Functional connectivity of the visual cortex in chronic migraine before and after medication withdrawal therapy.

Acute withdrawal of headache medication in chronic migraine patients with medication overuse may lead to a dramatic reduction in headache frequency and severity. However, the brain networks underlying chronic migraine and a favorable response to acute withdrawal are still poorly understood. The goal of the present study was to characterize the pattern of intrinsic magnetic resonance imaging (MRI) functional connectivity (FC) specific to chronic migraine and to identify changes in FC that characterize subjects with CM reverting to less frequent headaches. Subjects with chronic migraine (N = 99) underwent a resting-state functional MRI scan before and after three months of medication withdrawal therapy. In addition, we included four control groups who were scanned once: healthy participants (N = 27), patients with episodic migraine (N = 25), patients with chronic back pain (N = 22), and patients with clinical depression (N = 17). Using dual regression analysis, we compared whole-brain voxel-level functional connectivity with ten well-known resting-state networks between chronic migraine and control groups, and between responders to treatment (≥50 % reduction in monthly headache days) and non-responders (<50 % reduction), before and after treatment. Subjects with chronic migraine showed differences in FC with a number of RS-networks, most of which involved the visual cortex, compared with healthy controls. A comparison with patients with episodic migraine, chronic pain and depression showed differences in the same direction, suggesting that altered patterns of functional connectivity in chronic migraine patients could to some extent be explained by shared symptomatology with other pain, depression, or migraine conditions. A comparison between responders and non-responders indicated that effective withdrawal reduced FC with the visual cortex for responders. Interestingly, responders already differed in functional connectivity of the visual cortex at baseline compared with non-responders. Altogether, we show that chronic migraine and successful medication withdrawal therapy are linked to changes in the functional connectivity of the visual cortex. These neuroimaging findings provide new insights into the pathways underlying migraine chronification and its reversibility.

Pupil size reflects activation of subcortical ascending arousal system nuclei during rest.

Neuromodulatory nuclei that are part of the ascending arousal system (AAS) play a crucial role in regulating cortical state and optimizing task performance. Pupil diameter, under constant luminance conditions, is increasingly used as an index of activity of these AAS nuclei. Indeed, task-based functional imaging studies in humans have begun to provide evidence of stimulus-driven pupil-AAS coupling. However, whether there is such a tight pupil-AAS coupling during rest is not clear. To address this question, we examined simultaneously acquired resting-state fMRI and pupil-size data from 74 participants, focusing on six AAS nuclei: the locus coeruleus, ventral tegmental area, substantia nigra, dorsal and median raphe nuclei, and cholinergic basal forebrain. Activation in all six AAS nuclei was optimally correlated with pupil size at 0-2 s lags, suggesting that spontaneous pupil changes were almost immediately followed by corresponding BOLD-signal changes in the AAS. These results suggest that spontaneous changes in pupil size that occur during states of rest can be used as a noninvasive general index of activity in AAS nuclei. Importantly, the nature of pupil-AAS coupling during rest appears to be vastly different from the relatively slow canonical hemodynamic response function that has been used to characterize task-related pupil-AAS coupling.

Influence of vigilance-related arousal on brain dynamics: Potentials of new approaches.

Growing research has focused on how mesoscopic activity in the brain develops over time and space. Recent influential studies using functional imaging have characterized brain dynamics in terms of the spread of activation across the brain following a unimodal to transmodal axis. In parallel, a number of studies have assessed changes of brain connectivity in terms of vigilance-linked arousal. Here I offer a view on how these two lines of research can lead to a deeper understanding of how arousal shapes the brain's dynamic behavior. This knowledge could have great impact on the investigation of mental disease.

Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells.

Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. Ih channels. Ih channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the Ih channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the Ih activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of Ih channels as well as their neuromodulation. We show that Ih channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the Ih channels in layer V pyramidal cells is due to the interactions between Ih channels and a hot zone of low voltage-activated Ca2+ channels at the apical dendrite. Our simulations suggest that a combination of Ih-enhancing neuromodulation at the proximal part of the apical dendrite and Ih-inhibiting modulation at the distal part of the apical dendrite can increase the layer V pyramidal excitability more than either of the two alone. Our analyses uncover the effects of Ih-channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.

Pupil-based States of Brain Integration across Cognitive States.

Arousal is a potent mechanism that provides the brain with functional flexibility and adaptability to external conditions. Within the wake state, arousal levels driven by activity in the neuromodulatory systems are related to specific signatures of neural activation and brain synchrony. However, direct evidence is still lacking on the varying effects of arousal on macroscopic brain characteristics and across a variety of cognitive states in humans. Using a concurrent fMRI-pupillometry approach, we used pupil size as a proxy for arousal and obtained patterns of brain integration associated with increasing arousal levels. We carried out this analysis on resting-state data and data from two attentional tasks implicating different cognitive processes. We found that an increasing level of arousal was related to a state of increased brain integration. This effect was prominent in the salience, visual and default-mode networks in all conditions, while other regions showed task-specificity. Increased integration in the salience network was also related to faster pupil dilation in the two attentional tasks. Furthermore, task performance was related to arousal level, with lower accuracy at higher level of arousal. Taken together, our study provides evidence in humans for pupil size as an index of brain network state, and supports the role of arousal as a switch that drives brain coordination in specific brain regions according to the cognitive state.

Uncovering the locus coeruleus: Comparison of localization methods for functional analysis.

Functional neuroimaging of small brainstem structures in humans is gaining interest due to their potential importance in aging and many clinical conditions. Researchers have used different methods to measure activity in the locus coeruleus (LC), the main noradrenergic nucleus in the brain. However, the extent to which these different LC localization methods yield similar results is unclear. In the present article, we compared four different approaches to estimate localization of the LC in a large sample (N = 98): 1) a probabilistic map from a previous study, 2) masks segmented from neuromelanin-sensitive scans, both manually and semi-automatically, 3) components from a masked-independent components analysis of the functional data, and 4) a mask from pupil regression of the functional data. The four methods have all been used previously in the imaging community to localize the LC in vivo in humans. We report several measures of similarity between the LC masks obtained from the different methods. In addition, we compare functional connectivity maps obtained from the different masks. We conclude that sample-specific masks appear more suitable than masks obtained from an independent sample, that masks based on structural versus functional methods may capture different portions of LC, and that, at the group level, the creation of a "consensus" mask using more than one approach may give a better estimate of LC localization.

The role of norepinephrine in the pathophysiology of schizophrenia.

Several lines of evidence have suggested for decades a role for norepinephrine (NE) in the pathophysiology and treatment of schizophrenia. Recent experimental findings reveal anatomical and physiological properties of the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition. Here, we integrate these two lines of evidence. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, and stress, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of LC-associated functions for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits. We propose that schizophrenia phenomenology, in particular cognitive symptoms, may be explained by an abnormal interaction between genetic susceptibility and stress-initiated LC-NE dysfunction. This in turn, leads to imbalance between LC activity modes, dysfunctional regulation of brain network integration and neural gain, and deficits in cognitive functions. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia.

Distinct Neural Mechanisms Meet Challenges in Dynamic Visual Attention due to Either Load or Object Spacing.

When engaged in dynamic visuospatial tasks, the brain copes with perceptual and cognitive processing challenges. During multiple-object tracking (MOT), the number of objects to be tracked (i.e., load) imposes attentional demands, but so does spatial interference from irrelevant objects (i.e., close encounters). Presently, it is not clear whether the effect of load on accuracy solely depends on the number of close encounters. If so, the same cognitive and physiological mechanisms deal with increasing load by preparing for and dealing with spatial interference. However, this has never been directly tested. Such knowledge is important to understand the neurophysiology of dynamic visual attention and resolve conflicting views within visual cognition concerning sources of capacity limitations. We varied the processing challenge in MOT task in two ways: the number of targets and the minimum spatial proximity between targets and distractors. In a first experiment, we measured task-induced pupil dilations and saccades during MOT. In a separate cohort, we measured fMRI activity. In both cohorts, increased load and close encounters (i.e., close spatial proximity) led to reduced accuracy in an additive manner. Load was associated with pupil dilations, whereas close encounters were not. Activity in dorsal attentional areas and frequency of saccades were proportionally larger both with higher levels of load and close encounters. Close encounters recruited additionally ventral attentional areas that may reflect orienting mechanisms. The activity in two brainstem nuclei, ventral tegmental area/substantia nigra and locus coeruleus, showed clearly dissociated patterns. Our results constitute convergent evidence indicating that different mechanisms underlie processing challenges due to load and object spacing.

Correction to: Task context load induces reactive cognitive control: An fMRI study on cortical and brain stem activity.

The article Task context load induces reactive cognitive control.

Task context load induces reactive cognitive control: An fMRI study on cortical and brain stem activity.

Cognitive control is a highly dynamic process that relies on flexible engagement of prefrontal areas and of neuromodulatory systems in order to adapt to changing demands. A range of internal and external factors come into play when individuals engage in a task requiring cognitive control. Here we investigated whether increased working memory (WM) demands would induce a flexible change in cognitive control mode in young healthy individuals. We developed a novel variant of the well-known AX-continuous performance task (AX-CPT). We manipulated the cognitive demands of maintaining task-relevant contextual information and studied the impact of this manipulation on behavior and brain activity. We expected that low WM load would allow for a more effortful, proactive strategy, while high WM load would induce a strategy of less effortful, stimulus-driven reactive control. In line with our hypothesis, a web-based experiment revealed that increased load was associated with more reactive behavioral responses, and this finding was independently replicated in behavioral data acquired in the MRI scanner. The results from brain activity showed that the right dorsolateral prefrontal cortex was activated by cues in the proactive mode and by probes in the reactive mode. The analysis of task-induced brain stem activity indicated that both the dopaminergic and noradrenergic systems are involved in updating context representations, and that, respectively, these systems mediate a gating signal to the control network and are involved in the dynamic regulation of task engagement.

Ocular signatures of proactive versus reactive cognitive control in young adults.

During the execution of a cognitive task, the brain maintains contextual information to guide behavior and achieve desired goals. The AX-Continuous Performance Task is used to study proactive versus reactive cognitive control. Young adults tend to behave proactively in standard testing conditions. However, it remains unclear how interindividual variability (e.g., in cognitive and motivational factors) may drive people into more reactive or proactive control under the same task demands. We investigated the use of control strategies in a large population of healthy young adults. We computed the proactive behavioral index and consequently divided participants into proactive, reactive, and intermediate groups. We found that reactive participants were generally slower, presented lower context sensitivity, and larger response variability. Pupillary changes and blink rate index cognitive effort allocation. We measured, concomitantly to the task, the pupil size and frequency of blinks associated with the cue maintenance and response intervals. During the cue period, nonfrequent, nontarget cues led to increased pupil dilation and number of blinks in all participants. During the response interval, we found more errors and increased pupil dilation to the probe when all participants had to overcome a response bias generated by the frequent cue. Only reactive participants showed larger response-related pupil when they had to overcome a response bias related to the frequent probe. Contrary to expectations, groups did not differ in ocular measures in the cue period. In conclusion, interindividual differences in cognitive control between healthy adults can be mapped onto different patterns of effort allocation indexed by the pupil.

Greater Attention to Task-Relevant Threat Due to Orbitofrontal Lesion.

Injury to the orbitofrontal cortex (OFC) is a frequent consequence of head injury and may lead to dysfunctional regulation of emotional and social behavior. Dysfunctional emotional behavior may partly be related to the role of the OFC in emotion-attention interaction, as reported previously. In order to better understand its role in emotion-attention and emotion-cognitive control interactions, we investigated attention allocation to task-relevant and task-irrelevant threat-related emotional stimuli during a task requiring cognitive control in patients with lesion to the OFC. We measured the behavioral performance and event-related potentials (ERP) of 13 patients with OFC lesion and 11 control subjects during a Go/NoGo visual discrimination task. In the task, line drawings of threatening (spider) and neutral (flower) figures served as either task-relevant Go or NoGo signals, or as task-irrelevant distractors. Overall performance did not differ between the groups. In contrast to the control group performance, the orbitofrontal group performance was improved by relevant threat signal in comparison with neutral signal. Further, task-relevant threat signals evoked larger frontocentral N2-P3 amplitude in the orbitofrontal group. Taken together, behavioral and electrophysiological results suggest that patients with OFC injury allocated more attentional and cognitive control resources in the context of task-relevant emotional stimuli. This study provides new evidence for the role of the OFC in emotion-attention and emotion-cognitive control interactions. Further, the OFC seems to contribute to the balance between voluntary and involuntary attention networks in context of emotional stimuli. Better understanding of alterations in emotion-attention interaction offers insight into affective dysfunction due to OFC lesion.

Modulation of the default-mode network and the attentional network by self-referential processes in patients with disorder of consciousness.

Disorders of consciousness (DOC) are related to an altered capacity of the brain to successfully integrate and segregate information. Alterations in brain functional networks structure have been found in fMRI studies, which could account for the incapability of the brain to efficiently manage internally and externally generated information. Here we assess the modulation of neural activity in areas of the networks related to active introspective or extrospective processing in 9 patients with DOC and 17 controls using fMRI. In addition, we assess the functional connectivity between those areas in resting state. Patients were experimentally studied in an early phase after the event of brain injury (3±1 months after the event) and subsequently in a second session 4±1 months after the first session. The results showed that the concerted modulation of the default mode network (DMN) and attentional network (AN) in response to the active involvement in the task improved with the level of consciousness, reflecting an integral recovery of the brain in its ability to be engaged in cognitive processes. In addition, functional connectivity decreased between the DMN and AN with recovery. Our results help to further understand the neural underpins of the disorders of consciousness.

Enhanced attention capture by emotional stimuli in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) may be associated with compromised executive functioning and altered emotional reactivity. Despite frequent affective and cognitive symptoms in mTBI, objective evidence for brain dysfunction is often lacking. Previously we have reported compromised performance in symptomatic mTBI patients in an executive reaction time (RT) test, a computer-based RT test engaging several executive functions simultaneously. Here, we investigated the cognitive control processes in mTBI in context of threat-related stimuli. We used behavioral measures and event-related potentials (ERP) to investigate attentional capture by task-relevant and task-irrelevant emotional stimuli during a Go-NoGo task requiring cognitive control. We also assessed subjective cognitive, somatic, and emotional symptoms with questionnaires. Twenty-seven subjects with previous mTBI and 17 controls with previous ankle injury participated in the study over 9 months post-injury. Electroencephalogram (EEG) was recorded while patients performed a modified executive RT-test. N2-P3 ERP component was used as a general measure of allocated attentional and executive processing resources. Although at the time of the testing, the mTBI and the control groups did not differ in symptom endorsement, mTBI patients reported having had more emotional symptoms overall since the injury than controls. The overall RT-test performance levels did not differ between groups. However, when threat-related emotional stimuli were used as Go-signals, the mTBI group was faster than the control group. In comparison to neutral stimuli, threat-related stimuli were associated with increased N2-P3 amplitude in all conditions. This threat-related enhancement of the N2-P3 complex was greater in mTBI patients than in controls in response to Go signals and NoGo signals, independent of relevance. We conclude that mTBI may be associated with enhanced attentional and executive resource allocation to threat-related stimuli. Along with behavioral evidence for enhanced attention allocation to threat stimuli, increased brain responses to threat were observed in mTBI. Enhanced attention capture by threat-related emotional stimuli may reflect inefficient top-down control of bottom-up influences of emotion, and might contribute to affective symptoms in mTBI.

Lateralization of brain activity during motor planning of proximal and distal gestures.

Praxis functions are predominantly processed by the left hemisphere. However, limb apraxia is found in less than 50% of patients with left hemisphere damage, and also, although infrequently, in patients with right hemisphere damage. We studied brain representation of preparation/planning of tool-use pantomime separating the gestures involving mostly distal limb control (e.g., using scissors) from those involving proximal limb control (e.g., hammering). During the fMRI scan transitive pantomimes were performed with the dominant and the non-dominant hand by right-handed healthy subjects. Random and voxel-based analysis through laterality index (LI) calculation, demonstrated that for both limbs, distal gesture planning was in general left lateralized, while for the proximal condition the representation was found to be more bilateral particularly in the inferior frontal gyrus. LI distributions across subjects indicated that while the majority of subjects are left-hemispheric dominant for praxis, there are a minority with the opposite lateralization. Functional connectivity analysis showed that while the correlation between homolog areas involved in gesture production was high irrespective of gesture type, their correlation to the supplementary motor area was high in proximal but not distal conditions. Therefore, transitive gestures, when pantomimed to verbal commands, are differentially represented inter and intra hemispherically depending on whether the gesture is performed with the right or left arm or whether it involves predominantly distal or proximal limb movements. Furthermore, the representation of the different types of gestures may be related to a modulation of the connectivity between areas involved in motor planning.

Low attentional engagement makes attention network activity susceptible to emotional interference.

The aim of this study was to investigate whether emotion-attention interaction depends on attentional engagement. To investigate emotional modulation of attention network activation, we used a functional MRI paradigm consisting of a visuospatial attention task with either frequent (high-engagement) or infrequent (low-engagement) targets and intermittent emotional or neutral distractors. The attention task recruited a bilateral frontoparietal network with no emotional interference on network activation when the attentional engagement was high. In contrast, when the attentional engagement was low, the unpleasant stimuli interfered with the activation of the frontoparietal attention network, especially in the right hemisphere. This study provides novel evidence for low attentional engagement making attention control network activation susceptible to emotional interference.

Disruption of transfer entropy and inter-hemispheric brain functional connectivity in patients with disorder of consciousness.

Severe traumatic brain injury can lead to disorders of consciousness (DOC) characterized by deficit in conscious awareness and cognitive impairment including coma, vegetative state, minimally consciousness, and lock-in syndrome. Of crucial importance is to find objective markers that can account for the large-scale disturbances of brain function to help the diagnosis and prognosis of DOC patients and eventually the prediction of the coma outcome. Following recent studies suggesting that the functional organization of brain networks can be altered in comatose patients, this work analyzes brain functional connectivity (FC) networks obtained from resting-state functional magnetic resonance imaging (rs-fMRI). Two approaches are used to estimate the FC: the Partial Correlation (PC) and the Transfer Entropy (TE). Both the PC and the TE show significant statistical differences between the group of patients and control subjects; in brief, the inter-hemispheric PC and the intra-hemispheric TE account for such differences. Overall, these results suggest two possible rs-fMRI markers useful to design new strategies for the management and neuropsychological rehabilitation of DOC patients.