Modulation Of Functional Connectivity Research Articles

Modulations of Inter-Hemispherical Phase Coupling in Human Single Leg Stance

Introduction: Recent findings from neuroimaging studies provided initial insights into cortical contributions to postural control. These studies observed enhanced cortical activation and connectivity when task-difficulty and postural instability increased. However, little attention has been paid to the allocation of cortical networks appearing with a decreasing base of support from bipedal to single leg stance. Therefore, the aim of the present study was to investigate modulations of functional connectivity from bipedal to single leg stance. Experimental procedures: Cortical activity during bipedal and single leg stance (left) was investigated in 15 male subjects using 128 channel mobile electroencephalography (EEG), while standing on a triaxial force plate. Power spectral density was calculated for theta (4–7 Hz), alpha-1 (8–10 Hz) and alpha-2 (10–12 Hz) frequency bands. Estimations of the phase lag index (PLI) were conducted as a measure of functional connectivity. Moreover, postural control was analyzed by the area of sway and sway velocity. Results: The results demonstrated a significantly increased area of sway and decreased alpha-2 power in single leg compared to bipedal stance. Furthermore, PLIs within the alpha-2 frequency band showed significantly decreased inter-hemispherical phase coupling in single leg stance, associated with connections involving the left motor region. Discussion: Altogether, the present findings may indicate modulations of cortical contributions in single leg compared to bipedal stance. The present data suggest that decreased inter-hemispherical functional connectivity, in conjunction with a global increase in cortical excitability, may indicate enhanced alertness and task-specific selective inhibition of motor networks in favor of postural control.

Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam.

The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood‐oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo‐controlled, three‐way crossover design with ketamine and midazolam. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting‐state networks. Independent components analysis (ICA)‐denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross‐modal comparisons of pharmacologically‐modulated functional connectivity.

Habitual physical activity mediates the acute exercise-induced modulation of anxiety-related amygdala functional connectivity

Aerobic exercise, in relation to physical activity, has been shown to have beneficial effects on anxiety. However, the underlyig neural mechanism remains elusive. Using a within-subject crossover design, this fMRI study examined how exercise (12-min treadmill running versus walking) mediated amygdala reactivity to explicit and implicit (backward masked) perception of emotional faces in young adults (N = 40). Results showed that acute exercise-induced differences of state anxiety (STAI-S) varied as a function of individual’s habitual physical activity (IPAQ). Subjects with high IPAQ levels showed significant STAI-S reduction (P < 0.05). Path analyses indicated that IPAQ explained 14.67% of the variance in acute exercise-induced STAI-S differences. Running elicited stronger amygdala reactivity to implicit happiness than fear, whereas walking did the opposite. The exercise-induced amygdala reactivity to explicit fear was associated with the IPAQ scores and STAI-S differences. Moreover, after running, the amygdala exhibited a positive functional connectivity with the orbitofrontal cortex and insula to implicit happiness, but a negative connectivity with the parahippocampus and subgenual cingulate to implicit fear. The findings suggest that habitual physical activity could mediate acute exercise-induced anxiolytic effects in regards to amygdala reactivity, and help establish exercise training as a form of anxiolytic therapy towards clinical applications.

Combining fMRI during resting state and an attention bias task in children

Neuroimaging studies typically focus on either resting state or task-based fMRI data. Prior research has shown that similarity in functional connectivity between rest and cognitive tasks, interpreted as reconfiguration efficiency, is related to task performance and IQ. Here, we extend this approach from adults to children, and from cognitive tasks to a threat-based attention task. The goal of the current study was to examine whether similarity in functional connectivity during rest and an attention bias task relates to threat bias, IQ, anxiety symptoms, and social reticence. fMRI was measured during resting state and during the dot-probe task in 41 children (M = 13.44, SD = 0.70). Functional connectivity during rest and dot-probe was positively correlated, suggesting that functional hierarchies in the brain are stable. Similarity in functional connectivity between rest and the dot-probe task only related to threat bias (puncorr < .03). This effect did not survive correction for multiple testing. Overall, children who allocate more attention towards threat also may possess greater reconfiguration efficiency in switching from intrinsic to threat-related attention states. Finally, functional connectivity correlated negatively across the two conditions of the dot-probe task. Opposing patterns of modulation of functional connectivity by threat-congruent and threat-incongruent trials may reflect task-specific network changes during two different attentional processes.

Alterations of Functional Brain Connectivity After Long-Duration Spaceflight as Revealed by fMRI.

The present study reports alterations of task-based functional brain connectivity in a group of 11 cosmonauts after a long-duration spaceflight, compared to a healthy control group not involved in the space program. To elicit the postural and locomotor sensorimotor mechanisms that are usually most significantly impaired when space travelers return to Earth, a plantar stimulation paradigm was used in a block design fMRI study. The motor control system activated by the plantar stimulation involved the pre-central and post-central gyri, SMA, SII/operculum, and, to a lesser degree, the insular cortex and cerebellum. While no post-flight alterations were observed in terms of activation, the network-based statistics approach revealed task-specific functional connectivity modifications within a broader set of regions involving the activation sites along with other parts of the sensorimotor neural network and the visual, proprioceptive, and vestibular systems. The most notable findings included a post-flight increase in the stimulation-specific connectivity of the right posterior supramarginal gyrus with the rest of the brain; a strengthening of connections between the left and right insulae; decreased connectivity of the vestibular nuclei, right inferior parietal cortex (BA40) and cerebellum with areas associated with motor, visual, vestibular, and proprioception functions; and decreased coupling of the cerebellum with the visual cortex and the right inferior parietal cortex. The severity of space motion sickness symptoms was found to correlate with a post- to pre-flight difference in connectivity between the right supramarginal gyrus and the left anterior insula. Due to the complex nature and rapid dynamics of adaptation to gravity alterations, the post-flight findings might be attributed to both the long-term microgravity exposure and to the readaptation to Earth’s gravity that took place between the landing and post-flight MRI session. Nevertheless, the results have implications for the multisensory reweighting and gravitational motor system theories, generating hypotheses to be tested in future research.

Modulating functional connectivity between medial frontopolar cortex and amygdala by inhibitory and excitatory transcranial magnetic stimulation.

The prefrontal-limbic network in the human brain plays a major role in social cognition, especially cognitive control of emotion. The medial frontopolar cortex (mFP; Brodmann Area 10) and the amygdala are part of this network and display correlated neuronal activity in time, as measured by functional magnetic resonance imaging (fMRI). This functional connectivity is dynamic, sensitive to training, and affected in mental disorders. However, the effects of neurostimulation on functional connectivity within this network have not yet been systematically investigated. Here, we investigate the effects of both low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) to the right mFP on functional connectivity between mFP and amygdala, as measured with resting state fMRI (rsfMRI). Three groups of healthy participants received either low-frequency rTMS (1 Hz; N = 18), sham TMS (1 Hz, subthreshold; N = 18) or high-frequency rTMS (20 Hz; N = 19). rsfMRI was acquired before and after (separate days). We hypothesized a modulation of functional connectivity in opposite directions compared to sham TMS through adjustment of the stimulation frequency. Groups differed in functional connectivity between mFP and amygdala after stimulation compared to before stimulation (low-frequency: decrease, high-frequency: increase). Motion or induced changes in neuronal activity were excluded as confounders. Results show that rTMS is effective for increasing and decreasing functional coherence between prefrontal and limbic regions. This finding is relevant for social and affective neuroscience as well as novel treatment approaches in psychiatry.

Oxycodone-Mediated Activation of the Mu Opioid Receptor Reduces Whole Brain Functional Connectivity in Mice.

Oxycodone is a potent medicinal opioid analgesic to treat pain. It is also addictive and a main cause for the current opioid crisis. At present, the impact of oxycodone on coordinated brain network activities, and contribution of the mu opioid receptor (MOR) to these effects, is unknown. We used pharmacological magnetic resonance imaging in mice to characterize MOR-mediated oxycodone effects on whole-brain functional connectivity (FC). Control (CTL) and MOR knockout (KO) animals were imaged under dexmedetomidine in a 7Tesla scanner. Acquisition was performed continuously before and after 2 mg/kg oxycodone administration (analgesic in CTL mice). Independent component analysis (data-driven) produced a correlation matrix, showing widespread oxycodone-induced reduction of FC across 71 components. Isocortex, nucleus accumbens (NAc), pontine reticular nucleus, and periacqueducal gray (PAG) components showed the highest number of significant changes. Seed-to-voxel FC analysis (hypothesis-driven) was then focused on PAG and NAc considered key pain and reward centers. The two seeds showed reduced FC with 8 and 22 Allen Brain Atlas-based regions, respectively, in CTL but not KO mice. Further seed-to-seed quantification showed highest FC modifications of both PAG and NAc seeds with hypothalamic and amygdalar areas, as well as between them, revealing the strongest impact across reward and aversion/pain centers of the brain. In conclusion, we demonstrate that oxycodone reduces brain communication in a MOR-dependent manner, and establish a preliminary whole-brain FC signature of oxycodone. This proof-of-principle study provides a unique platform and reference data set to test other MOR opioid agonists and perhaps discover new mechanisms and FC biomarkers predicting safer analgesics.

Modulation of Functional Connectivity Between Dopamine Neurons of the Rat Ventral Tegmental Area in vitro.

Micro Electrode Arrays were used to simultaneously record spontaneous extracellular action potentials from 10 to 30 dopamine neurons in acute brain slices from the lateral Ventral Tegmental Area (VTA) of the rat. The spike train of an individual neuron was used to characterize the firing pattern: firing rate, firing irregularity and oscillation frequency. Functional connectivity between a pair of neurons was quantified by the Paired Phase Consistency (PPC), taking the oscillation frequency as reference. Under baseline conditions the PPC was significantly different from zero and 42 of the 386 pairs of VTA neurons showed significant coupling. Fifty percent of the recorded dopamine neurons were part of the coupled VTA network. Raising extracellular potassium from 3.5 to 5 mM increased the mean firing rate of the dopamine neurons by 45%. The same increase could be induced by bath application of 300 μm glutamate. High potassium reduced the PPC, but it did not change during the glutamate application. Our findings imply that manipulating excitability has distinct and specific consequences for functional connectivity in the VTA network that cannot be directly predicted from the changes in neuronal firing rates. Functional connectivity reflects the spatial organization and synchronization of the VTA output and thus represents a unique element of the message that is sent to the mesolimbic projection area. It adds a dimension to pharmacological manipulation of the VTA micro circuit that might help to understand the pharmacological (side) effects of e.g., anti-psychotic drugs.

Links Between the Amplitude Modulation of Low-Frequency Spontaneous Fluctuation Across Resting State Conditions and Thalamic Functional Connectivity.

A comparison of the different types of resting state reveals some interesting characteristics of spontaneous brain activity that cannot be found in a single condition. Differences in the amplitude of low-frequency fluctuation (ALFF) between the eyes open (EO) and the eyes closed (EC) almost have a spatially distinct pattern with traditional EO-EC activation within sensory systems, suggesting the divergent functional roles of ALFF and activation. However, the underlying mechanism is far from clear. Since the thalamus plays an essential role in sensory processing, one critical step toward understanding the divergences is to depict the relationships between the thalamus and the ALFF modulation in sensory regions. In this preliminary study, we examined the association between the changes of ALFF and the changes of thalamic functional connectivity (FC) between EO and EC. We focused on two visual thalamic nuclei, the lateral geniculate nucleus (LGN) and the pulvinar (Pu). FC results showed that LGN had stronger synchronization with regions in lateral but not in medial visual networks, while Pu had a weaker synchronization with auditory and sensorimotor areas during EO compared with EC. Moreover, the patterns of FC modulation exhibited considerable overlaps with the ALFF modulation, and there were significant correlations between them across subjects. Our findings support the crucial role of the thalamus in amplitude modulation of low-frequency spontaneous activity in sensory systems, and may pave the way to elucidate the mechanisms governing distinction between evoked activation and modulation of low-frequency spontaneous brain activity.

Macroscopic phase resetting-curves determine oscillatory coherence and signal transfer in inter-coupled neural circuits.

Macroscopic oscillations of different brain regions show multiple phase relationships that are persistent across time and have been implicated in routing information. While multiple cellular mechanisms influence the network oscillatory dynamics and structure the macroscopic firing motifs, one of the key questions is to identify the biophysical neuronal and synaptic properties that permit such motifs to arise. A second important issue is how the different neural activity coherence states determine the communication between the neural circuits. Here we analyse the emergence of phase-locking within bidirectionally delayed-coupled spiking circuits in which global gamma band oscillations arise from synaptic coupling among largely excitable neurons. We consider both the interneuronal (ING) and the pyramidal-interneuronal (PING) population gamma rhythms and the inter coupling targeting the pyramidal or the inhibitory neurons. Using a mean-field approach together with an exact reduction method, we reduce each spiking network to a low dimensional nonlinear system and derive the macroscopic phase resetting-curves (mPRCs) that determine how the phase of the global oscillation responds to incoming perturbations. This is made possible by the use of the quadratic integrate-and-fire model together with a Lorentzian distribution of the bias current. Depending on the type of gamma (PING vs. ING), we show that incoming excitatory inputs can either speed up the macroscopic oscillation (phase advance; type I PRC) or induce both a phase advance and a delay (type II PRC). From there we determine the structure of macroscopic coherence states (phase-locking) of two weakly synaptically-coupled networks. To do so we derive a phase equation for the coupled system which links the synaptic mechanisms to the coherence states of the system. We show that a synaptic transmission delay is a necessary condition for symmetry breaking, i.e. a non-symmetric phase lag between the macroscopic oscillations. This potentially provides an explanation to the experimentally observed variety of gamma phase-locking modes. Our analysis further shows that symmetry-broken coherence states can lead to a preferred direction of signal transfer between the oscillatory networks where this directionality also depends on the timing of the signal. Hence we suggest a causal theory for oscillatory modulation of functional connectivity between cortical circuits.

Neural field theory of effects of brain modifications and lesions on functional connectivity: Acute effects, short-term homeostasis, and long-term plasticity.

Neural field theory is used to predict the functional connectivity effects of lesions or other modifications to effective connectivity. Widespread initial changes are predicted after localized or diffuse changes to white or gray matter, consistent with observations, and enabling lesion severity indexes to be defined. It is shown how short-term homeostasis and longer-term plasticity can reduce perturbations while maintaining brain criticality under conditions where some connections remain fixed because of damage in the lesion core. The extent to which such effects can compensate for initial connectivity changes is then explored, showing that the strongest corrective changes are concentrated toward the edges of the perturbation if it is localized and its core is fixed. The results are applicable to inferring underlying connectivity changes and to interpreting and monitoring functional connectivity modifications after lesions, injury, surgery, drugs, or brain stimulation.

Naltrexone Acutely Enhances Connectivity Between the Ventromedial Prefrontal Cortex and a Left Frontoparietal Network.

Naltrexone, an opioid receptor antagonist that is Food and Drug Administration approved for treating alcohol use disorder (AUD), reduces alcohol craving and intake. Despite known pharmacological properties, little is known regarding the effects of naltrexone on neural circuit function. Thus, a data-driven examination of the neural effects of naltrexone in human subjects may offer novel insight into its treatment mechanisms. Twenty-one alcohol using males (22 to 39) participated in a double-blind, placebo-controlled crossover study of the effects of naltrexone on brain voxel-wise functional connectivity (FC) using intersubject FC correlation mapping. We first cross-correlated the time series from each gray matter voxel to produce a 6,356×6,356 FC matrix for each subject and session. We then subtracted the placebo FC matrix from the naltrexone FC matrix. To identify brain regions demonstrating significant reconfiguration of whole-brain FC patterns following naltrexone treatment, we statistically quantified the consistency of patterns of voxel FC changes across subjects. Permutation testing identified significant clusters of voxels undergoing significant reconfiguration. Using the identified clusters in a seed-based FC analysis, we then compared the FC patterns of affected brain areas on placebo versus naltrexone in a paired t-test. Ridge regression analyses identified self-report measures, including substance use, that significantly predicted individual differences in FC among naltrexone-modulated regions. Two clusters in the rostral anterior cingulate cortex (rACC)/ventromedial prefrontal cortex (vmPFC) demonstrated significant modulation of FC by naltrexone. Using these 2 proximal clusters as a single seed, specific FC changes were identified in regions associated with a left frontoparietal network (increasing), as well as visual and motor regions (decreasing). Stronger FC between the rACC/vmPFC and this set of regions on placebo was associated with more external locus of control, whereas weaker connectivity was associated with greater substance use problems. Naltrexone strengthened these connections most among individuals who reported greater drinking to cope. Enhancing connectivity between the rACC/vmPFC, implicated in alcohol craving, and components of a left frontoparietal network involved in executive control may represent an effective strategy for the treatment of AUD.

Two-year dynamic functional network connectivity in clinically isolated syndrome

Background: The features of functional network connectivity reorganization at the earliest stages of MS have not been investigated yet. Objective: To combine static and dynamic analysis of resting state (RS) functional connectivity (FC) to identify mechanisms of clinical dysfunction and recovery occurring in clinically isolated syndrome (CIS) patients. Methods: RS functional magnetic resonance imaging (fMRI) and clinical data were prospectively acquired from 50 CIS patients and 13 healthy controls (HC) at baseline, month 12 and month 24. Between-group differences and longitudinal evolution of network FC were analysed across 41 functionally relevant networks. Results: At follow-up, 47 patients developed MS. Disability remained stable (and relatively low). CIS and HC exhibited two recurring RS FC states (states 1 and 2, showing low and high internetwork connectivity, respectively). At baseline, patients showed reduced state 2 connectivity strength in the default-mode and cerebellar networks, and no differences in global dynamism versus HC. A selective FC reduction in networks affected by the clinical attack was also detected. At follow-up, increased state 2 connectivity strength and global connectivity dynamism was observed in patients versus HC. Conclusion: Longitudinal FC modifications occurring relatively early in the course of multiple sclerosis may represent a protective mechanism contributing to preserve clinical function over time.

Somatosensory Stimulation With XNKQ Acupuncture Modulates Functional Connectivity of Motor Areas.

Xingnao Kaiqiao (XNKQ) acupuncture is an acupuncture technique used for stroke patients. In 24 healthy volunteers, we applied this complex acupuncture intervention, which consists of a manual needle-stimulation on five acupuncture points (DU26 unilaterally, PC6, and SP6 bilaterally). XNKQ was compared to three control conditions: (1) insertion of needles on the XNKQ acupuncture points without stimulation, (2) manual needle-stimulation on five nearby non-acupuncture points, and (3) insertion of needles on the non-acupuncture points without stimulation. In a within-subject design, we investigated functional connectivity changes in resting-state functional magnetic resonance imaging (fMRI) by means of the data-driven eigenvector centrality (EC) approach. With a 2 × 2 factorial within-subjects design with two-factor stimulation (stimulation vs. non-stimulation) and location (acupuncture points vs. non-acupuncture points), we found decreased EC in the precuneus after needle-stimulation (stimulation<non-stimulation), whereas the factor location showed no statistically significant EC differences. XNKQ acupuncture compared with needle-stimulation on non-acupuncture points showed decreased EC primarily in subcortical structures such as the caudate nucleus, subthalamic nucleus, and red nucleus. Post-hoc seed-based analysis revealed that the decrease in EC was mainly driven by reduced temporal correlation to primary sensorimotor cortices. The comparison of XNKQ acupuncture with the other two (non-stimulation) interventions showed no significant differences in EC. Our findings support the importance of the stimulation component of the acupuncture intervention and hint toward the modulation of functional connectivity by XNKQ acupuncture, especially in areas involved in motor function. As a next step, similar mechanisms should be validated in stroke patients suffering from motor deficits.ClinicalTrials.gov ID: NCT02453906

Estimation of Functional Connectivity Modulations During Task Engagement and Their Neurovascular Underpinnings Through Hemodynamic Reorganization Method.

This study proposes an approach to understand the effect of task engagement through integrated analysis of modulations in functional networks and associated changes in their neurovascular underpinnings at every voxel. For this purpose, a novel approach that brings reorganization in acquired task-functional magnetic resonance imaging information based on hemodynamic characteristics of every task stimulus is proposed and validated. At first, modulations in functional networks of visual target detection task were estimated at every voxel through proposed methodology. It revealed task stimulus dependency in the modulation of default mode network (DMN). The DMN modulated as task negative network (TNN) during target stimulus. On the contrary, it was not entirely TNN during nontarget stimulus. The frontal-parietal and visual networks modulated as task positive network during both task stimuli. Further, modulations of neurovascular underpinnings associated with engagement of task were estimated by correlating the hemodynamically reorganized task blood oxygen level dependent information with simultaneously acquired electroencephalography frequency powers. It revealed the strong association of neurovascular underpinnings with their modulation of functional networks and the associated neuronal activity during task engagement. Finally, graph theoretical parameters such as local, global efficiency and clustering coefficient were also measured at the specific regions for validating the results of proposed method. Modulation observed in graph theory measures clearly validated the activation and deactivation of functional networks observed by the proposed method during task engagement. Thus, the voxel-wise estimation of task-related modulation of functional networks and associated neurovascular underpinnings through proposed technique provide better insights into neuronal mechanism involved during engagement in a task.

Passive music listening: A modulation of resting-state functional connectivity to better dissociate tinnitus

Previous fMRI studies have shown tinnitus-related changes in resting-state functional connectivity (rs-fc) and have the potential for serving as biomarkers of tinnitus. In this study, we further investigated the effect of tinnitus on three intrinsic neural networks—the auditory network, the dorsal attention network (DAN), and the default mode network (DMN) while the participants were at rest or under a passive music listening condition. Our results indicated that listening to music altered the auditory network in both groups, with increased connectivity between inferior frontal gyrus and auditory areas in controls. This alternation was observed only in the patients with mild tinnitus handicap and was absent in the patients with severe tinnitus handicap. The effect of music on the DAN hinged upon hearing sensitivity: decreased connectivity between the lateral occipital cortex and the DAN, and increased connectivity between the precuneus and the DAN was observed in controls and patients with normal hearing, compared to those with hearing loss. Furthermore, passive music listening modulated the coherency of the DMN based on tinnitus status and/or hearing sensitivity. Our findings highlight the efficacy of rs-fc in dissociating the relatively heterogeneous tinnitus population and its subgroups from controls, using rest and listening to music.

Resting-state functional MRI demonstrates brain network reorganization in neuromyelitis optica spectrum disorder (NMOSD).

BackgroundThe relation between brain functional connectivity of patients with neuromyelitis optica spectrum disorder (NMOSD) and the degree of disability remains unclear.ObjectiveCompare brain functional connectivity of patients with NMOSD to healthy subjects in resting-state functional MRI (rs-fMRI).MethodsWe compared the rs-fMRI connectivity in 12 NMOSD patients with 20 healthy subjects matched for age and sex. Graph theory analysis was used to quantify the role of each node using a set of metrics: degree, global efficiency, clustering and modularity. To summarize the abnormal connectivity profile of brain regions in patients compared to healthy subjects, we defined a hub disruption index κ.ResultsConcerning the global organization of networks in NMOSD, a small-world topology was preserved without significant modification concerning all average metrics. However, visual networks and the sensorimotor network showed decreased connectivity with high interindividual variability. The hub disruption index κ was correlated to the Expanded Disability Status Scale (EDSS).ConclusionThese results demonstrate a correlation between disability according to the EDSS and neuronal reorganization using the rs-fMRI graph methodology. The conservation of a normal global topological structure despite local modifications in functional connectivity seems to show brain plasticity in response to the disability.

Superconditioning TMS unmasks latent voluntary innervation in MND – A case report

Motor neuron disease (MND) includes both ALS and Progressive Muscular Atrophy (PMA) as variants. Abnormalities in brain excitability and upper motor neuron (UMN) function are characteristic of ALS, but by definition are absent in PMA. Transcranial magnetic stimulation (TMS) may be useful in demonstrating UMN pathology, but loss of muscle responsiveness with disease progression limits its usefulness in later stages of MND. We have developed a novel form of TMS comprised of 4 stimulating pulses that can enhance MEPs in target muscles already responding to traditional TMS inputs, in some cases even restoring MEPs in target muscles rendered unresponsive by the disease. An example of restored MEPs in response to this superconditioning TMS pattern (TMSsc) in a person with PMA is described, along with an unexpected finding. Despite a prolonged (> 5 year) history of movement paralysis in his right tibialis anterior (TA), immediately after cessation of TMSsc delivery the subject could now easily contract and relax this muscle; the presence of a latent pathway for voluntary innervation of his right TA was revealed. This modulation of central motor functional connectivity in response to TMSsc suggests a further, clinically-significant benefit of this form of noninvasive brain stimulation beyond its ability to enhance MEPs to traditional TMS inputs.

Analysis of KCNH2 and CACNA1C schizophrenia risk genes on EEG functional network modulation during an auditory odd-ball task.

A deficit in task-related functional connectivity modulation from electroencephalogram (EEG) has been described in schizophrenia. The use of measures of neuronal connectivity as an intermediate phenotype may allow identifying genetic factors involved in these deficits, and therefore, establishing underlying pathophysiological mechanisms. Genes involved in neuronal excitability and previously associated with the risk for schizophrenia may be adequate candidates in relation to functional connectivity alterations in schizophrenia.The objective was to study the association of two genes of voltage-gated ion channels (CACNA1C and KCNH2) with the functional modulation of the cortical networks measured with EEG and graph-theory parameter during a cognitive task, both in individuals with schizophrenia and healthy controls. Both CACNA1C (rs1006737) and KCNH2 (rs3800779) were genotyped in 101 controls and 50 schizophrenia patients. Small-world index (SW) was calculated from EEG recorded during an odd-ball task in two different temporal windows (pre-stimulus and response). Modulation was defined as the difference in SW between both windows. Genetic, group and their interaction effects on SW in the pre-stimulus window and in modulation were evaluated using ANOVA. The CACNA1C genotype was not associated with SW properties. KCNH2 was significantly associated with SW modulation. Healthy subjects showed a positive SW modulation irrespective of the KCNH2 genotype, whereas within patients allele-related differences were observed. Patients carrying the KCNH2 risk allele (A) presented a negative SW modulation and non-carriers showed SW modulation similar to the healthy subjects. Our data suggest that KCNH2 genotype contributes to the efficient modulation of brain electrophysiological activity during a cognitive task in schizophrenia patients.

Alterations in grey matter density and functional connectivity in trigeminal neuropathic pain and trigeminal neuralgia: A systematic review and meta-analysis.

Various studies reported changes in grey matter volumes and modifications in functional connectivity of cortical and subcortical structures in patients suffering from trigeminal neuralgia (TN) and trigeminal neuropathic pain (TNP). This study meta-analyzed the concordant structural and functional changes in foci and provide further understanding of the anatomy and biology of TN/TNP. Relevant articles on magnetic resonance imaging (MRI) and functional MRI in TN/TNP, published before August 2018, were searched for on PubMed and Embase. Following exclusion of unsuitable studies, a meta-analysis was performed using activation likelihood estimation (ALE). In total, 322 paper were identified, 11 of which could be included based on the predefined inclusion and exclusion criteria. Eight papers, totaling 279 subjects, discussing structural changes and four papers, totaling 102 subjects, discussing functional changes were included (i.e., one paper investigated both structural and functional alterations). ALE analysis showed that in TN/TNP, grey matter decreases are found in the thalamus, (anterior) cingulate gyrus, bilateral striatum, the superior-, middle- and transverse temporal gyrus, subcallosal gyrus, the bilateral insular cortex, the pre- and postcental gyrus, the middle frontal gyrus bilaterally and the anterior cerebellar lobe. Grey matter increases were seen in the periaqueductal grey (PAG). Increased resting state functional organization was found within the bilateral middle- and superior frontal gyri, the (posterior) cingulate cortex and the thalamus/pulvinar. Structural and functional changes meta-analyzed in this paper may contribute to elucidating the central pathophysiological mechanisms involved in TN/TNP. These results may be used as biomarkers to predict the response to medication and, ideally, in the future to offer personalized treatments.