Intra- and Inter-Network connectivity of the default mode network differentiates Treatment-Resistant depression from Treatment-Sensitive depression.

Understanding why some patients with depression remain resistant to antidepressant medication could be elucidated by investigating their associated neural features. Although research has consistently demonstrated abnormalities in the anterior cingulate cortex (ACC) - a region that is part of the default mode network (DMN) - in treatment-resistant depression (TRD), a considerable research gap exists in discerning how these neural networks distinguish TRD from treatment-sensitive depression (TSD). We aimed to evaluate the resting-state functional connectivity (rsFC) of the ACC with other regions of the DMN to better understand the role of this structure in the pathophysiology of TRD. 35 TRD patients, 35 TSD patients, and 38 healthy controls (HC) underwent a resting-state functional MRI protocol. Seed-based functional connectivity analyses were performed, comparing the three groups for the connectivity between two subregions of the ACC (the subgenual ACC (sgACC) and the rostral ACC (rACC)) and the DMN (p < 0.05 FWE corrected). Furthermore, inter-network connectivity of the DMN with other neural networks was explored by independent component (ICA) analyses (p < 0.01, FDR corrected). The results demonstrated hyperconnectivity between the rACC and the posterior cingulate cortex in TRD relative to TSD and HC (F(2,105) = 5.335, p < 0.05). ICA found DMN connectivity to regions of the visual network (TRDTSD), differentiating the two clinical groups. These results provide confirmatory evidence of DMN hyperconnectivity and preliminary evidence for its interactions with other neural networks as key neural mechanisms underlying treatment non-responsiveness.

Abnormal habenula functional connectivity characterizes treatment-resistant depression.

BACKGROUND: A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD. METHODS: 35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons. RESULTS: The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation. CONCLUSIONS: This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression.

GABAergic inhibition reduces the impact of synaptic excitation on somatic excitation.

The effect of excitatory synaptic input on the excitation of the cell body is believed to vary depending on where and when the synaptic activation occurs in dendritic trees and the spatiotemporal modulation by inhibitory synaptic input. However, few studies have examined how individual synaptic inputs influence the excitability of the cell body in spontaneously active neuronal networks mainly because of the lack of an appropriate method. We developed a calcium imaging technique that monitors synaptic inputs to hundreds of spines from a single neuron with millisecond resolution in combination with whole-cell patch-clamp recordings of somatic excitation. In rat hippocampal CA3 pyramidal neurons ex vivo, a fraction of the excitatory synaptic inputs were not detectable in the cell body against background noise. These synaptic inputs partially restored their somatic impact when a GABAA receptor blocker was intracellularly perfused. Thus, GABAergic inhibition reduces the influence of some excitatory synaptic inputs on the somatic excitability. Numerical simulation using a single neuron model demonstrates that the timing and locus of a dendritic GABAergic input are critical to exert this effect. Moreover, logistic regression analyses suggest that the GABAergic inputs sectionalize spine activity; that is, only some subsets of synchronous synaptic activity seemed to be preferably passed to the cell body. Thus, dendrites actively sift inputs from specific presynaptic cell assemblies.

Flashing Lights Induce Prolonged Distortions in Visual Cortical Responses and Visual Perception.

The primary sensory neocortex generates an internal representation of the environment, and its circuit reorganization is thought to lead to a modification of sensory perception. This reorganization occurs primarily through activity-dependent plasticity and has been well documented in animals during early developmental stages. Here, we describe a new method for the noninvasive induction of long-term plasticity in the mature brain: simple transient visual stimuli (i.e., flashing lights) can be used to induce prolonged modifications in visual cortical processing and visually driven behaviors. Our previous studies have shown that, in the primary visual cortex (V1) of mice, a flashing light stimulus evokes a long-delayed response that persists for seconds. When the mice were repetitively presented with drifting grating stimuli (conditioned stimuli) during the flash stimulus-evoked delayed response period, the V1 neurons exhibited a long-lasting decrease in responsiveness to the conditioned stimuli. The flash stimulus-induced underrepresentation of the grating motion was specific to the direction of the conditioned stimuli and was associated with a decrease in the animal's ability to detect the motion of the drifting gratings. The neurophysiological and behavioral plasticity both persisted for at least several hours and required N-methyl-d-aspartate receptor activation in the visual cortex. We propose that flashing light stimuli can be used as an experimental tool to investigate the visual function and plasticity of neuronal representations and perception after a critical period of neocortical plasticity.

cAMP-Dependent Calcium Oscillations of Astrocytes: An Implication for Pathology.

Astrocytes in various brain regions exhibit spontaneous intracellular calcium elevations both in vitro and in vivo; however, neither the temporal pattern underlying this activity nor its function has been fully evaluated. Here, we utilized a long-term optical imaging technique to analyze the calcium activity of more than 4000 astrocytes in acute hippocampal slices as well as in the neocortex and hippocampus of head-restrained mice. Although astrocytic calcium activity was largely sparse and irregular, we observed a subset of cells in which the fluctuating calcium oscillations repeated at a regular interval of ∼30 s. These intermittent oscillations i) depended on type 2 inositol 1,4,5-trisphosphate receptors; ii) consisted of a complex reverberatory interaction between the soma and processes of individual astrocytes; iii) did not synchronize with those of other astrocytes; iv) did not require neuronal firing; v) were modulated through cAMP-protein kinase A signaling; vi) were facilitated under pathological conditions, such as energy deprivation and epileptiform hyperexcitation; and vii) were associated with enhanced hypertrophy in astrocytic processes, an early hallmark of reactive gliosis, which is observed in ischemia and epilepsy. Therefore, calcium oscillations appear to be associated with a pathological state in astrocytes.

Functional Organization of Flash-Induced V1 Offline Reactivation.

The primary visual cortex exhibits a late, long response with a latency of >300 ms and an immediate early response that occurs ∼100 ms after a visual stimulus. The late response is thought to contribute to visual functions such as sensory perception, iconic memory, working memory, and forming connections between temporally separated stimuli. However, how the visual late response is generated and organized is not completely understood. In the mouse primary visual cortex in vivo, we isolated long-delayed responses by using a brief light-flash stimulus for which the stimulus late response occurred long after the stimulus offset and was not contaminated by the instantaneous response evoked by the stimulus. Using whole-cell patch-clamp recordings, we demonstrated that the late rebound response was shaped by a net-balanced increase in excitatory and inhibitory synaptic conductances, whereas transient imbalances were caused by intermittent inhibitory barrage. In contrast to the common assumption that the neocortical late response reflects a feedback signal from the downstream higher-order cortical areas, our pharmacological and optogenetic analyses demonstrated that the late responses likely have a thalamic origin. Therefore, the late component of a sensory-evoked cortical response should be interpreted with caution. SIGNIFICANCE STATEMENT: The long-delayed responses of neocortical neurons are thought to arise from cortical feedback activity that is related to sensory perception and cognition. The mechanism of neocortical late responses was investigated using multiple electrophysiological techniques and the findings indicate that it actually arises from the thalamus. In addition, during the late response, excitation and inhibition are balanced, but inhibition is dominant in patterning action potentials.

Spatial clusters of constitutively active neurons in mouse visual cortex.

The networks of neocortical neurons are coordinated by spontaneous activity, the level of which exhibits high heterogeneity among neurons, ranging from low activity levels to very high activity levels, even in the same network. Highly active neurons represent a small proportion in the cerebral cortex and are mingled in a web of the vast majority of neurons with low firing rates. However, little is known about the spatial arrangement of these highly active cells within the cerebral cortex. Here, we visualized their spatial distribution by labeling them with c-Fos, a neuronal activity marker, in the mouse primary visual cortex. By introducing energy-like and entropy-like parameters that did not require arbitrary thresholds for c-Fos positivity, we found that strongly c-Fos-expressing neurons were clustered in the vicinity. The cluster size measured approximately 100 µm in diameter and was smaller in layer 2/3 than in layers 5 and 6. Layer 1 neurons did not exhibit a clustered pattern of c-Fos-expressing neurons. Our novel statistical approaches are not subject to human bias and are thus widely applicable to evaluate the spatial bias of any particles.

Neocortical Rebound Depolarization Enhances Visual Perception.

Animals are constantly exposed to the time-varying visual world. Because visual perception is modulated by immediately prior visual experience, visual cortical neurons may register recent visual history into a specific form of offline activity and link it to later visual input. To examine how preceding visual inputs interact with upcoming information at the single neuron level, we designed a simple stimulation protocol in which a brief, orientated flashing stimulus was subsequently coupled to visual stimuli with identical or different features. Using in vivo whole-cell patch-clamp recording and functional two-photon calcium imaging from the primary visual cortex (V1) of awake mice, we discovered that a flash of sinusoidal grating per se induces an early, transient activation as well as a long-delayed reactivation in V1 neurons. This late response, which started hundreds of milliseconds after the flash and persisted for approximately 2 s, was also observed in human V1 electroencephalogram. When another drifting grating stimulus arrived during the late response, the V1 neurons exhibited a sublinear, but apparently increased response, especially to the same grating orientation. In behavioral tests of mice and humans, the flashing stimulation enhanced the detection power of the identically orientated visual stimulation only when the second stimulation was presented during the time window of the late response. Therefore, V1 late responses likely provide a neural basis for admixing temporally separated stimuli and extracting identical features in time-varying visual environments.

Intact internal dynamics of the neocortex in acutely paralyzed mice.

Animals collect sensory information through self-generated movements. Muscle movements drive active feedback of sensory information and determine large parts of the sensory inputs the animal receives; however, little is known about how this active feedback process modulates the ongoing dynamics of the brain. We made electrophysiological recordings from layer 2/3 neurons of the mouse neocortex and compared spontaneous cortical activity in local field potentials and intracellular potential fluctuations between normal and hypomyotonic conditions. We found that pancuronium-induced paralysis did not affect the electrophysiological properties of ongoing cortical activity and its perturbation evoked by visual and tactile stimuli. Thus, internal cortical dynamics are not much affected by active muscle movements, at least, in an acute phase.