topographical representations of odorant structure in olfactory bulb form the perceptual basis of odor quality. Whether central olfactory regions are similarly organized is unclear. Using an olfactory version of fMRI cross-adaptation, we measured neural responses in primary olfactory (piriform) cortex as subjects smelled pairs of odorants systematically differing in quality and molecular functional group (as one critical attribute of odorant structure). Our results indicate a double dissociation in piriform cortex, whereby posterior regions encode quality (but not structure) and anterior regions encode structure (but not quality). The presence of structure-based codes suggests fidelity of sensory information arising from olfactory bulb. In turn, quality-based codes are independent of any simple structural configuration, implying that synthetic mechanisms may underlie our experience of smell.     

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.     

Evidence for the connections between a clutch cell and a corticotectal neuron in area 17 of the cat visual cortex

Evidence is presented for the synaptic connectivity between a physiologically characterized and intracellularly filled GABAergic interneuron and a corticotectal pyramidal neuron in area 17 of the cat visual cortex. The interneuron was located in layer 4 and had the morphological characteristics of a clutch cell. The physiological data demonstrated that the clutch cell received direct X-type innervation from the dorsal lateral geniculate nucleus. These results indicate that a GABAergic neuron is directly involved during the first cortical stages of geniculocorticotectal interactions. Furthermore, the proximal location of the clutch-cell inputs to the labelled dendrite suggests a strategic siting of intracortical feedforward inhibition.     

Bulbocortical interplay in olfactory information processing via synchronous oscillations

Emergence of synchronous oscillatory activity is an inherent feature of the olfactory systems of insects, mollusks and mammals. A class of simple computational models of the mammalian olfactory system consisting of olfactory bulb and olfactory cortex is constructed to explore possible roles of the related neural circuitry in olfactory information processing via synchronous oscillations. In the models, the bulbar neural circuitry is represented by a chain of oscillators and that of cortex is analogous to an associative memory network with horizontal synaptic connections. The models incorporate the backprojection from cortical units to the bulbar oscillators in particular ways. They exhibit rapid and robust synchronous oscillations in the presence of odorant stimuli, while they show either nonoscillatory states or propagating waves in the absence of stimuli, depending on the values of model parameters. In both models, the backprojection is shown to enhance the establishment of large-scale synchrony. The results suggest that the modulation of neural activity through centrifugal inputs may play an important role at the early stage of cortical information processing.     

Modeling the role of gap junctions between excitatory neurons in the developing visual cortex

Recent experiments in the developing mammalian visual cortex have revealed that gap junctions couple excitatory cells and potentially influence the formation of chemical synapses. In particular, cells that were coupled by a gap junction during development tend to share an orientation preference and are preferentially coupled by a chemical synapse in the adult cortex, a property that is diminished when gap junctions are blocked. In this work, we construct a simplified model of the developing mouse visual cortex including spike-timing-dependent plasticity of both the feedforward synaptic inputs and recurrent cortical synapses. We use this model to show that synchrony among gap-junction-coupled cells underlies their preference to form strong recurrent synapses and develop similar orientation preference; this effect decreases with an increase in coupling density. Additionally, we demonstrate that gap-junction coupling works, together with the relative timing of synaptic development of the feedforward and recurrent synapses, to determine the resulting cortical map of orientation preference.     

Functional Connectivity of the Posteromedial Cortex

As different areas within the PMC have different connectivity patterns with various cortical and subcortical regions, we hypothesized that distinct functional modules may be present within the PMC. Because the PMC appears to be the most active region during resting state, it has been postulated to play a fundamental role in the control of baseline brain functioning within the default mode network (DMN). Therefore one goal of this study was to explore which components of the PMC are specifically involved in the DMN. In a sample of seventeen healthy volunteers, we performed an unsupervised voxelwise ROI-based clustering based on resting state functional connectivity. Our results showed four clusters with different network connectivity. Each cluster showed positive and negative correlations with cortical regions involved in the DMN. Progressive shifts in PMC functional connectivity emerged from anterior to posterior and from dorsal to ventral ROIs. Ventral posterior portions of PMC were found to be part of a network implicated in the visuo-spatial guidance of movements, whereas dorsal anterior portions of PMC were interlinked with areas involved in attentional control. Ventral retrosplenial PMC selectively correlated with a network showing considerable overlap with the DMN, indicating that it makes essential contributions in self-referential processing, including autobiographical memory processing. Finally, ventral posterior PMC was shown to be functionally connected with a visual network.The paper represents the first attempt to provide a systematic, unsupervised, voxelwise clustering of the human posteromedial cortex (PMC), using resting-state functional connectivity data. Moreover, a ROI-based parcellation was used to confirm the results.     

Mirrored STDP Implements Autoencoder Learning in a Network of Spiking Neurons

The autoencoder algorithm is a simple but powerful unsupervised method for training neural networks. Autoencoder networks can learn sparse distributed codes similar to those seen in cortical sensory areas such as visual area V1, but they can also be stacked to learn increasingly abstract representations. Several computational neuroscience models of sensory areas, including Olshausen & Field’s Sparse Coding algorithm, can be seen as autoencoder variants, and autoencoders have seen extensive use in the machine learning community. Despite their power and versatility, autoencoders have been difficult to implement in a biologically realistic fashion. The challenges include their need to calculate differences between two neuronal activities and their requirement for learning rules which lead to identical changes at feedforward and feedback connections. Here, we study a biologically realistic network of integrate-and-fire neurons with anatomical connectivity and synaptic plasticity that closely matches that observed in cortical sensory areas. Our choice of synaptic plasticity rules is inspired by recent experimental and theoretical results suggesting that learning at feedback connections may have a different form from learning at feedforward connections, and our results depend critically on this novel choice of plasticity rules. Specifically, we propose that plasticity rules at feedforward versus feedback connections are temporally opposed versions of spike-timing dependent plasticity (STDP), leading to a symmetric combined rule we call Mirrored STDP (mSTDP). We show that with mSTDP, our network follows a learning rule that approximately minimizes an autoencoder loss function. When trained with whitened natural image patches, the learned synaptic weights resemble the receptive fields seen in V1. Our results use realistic synaptic plasticity rules to show that the powerful autoencoder learning algorithm could be within the reach of real biological networks.     

Specificity and Plasticity of Thalamocortical Connections in Sema6A Mutant Mice

The establishment of connectivity between specific thalamic nuclei and cortical areas involves a dynamic interplay between the guidance of thalamocortical axons and the elaboration of cortical areas in response to appropriate innervation. We show here that Sema6A mutants provide a unique model to test current ideas on the interactions between subcortical and cortical guidance mechanisms and cortical regionalization. In these mutants, axons from the dorsal lateral geniculate nucleus (dLGN) are misrouted in the ventral telencephalon. This leads to invasion of presumptive visual cortex by somatosensory thalamic axons at embryonic stages. Remarkably, the misrouted dLGN axons are able to find their way to the visual cortex via alternate routes at postnatal stages and reestablish a normal pattern of thalamocortical connectivity. These findings emphasize the importance and specificity of cortical cues in establishing thalamocortical connectivity and the spectacular capacity of the early postnatal cortex for remapping initial sensory representations.     

Spatial learning and action planning in a prefrontal cortical network model

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive "insight" capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.     

Long-term modifications in the strength of excitatory associative inputs in the piriform cortex

Afferent olfactory information, in vivo and in vitro, can be rapidly adapted to through a metabotropic glutamate receptor (mGluR)-mediated attenuation of synaptic strength. Specific cellular and synaptic mechanisms underlying olfactory learning and habituation at the cortical level remain unclear. Through whole-cell recording, excitatory postsynaptic currents (EPSCs) were obtained from piriform cortex (PC) principal cells. Using a coincidental, pre- and postsynaptic stimulation protocol, long-term depression (LTD) in synaptic strength was induced at associative, excitatory synapses onto layer II pyramidal neurons of the mouse (P15-27) PC. LTD was mimicked and occluded by mGluR agonists and blocked by nonselective mGluR antagonist (RS)-alpha-methyl-4-sulfonophenylglycine (MSPG) but not by N-methyl-D-aspartic acid (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV). Analysis of the paired-pulse ratio, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/NMDA current ratio, and spontaneous EPSCs indicate that electrically induced LTD was mediated predominantly by postsynaptic mechanisms. Additionally, presynaptic mGluRs were involved in agonist-mediated synaptic depression. Immunohistochemical analysis supports the presence of multiple subclasses of mGluRs throughout the PC, with large concentrations of several receptors present in layer II. These observations provide further evidence of activity-dependent, long-term modification of associative inputs and its underlying mechanisms. Cortical adaptation at associative synapses provides an additional link between cortical olfactory processing and subcortical centers that influence behavior.     

Decoding the different states of visual attention using functional and effective connectivity features in fMRI data

The present paper concentrates on the impact of visual attention task on structure of the brain functional and effective connectivity networks using coherence and Granger causality methods. Since most studies used correlation method and resting-state functional connectivity, the task-based approach was selected for this experiment to boost our knowledge of spatial and feature-based attention. In the present study, the whole brain was divided into 82 sub-regions based on Brodmann areas. The coherence and Granger causality were applied to construct functional and effective connectivity matrices. These matrices were converted into graphs using a threshold, and the graph theory measures were calculated from it including degree and characteristic path length. Visual attention was found to reveal more information during the spatial-based task. The degree was higher while performing a spatial-based task, whereas characteristic path length was lower in the spatial-based task in both functional and effective connectivity. Primary and secondary visual cortex (17 and 18 Brodmann areas) were highly connected to parietal and prefrontal cortex while doing visual attention task. Whole brain connectivity was also calculated in both functional and effective connectivity. Our results reveal that Brodmann areas of 17, 18, 19, 46, 3 and 4 had a significant role proving that somatosensory, parietal and prefrontal regions along with visual cortex were highly connected to other parts of the cortex during the visual attention task. Characteristic path length results indicated an increase in functional connectivity and more functional integration in spatial-based attention compared with feature-based attention. The results of this work can provide useful information about the mechanism of visual attention at the network level.     

Plasticity-Driven Self-Organization under Topological Constraints Accounts for Non-random Features of Cortical Synaptic Wiring

Understanding the structure and dynamics of cortical connectivity is vital to understanding cortical function. Experimental data strongly suggest that local recurrent connectivity in the cortex is significantly non-random, exhibiting, for example, above-chance bidirectionality and an overrepresentation of certain triangular motifs. Additional evidence suggests a significant distance dependency to connectivity over a local scale of a few hundred microns, and particular patterns of synaptic turnover dynamics, including a heavy-tailed distribution of synaptic efficacies, a power law distribution of synaptic lifetimes, and a tendency for stronger synapses to be more stable over time. Understanding how many of these non-random features simultaneously arise would provide valuable insights into the development and function of the cortex. While previous work has modeled some of the individual features of local cortical wiring, there is no model that begins to comprehensively account for all of them. We present a spiking network model of a rodent Layer 5 cortical slice which, via the interactions of a few simple biologically motivated intrinsic, synaptic, and structural plasticity mechanisms, qualitatively reproduces these non-random effects when combined with simple topological constraints. Our model suggests that mechanisms of self-organization arising from a small number of plasticity rules provide a parsimonious explanation for numerous experimentally observed non-random features of recurrent cortical wiring. Interestingly, similar mechanisms have been shown to endow recurrent networks with powerful learning abilities, suggesting that these mechanism are central to understanding both structure and function of cortical synaptic wiring.     

Combined Hebbian development of geniculocortical and lateral connectivity in a model of primary visual cortex

We present a network model of visual map development in layer 4 of primary visual cortex. Our model comprises excitatory and inhibitory spiking neurons. The input to the network consists of correlated spike trains to mimick the activity of neurons in the lateral geniculate nucleus (LGN). An activity-driven Hebbian learning mechanism governs the development of both the network's lateral connectivity and feedforward projections from LGN to cortex. Plasticity of inhibitory synapses has been included into the model so as to control overall cortical activity. Even without feedforward input, Hebbian modification of the excitatory lateral connections can lead to the development of an intracortical orientation map. We have found that such an intracortical map can guide the development of feedforward connections from LGN to cortical simple cells so that the structure of the final feedforward orientation map is predetermined by the intracortical map. In a scenario in which left- and right-eye geniculocortical inputs develop sequentially one after the other, the resulting maps are therefore very similar, provided the intracortical connectivity remains unaltered. This may explain the outcome of so-called reverse lid-suture experiments, where animals are reared so that both eyes never receive input at the same time, but the orientation maps measured separately for the two eyes are nevertheless nearly identical. Received: 20 December 1999 / Accepted in revised form: 9 June 2000     

Sound-driven synaptic inhibition in primary visual cortex

Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.     

Untypical connectivity from olfactory sensory neurons expressing OR37 into higher brain centers visualized by genetic tracing

The OR37 subfamily of odorant receptors (ORs) exists exclusively in mammals. In contrast to ORs in general, they are highly conserved within and across species. These unique features raise the question, whether olfactory information gathered by the OR37 sensory cells is processed in specially designated brain areas. To elucidate the wiring of projection neurons from OR37 glomeruli into higher brain areas, tracing experiments were performed. The application of DiI onto the ventral area of the olfactory bulb, which harbors the OR37 glomeruli, led to the labeling of fibers not only in the typical olfactory cortical regions, but also in the medial amygdala and the hypothalamus. To visualize the projections from a defined OR37 glomerulus more precisely, transgenic mice were studied in which olfactory sensory neurons co-express the receptor subtype OR37C and the transsynaptic tracer wheat germ agglutinin (WGA). WGA became visible not only in the OR37C sensory neurons and the corresponding OR37C glomerulus, but also in cell somata located in the mitral/tufted cell layer adjacent to the OR37C glomerulus, indicating a transfer of WGA onto projection neurons. In the brain, WGA immunoreactivity was not detectable in typical olfactory cortical areas, but instead in distinct areas of the medial amygdala. Detailed mapping revealed that the WGA immunoreactivity was restricted to the posterior-dorsal subnucleus of the medial amygdala. In addition, WGA immunoreactivity was visible in some well-circumscribed areas of the hypothalamus. These results are indicative for a unique connectivity from OR37C sensory cells into higher brain centers.     

Four concurrent feedforward and feedback networks with different roles in the visual cortical hierarchy

Visual stimuli evoke fast-evolving activity patterns that are distributed across multiple cortical areas. These areas are hierarchically structured, as indicated by their anatomical projections, but how large-scale feedforward and feedback streams are functionally organized in this system remains an important missing clue to understanding cortical processing. By analyzing visual evoked responses in laminar recordings from 6 cortical areas in awake mice, we uncovered a dominant feedforward network with scale-free interactions in the time domain. In addition, we established the simultaneous presence of a gamma band feedforward and 2 low frequency feedback networks, each with a distinct laminar functional connectivity profile, frequency spectrum, temporal dynamics, and functional hierarchy. We could identify distinct roles for each of these 4 processing streams, by leveraging stimulus contrast effects, analyzing receptive field (RF) convergency along functional interactions, and determining relationships to spiking activity. Our results support a dynamic dual counterstream view of hierarchical processing and provide new insight into how separate functional streams can simultaneously and dynamically support visual processes.

Visual stimuli evoke fast-evolving activity patterns that are distributed across multiple cortical areas, but how large-scale feedforward and feedback streams are functionally organized in this system remains unclear. Visual evoked responses in laminar recordings from six cortical areas in awake mice reveal how layers and rhythms dynamically orchestrate functional streams in vision.     

Changes in Cerebral Blood Flow during Olfactory Stimulation in Patients with Multiple Chemical Sensitivity: A Multi-Channel Near-Infrared Spectroscopic Study

Multiple chemical sensitivity (MCS) is characterized by somatic distress upon exposure to odors. Patients with MCS process odors differently from controls. This odor-processing may be associated with activation in the prefrontal area connecting to the anterior cingulate cortex, which has been suggested as an area of odorant-related activation in MCS patients. In this study, activation was defined as a significant increase in regional cerebral blood flow (rCBF) because of odorant stimulation. Using the well-designed card-type olfactory test kit, changes in rCBF in the prefrontal cortex (PFC) were investigated after olfactory stimulation with several different odorants. Near-infrared spectroscopic (NIRS) imaging was performed in 12 MCS patients and 11 controls. The olfactory stimulation test was continuously repeated 10 times. The study also included subjective assessment of physical and psychological status and the perception of irritating and hedonic odors. Significant changes in rCBF were observed in the PFC of MCS patients on both the right and left sides, as distinct from the center of the PFC, compared with controls. MCS patients adequately distinguished the non-odorant in 10 odor repetitions during the early stage of the olfactory stimulation test, but not in the late stage. In comparison to controls, autonomic perception and negative affectivity were poorer in MCS patients. These results suggest that prefrontal information processing associated with odor-processing neuronal circuits and memory and cognition processes from past experience of chemical exposure play significant roles in the pathology of this disorder.