Alterations in pain processing circuitries in episodic migraine

Background The precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli. Methods Functional magnetic resonance imaging was performed in 29 healthy controls and 25 migraineurs during the interictal and immediately (within 24-h) prior to migraine phases. We assessed activation of higher cortical areas during noxious orofacial heat stimulation using a thermode device and assessed whole scan and pain-related changes in connectivity. Results Despite similar overall pain intensity ratings between all three groups, migraineurs in the group immediately prior to migraine displayed greater activation of the ipsilateral nucleus accumbens, the contralateral ventrolateral prefrontal cortex and two clusters in the dorsolateral prefrontal cortex (dlPFC). Reduced whole scan dlPFC [Z + 44] connectivity with cortical/subcortical and brainstem regions involved in pain modulation such as the putamen and primary motor cortex was demonstrated in migraineurs. Pain-related changes in connectivity of the dlPFC and the hypothalamus immediately prior to migraine was also found to be reduced with brainstem pain modulatory areas such as the rostral ventromedial medulla and dorsolateral pons. Conclusions These data reveal that the modulation of brainstem pain modulatory areas by higher cortical regions may be aberrant during pain and these alterations in this descending pain modulatory pathway manifests exclusively prior to the development of a migraine attack.

Anterior Cruciate Ligament Reconstructed Patients Who Recovered Normal Postural Control Have Dissimilar Brain Activation Patterns Compared to Healthy Controls

Postural control, which is a fundamental functional skill, reflects integration and coordination of sensory information. Damaged anterior cruciate ligament (ACL) may alter neural activation patterns in the brain, despite patients’ surgical reconstruction (ACLR). However, it is unknown whether ACLR patients with normal postural control have persistent neural adaptation in the brain. Therefore, we explored theta (4–8 Hz) and alpha-2 (10–12 Hz) oscillation bands at the prefrontal, premotor/supplementary motor, primary motor, somatosensory, and primary visual cortices, in which electrocortical activation is highly associated with goal-directed decision-making, preparation of movement, motor output, sensory input, and visual processing, respectively, during first 3 s of a single-leg stance at two different task complexities (stable/unstable) between ACLR patients and healthy controls. We observed that ACLR patients showed similar postural control ability to healthy controls, but dissimilar neural activation patterns in the brain. To conclude, we demonstrated that ACLR patients may rely on more neural sources on movement preparation in conjunction with sensory feedback during the early single-leg stance period relative to healthy controls to maintain postural control. This may be a compensatory protective mechanism to accommodate for the altered sensory inputs from the reconstructed knee and task complexity. Our study elucidates the strategically different brain activity utilized by ACLR patients to sustain postural control.

The Activated Macrophage – A Tough Fortress for Virus Invasion: How Viruses Strike Back

Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.

Task-dependent neural control of regions within human genioglossus

Anatomical and imaging evidence suggests neural control of oblique and horizontal compartments of the genioglossus differs. However, neurophysiological evidence for differential control remains elusive. This study aimed to determine whether there are differences in neural drive to the oblique and horizontal regions of the genioglossus during swallowing and tongue protrusion. Adult participants (N=63; 48M) were recruited from a sleep clinic; 41 had Obstructive Sleep Apnoea (OSA: 34M, 8F). Electromyographic (EMG) was recorded at rest (awake, supine) using 4 intramuscular fine-wire electrodes inserted percutaneously into the anterior oblique, posterior oblique, anterior horizontal and posterior horizontal genioglossus. Epiglottic pressure and nasal airflow were also measured. During swallowing, two distinct EMG patterns were observed- a monophasic response (single EMG peak) and a biphasic response (two bursts of EMG). Peak EMG and timing of the peak relative to epiglottic pressure were significantly different between patterns (linear mixed models, p<0.001). Monophasic activation was more likely in the horizontal than oblique region during swallowing (OR=6.83, CI=3.46-13.53, p<0.001). In contrast, during tongue protrusion, activation patterns and EMG magnitude were not different between regions. There were no systematic differences in EMG patterns during swallowing or tongue protrusion between OSA and non-OSA groups. These findings provide evidence for functional differences in the motoneuronal output to the oblique and horizontal compartments, enabling differential task-specific drive. Given this, it is important to identify the compartment from which EMG is acquired. We propose that the EMG patterns during swallowing may be used to identify the compartment where a recording electrode is located.

Heterogeneity of social cognition in temporo-parietal junction: Overlapping yet distinct representation between visual perspective-taking and theory of mind

Visual perspective taking (VPT), particularly level 2 VPT (VPT2), which allows an individual to understand that the same object can be seen differently by others, is related to the theory of mind (ToM), because both functions require a decoupled representation from oneself. Although previous neuroimaging studies have shown that VPT and ToM activate the temporo-parietal junction (TPJ), it is unclear whether common neural substrates are involved in VPT and ToM. To clarify this point, the present study directly compared the TPJ activation patterns of individual participants performing VPT2 and ToM tasks using functional magnetic resonance imaging and within-subjects design. VPT2-induced activations were compared with activations observed during a mental rotation task as a control task, whereas ToM-related activities were identified with a standard ToM localizer using false-belief stories. A whole-brain analysis revealed that VPT2 and ToM activated overlapping areas in the posterior part of the TPJ. By comparing the activations induced by VPT2 and ToM in individual participants, we found that the peak voxels induced by ToM were located significantly more anteriorly and dorsally within the bilateral TPJ than those measured during the VPT2 task. We further confirmed that these activity areas were spatially distinct from the nearby extrastriate body area (EBA), visual motion area (MT+), and the posterior superior temporal sulcus (pSTS) using independent localizer scans. Our findings revealed that VPT2 and ToM have distinct representations, albeit partially overlapping, indicating the functional heterogeneity of social cognition within the TPJ.

Atrial fibrillation driver identification through regional mutual information networks: a modeling perspective

Purpose Effective identification of electrical drivers within remodeled tissue is a key for improving ablation treatment for atrial fibrillation. We have developed a mutual information, graph-based approach to identify and propose fault tolerance metric of local efficiency as a distinguishing feature of rotational activation and remodeled atrial tissue. Methods Voltage data were extracted from atrial tissue simulations (2D Karma, 3D physiological, and the Multiscale Cardiac Simulation Framework (MSCSF)) using multi-spline open and parallel regional mapping catheter geometries. Graphs were generated based on varied mutual information thresholds between electrode pairs and the local efficiency for each graph was calculated. Results High-resolution mapping catheter geometries can distinguish between rotational and irregular activation patterns using the derivative of local efficiency as a function of increasing mutual information threshold. The derivative is decreased for rotational activation patterns comparing to irregular activations in both a simplified 2D model (0.0017 ± 1 × 10−4 vs. 0.0032 ± 1 × 10−4, p < 0.01) and a more realistic 3D model (0.00092 ± 5 × 10−5 vs. 0.0014 ± 4 × 10−5, p < 0.01). Average local efficiency derivative can also distinguish between degrees of remodeling. Simulations using the MSCSF model, with 10 vs. 90% remodeling, display distinct derivatives in the grid design parallel spline catheter configuration (0.0015 ± 5 × 10−5 vs. 0.0019 ± 6 × 10−5, p < 0.01) and the flower shaped open spline configuration (0.0011 ± 5 × 10−5 vs. 0.0016 ± 4 × 10−5, p < 0.01). Conclusion A decreased derivative of local efficiency characterizes rotational activation and varies with atrial remodeling. This suggests a distinct communication pattern in cardiac rotational activation detectable via high-resolution regional mapping and could enable identification of electrical drivers for targeted ablation.

Cortical glutamatergic projection neuron types contribute to distinct functional subnetworks

The cellular basis of cerebral cortex functional architecture remains not well understood. A major challenge is to monitor and decipher neural network dynamics across broad cortical areas yet with projection neuron (PN) type resolution in real time during behavior. Combining genetic targeting and wide-field imaging, we monitored activity dynamics of subcortical-projecting (PTFezf2) and intratelencephalic-projecting (ITPlxnD1) types across dorsal cortex of mice during multiple brain states and behaviors. ITPlxnD1 and PTFezf2 showed distinct activation patterns during wakeful resting, spontaneous movements, and upon sensory stimulation. Distinct ITPlxnD1 and PTFezf2 subnetworks dynamically tuned to different sensorimotor components of a naturalistic feeding behavior, and optogenetic inhibition of subnetwork nodes disrupted specific behavioral components. ITPlxnD1 and PTFezf2 projection patterns supported their subnetwork activation patterns. Our results suggest that, in addition to the concept of columnar organization, dynamic areal and PN type-specific subnetworks is a key feature of cortical functional architecture linking microcircuit components with global brain networks.

Effects of age and knee osteoarthritis on the modular control of walking: A pilot study

Background Older adults and individuals with knee osteoarthritis (KOA) often exhibit reduced locomotor function and altered muscle activity. Identifying age- and KOA-related changes to the modular control of gait may provide insight into the neurological mechanisms underlying reduced walking performance in these populations. The purpose of this pilot study was to determine if the modular control of walking differs between younger and older adults without KOA and adults with end-stage KOA. Methods Kinematic, kinetic, and electromyography data were collected from ten younger (23.5 ± 3.1 years) and ten older (63.5 ± 3.4 years) adults without KOA and ten adults with KOA (64.0 ± 4.0 years) walking at their self-selected speed. Separate non-negative matrix factorizations of 500 bootstrapped samples determined the number of modules required to reconstruct each participant’s electromyography. One-way Analysis of Variance tests assessed the effect of group on walking speed and the number of modules. Kendall rank correlations (τb) assessed the association between the number of modules and self-selected walking speed. Results The number of modules required in the younger adults (3.2 ± 0.4) was greater than in the individuals with KOA (2.3 ± 0.7; p = 0.002), though neither cohorts’ required number of modules differed significantly from the unimpaired older adults (2.7 ± 0.5; p ≥ 0.113). A significant association between module number and walking speed was observed (τb = 0.350, p = 0.021) and individuals with KOA walked significantly slower (0.095 ± 0.21 m/s) than younger adults (1.24 ± 0.15 m/s; p = 0.005). Individuals with KOA also exhibited altered module activation patterns and composition (which muscles are associated with each module) compared to unimpaired adults. Conclusion These findings suggest aging alone may not significantly alter modular control; however, the combined effects of knee osteoarthritis and aging may together impair the modular control of gait.