Altered sense of self during seizures in the posteromedial cortex.

The posteromedial cortex (PMC) is known to be a core node of the default mode network. Given its anatomical location and blood supply pattern, the effects of targeted disruption of this part of the brain are largely unknown. Here, we report a rare case of a patient (S19_137) with confirmed seizures originating within the PMC. Intracranial recordings confirmed the onset of seizures in the right dorsal posterior cingulate cortex, adjacent to the marginal sulcus, likely corresponding to Brodmann area 31. Upon the onset of seizures, the patient reported a reproducible sense of self-dissociation-a condition he described as a distorted awareness of the position of his body in space and feeling as if he had temporarily become an outside observer to his own thoughts, his "me" having become a separate entity that was listening to different parts of his brain speak to each other. Importantly, 50-Hz electrical stimulation of the seizure zone and a homotopical region within the contralateral PMC induced a subjectively similar state, reproducibly. We supplement our clinical findings with the definition of the patient's network anatomy at sites of interest using cortico-cortical-evoked potentials, experimental and resting-state electrophysiological connectivity, and individual-level functional imaging. This rare case of patient S19_137 highlights the potential causal importance of the PMC for integrating self-referential information and provides clues for future mechanistic studies of self-dissociation in neuropsychiatric populations.

Temporal order of signal propagation within and across intrinsic brain networks.

We studied the temporal dynamics of activity within and across functional MRI (fMRI)-derived nodes of intrinsic resting-state networks of the human brain using intracranial electroencephalography (iEEG) and repeated single-pulse electrical stimulation (SPES) in neurosurgical subjects implanted with intracranial electrodes. We stimulated and recorded from 2,133 and 2,372 sites, respectively, in 29 subjects. We found that N1 and N2 segments of the evoked responses are associated with intra- and internetwork communications, respectively. In a separate cognitive experiment, evoked electrophysiological responses to visual target stimuli occurred with less temporal separation across pairs of electrodes that were located within the same fMRI-defined resting-state networks compared with those located across different resting-state networks. Our results suggest intranetwork prior to internetwork information processing at the subsecond timescale.

Intracranial Electroencephalography Reveals Selective Responses to Cognitive Stimuli in the Periventricular Heterotopias.

Our recent work suggests that non-lesional epileptic brain tissue is capable of generating normal neurophysiological responses during cognitive tasks, which are then seized by ongoing pathologic epileptic activity. Here, we aim to extend the scope of our work to epileptic periventricular heterotopias (PVH) and examine whether the PVH tissue also exhibits normal neurophysiological responses and network-level integration with other non-lesional cortical regions. As part of routine clinical assessment, three adult patients with PVH underwent implantation of intracranial electrodes and participated in experimental cognitive tasks. We obtained simultaneous recordings from PVH and remote cortical sites during rest as well as controlled experimental conditions. In all three subjects (two females), cognitive experimental conditions evoked significant electrophysiological responses in discrete locations within the PVH tissue that were correlated with responses seen in non-epileptic cortical sites. Moreover, the responsive PVH sites exhibited correlated electrophysiological activity with responsive, non-lesional cortical sites during rest conditions. Taken together, our work clearly demonstrates that the PVH tissue may be functionally organized and it may be functionally integrated within cognitively engaged cortical networks despite its anatomic displacement during neurodevelopment.SIGNIFICANCE STATEMENT Periventricular heterotopias (PVH) are developmentally abnormal brain tissues that frequently cause epileptic seizures. In a rare opportunity to obtain direct electrophysiological recordings from PVH, we were able to show that, contrary to common assumptions, PVH functional activity is similar to healthy cortical sites during a well-established cognitive task and exhibits clear resting state connectivity with the responsive cortical regions.

Pupillary Dynamics Link Spontaneous and Task-Evoked Activations Recorded Directly from Human Insula.

Spontaneous activations within neuronal populations can emerge similarly to "task-evoked" activations elicited during cognitive performance or sensory stimulation. We hypothesized that spontaneous activations within a given brain region have comparable functional and physiological properties to task-evoked activations. Using human intracranial EEG with concurrent pupillometry in 3 subjects (2 males, 1 female), we localized neuronal populations in the dorsal anterior insular cortex that showed task-evoked activations correlating positively with the magnitude of pupil dilation during a continuous performance task. The pupillary response peaks lagged behind insular activations by several hundreds of milliseconds. We then detected spontaneous activations, within the same neuronal populations of insular cortex, that emerged intermittently during a wakeful "resting state" and that had comparable electrophysiological properties (magnitude, duration, and spectral signature) to task-evoked activations. Critically, similar to task-evoked activations, spontaneous activations systematically preceded phasic pupil dilations with a strikingly similar temporal profile. Our findings suggest similar neurophysiological profiles between spontaneous and task-evoked activations in the human insula and support a clear link between these activations and autonomic functions measured by dynamics of pupillary dilation.SIGNIFICANCE STATEMENT Most of our knowledge about activations in the human brain is derived from studies of responses to external events and experimental conditions (i.e., "task-evoked" activations). We obtained direct neural recordings from electrodes implanted in human subjects and showed that activations emerge spontaneously and have strong similarities to task-evoked activations(e.g., magnitude, temporal profile) within the same populations of neurons. Within the dorsal anterior insula, a brain region implicated in salience processing and alertness, activations that are either spontaneous or task-evoked are coupled with brief dilations of the pupil. Our findings underscore how spontaneous brain activity, a major current focus of human neuroimaging studies aimed at developing biomarkers of disease, is relevant to ongoing physiological and possibly self-generated mental processes.

Brain state-based detection of attentional fluctuations and their modulation.

In the search for brain markers of optimal attentional focus, the mainstream approach has been to first define attentional states based on behavioral performance, and to subsequently investigate "neural correlates" associated with these performance variations. However, this approach constrains the range of contexts in which attentional states can be operationalized by relying on overt behavior, and assumes a one-to-one correspondence between behavior and brain state. Here, we reversed the logic of these previous studies and sought to identify behaviorally-relevant brain states based solely on brain activity, agnostic to behavioral performance. In four independent datasets, we found that the same two brain states were dominant during a sustained attention task. One state was behaviorally optimal, with higher accuracy and stability, but a greater tendency to mind wander (State1). The second state was behaviorally suboptimal, with lower accuracy and instability (State2). We further demonstrate how these brain states were impacted by motivation and attention-deficit/hyperactivity disorder (ADHD). Individuals with ADHD spent more time in suboptimal State2 and less time in optimal State1 than healthy controls. Motivation overcame the suboptimal behavior associated with State2. Our study provides compelling evidence for the existence of two attentional states from the sole viewpoint of brain activity.

Integration and segregation across large-scale intrinsic brain networks as a marker of sustained attention and task-unrelated thought.

Sustained attention is a fundamental cognitive process that can be decoupled from distinct external events, and instead emerges from ongoing intrinsic large-scale network interdependencies fluctuating over seconds to minutes. Lapses of sustained attention are commonly associated with the subjective experience of mind wandering and task-unrelated thoughts. Little is known about how fluctuations in information processing underpin sustained attention, nor how mind wandering undermines this information processing. To overcome this, we used fMRI to investigate brain activity during subjects' performance (n=29) of a cognitive task that was optimized to detect and isolate continuous fluctuations in both sustained attention (via motor responses) and task-unrelated thought (via subjective reports). We then investigated sustained attention with respect to global attributes of communication throughout the functional architecture, i.e., by the segregation and integration of information processing across large scale-networks. Further, we determined how task-unrelated thoughts related to these global information processing markers of sustained attention. The results show that optimal states of sustained attention favor both enhanced segregation and reduced integration of information processing in several task-related large-scale cortical systems with concurrent reduced segregation and enhanced integration in the auditory and sensorimotor systems. Higher degree of mind wandering was associated with losses of the favored segregation and integration of specific subsystems in our sustained attention model. Taken together, we demonstrate that intrinsic ongoing neural fluctuations are characterized by two converging communication modes throughout the global functional architecture, which give rise to optimal and suboptimal attention states. We discuss how these results might potentially serve as neural markers for clinically abnormal attention. SIGNIFICANCE STATEMENT: Most of our brain activity unfolds in an intrinsic manner, i.e., is unrelated to immediate external stimuli or tasks. Here we use a gradual continuous performance task to map this intrinsic brain activity to both fluctuations of sustained attention and mind wandering. We show that optimal sustained attention is associated with concurrent segregation and integration of information processing within many large-scale brain networks, while task-unrelated thought is related to sub-optimal information processing in specific subsystems of this sustained attention network model. These findings provide a novel information processing framework for investigating the neural basis of sustained attention, by mapping attentional fluctuations to genuinely global features of intra-brain communication.

What have we really learned from functional connectivity in clinical populations?

Functional connectivity (FC), or the statistical interdependence of blood-oxygen dependent level (BOLD) signals between brain regions using fMRI, has emerged as a widely used tool for probing functional abnormalities in clinical populations due to the promise of the approach across conceptual, technical, and practical levels. With an already vast and steadily accumulating neuroimaging literature on neurodevelopmental, psychiatric, and neurological diseases and disorders in which FC is a primary measure, we aim here to provide a high-level synthesis of major concepts that have arisen from FC findings in a manner that cuts across different clinical conditions and sheds light on overarching principles. We highlight that FC has allowed us to discover the ubiquity of intrinsic functional networks across virtually all brains and clarify typical patterns of neurodevelopment over the lifespan. This understanding of typical FC maturation with age has provided important benchmarks against which to evaluate divergent maturation in early life and degeneration in late life. This in turn has led to the important insight that many clinical conditions are associated with complex, distributed, network-level changes in the brain, as opposed to solely focal abnormalities. We further emphasize the important role that FC studies have played in supporting a dimensional approach to studying transdiagnostic clinical symptoms and in enhancing the multimodal characterization and prediction of the trajectory of symptom progression across conditions. We highlight the unprecedented opportunity offered by FC to probe functional abnormalities in clinical conditions where brain function could not be easily studied otherwise, such as in disorders of consciousness. Lastly, we suggest high priority areas for future research and acknowledge critical barriers associated with the use of FC methods, particularly those related to artifact removal, data denoising and feasibility in clinical contexts.

Direct Cortical Recordings Suggest Temporal Order of Task-Evoked Responses in Human Dorsal Attention and Default Networks.

The past decade has seen a large number of neuroimaging studies focused on the anticorrelated functional relationship between the default mode network (DMN) and the dorsal attention network (DAN). Due principally to the low temporal resolution of functional neuroimaging modalities, the fast-neuronal dynamics across these networks remain poorly understood. Here we report novel human intracranial electrophysiology data from six neurosurgical patients (four males) with simultaneous coverage of well characterized nodes of the DMN and DAN. Subjects performed an arithmetic processing task, shown previously to evoke reliable deactivations (below baseline) in the DMN, and activations in the DAN. In this cohort, we show that DMN deactivations lag DAN activations by approximately 200 ms. Our findings suggest a clear temporal order of processing across the two networks during the current task and place the DMN further than the DAN in a plausible information-processing hierarchy.SIGNIFICANCE STATEMENT The human brain contains an intrinsic and strictly organized network architecture. Our understanding of the interplay across association networks has relied primarily on the slow fluctuations of the hemodynamic response, and as such it has lacked essential evidence regarding the temporal dynamics of activity across these networks. The current study presents evidence from high spatiotemporal methods showing that well studied areas of the default mode network display delayed task-induced activity relative to divergent responses in dorsal attention network nodes. This finding provides direct and critical evidence regarding the temporal chronology of neuronal events across opposing brain networks.

Intracranial Electrophysiology Reveals Reproducible Intrinsic Functional Connectivity within Human Brain Networks.

Evidence for intrinsic functional connectivity (FC) within the human brain is largely from neuroimaging studies of hemodynamic activity. Data are lacking from anatomically precise electrophysiological recordings in the most widely studied nodes of human brain networks. Here we used a combination of fMRI and electrocorticography (ECoG) in five human neurosurgical patients with electrodes in the canonical "default" (medial prefrontal and posteromedial cortex), "dorsal attention" (frontal eye fields and superior parietal lobule), and "frontoparietal control" (inferior parietal lobule and dorsolateral prefrontal cortex) networks. In this unique cohort, simultaneous intracranial recordings within these networks were anatomically matched across different individuals. Within each network and for each individual, we found a positive, and reproducible, spatial correlation for FC measures obtained from resting-state fMRI and separately recorded ECoG in the same brains. This relationship was reliably identified for electrophysiological FC based on slow (<1 Hz) fluctuations of high-frequency broadband (70-170 Hz) power, both during wakeful rest and sleep. A similar FC organization was often recovered when using lower-frequency (1-70 Hz) power, but anatomical specificity and consistency were greatest for the high-frequency broadband range. An interfrequency comparison of fluctuations in FC revealed that high and low-frequency ranges often temporally diverged from one another, suggesting that multiple neurophysiological sources may underlie variations in FC. Together, our work offers a generalizable electrophysiological basis for intrinsic FC and its dynamics across individuals, brain networks, and behavioral states.SIGNIFICANCE STATEMENT The study of human brain networks during wakeful "rest", largely with fMRI, is now a major focus in both cognitive and clinical neuroscience. However, little is known about the neurophysiology of these networks and their dynamics. We studied neural activity during wakeful rest and sleep within neurosurgical patients with directly implanted electrodes. We found that network activity patterns showed striking similarities between fMRI and direct recordings in the same brains. With improved resolution of direct recordings, we also found that networks were best characterized with specific activity frequencies and that different frequencies show different profiles of within-network activity over time. Our work clarifies how networks spontaneously organize themselves across individuals, brain networks, and behavioral states.

Large-scale network interactions involved in dividing attention between the external environment and internal thoughts to pursue two distinct goals.

Previous research suggests that default-mode network (DMN) and dorsal attention network (DAN) are involved in internally- and externally-directed attention, respectively, through interactions with salience network (SN) and frontoparietal network (FPCN). Performing a task requiring external attention is often accompanied by a down-regulation of attention to internal thoughts, and vice-versa. In contrast, we often divide our attention between the external environment and internal thoughts to pursue distinct goals, yet virtually no prior research has examined how brain networks support this functionally critical neurocognitive process. In the current study, participants planned their responses for an upcoming alternate uses divergent thinking task (AUT-Condition), indicated whether arrows were pointing left or right (Arrows-Condition) or performed both tasks simultaneously (Dual-Task condition). Behaviorally, the Dual-Task condition was associated with equivalent generation of alternate uses but increased RT variability compared to the single-task conditions. Static connectivity analyses indicated that FPCN and SN increased their connectivity to DMN and reduced their connectivity to DAN during the Dual-Task condition and the AUT-Condition compared to the Arrows-Condition. Furthermore, DAN-SN connectivity was highest during the Arrows-Condition, intermediate during the Dual-Task condition and lowest during the AUT-Condition. Finally, time-varying connectivity analyses indicated that individuals who reported spending less time thinking of alternate uses during the Dual-Task condition spent more time in a state associated with performing the Arrows-Condition. Overall, our results suggest that interactions between DMN, FPCN, SN and DAN allow internal-external dual-tasking, and that time-varying functional connectivity between these networks is sensitive to attentional fluctuations between tasks during dual-tasking.

A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336262).

Spontaneous default network activity reflects behavioral variability independent of mind-wandering.

The brain's default mode network (DMN) is highly active during wakeful rest when people are not overtly engaged with a sensory stimulus or externally oriented task. In multiple contexts, increased spontaneous DMN activity has been associated with self-reported episodes of mind-wandering, or thoughts that are unrelated to the present sensory environment. Mind-wandering characterizes much of waking life and is often associated with error-prone, variable behavior. However, increased spontaneous DMN activity has also been reliably associated with stable, rather than variable, behavior. We aimed to address this seeming contradiction and to test the hypothesis that single measures of attentional states, either based on self-report or on behavior, are alone insufficient to account for DMN activity fluctuations. Thus, we simultaneously measured varying levels of self-reported mind-wandering, behavioral variability, and brain activity with fMRI during a unique continuous performance task optimized for detecting attentional fluctuations. We found that even though mind-wandering co-occurred with increased behavioral variability, highest DMN signal levels were best explained by intense mind-wandering combined with stable behavior simultaneously, compared with considering either single factor alone. These brain-behavior-experience relationships were highly consistent within known DMN subsystems and across DMN subregions. In contrast, such relationships were absent or in the opposite direction for other attention-relevant networks (salience, dorsal attention, and frontoparietal control networks). Our results suggest that the cognitive processes that spontaneous DMN activity specifically reflects are only partially related to mind-wandering and include also attentional state fluctuations that are not captured by self-report.

Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Ceruleus in Humans.

State-dependent activity of locus ceruleus (LC) neurons has long suggested a role for noradrenergic modulation of arousal. However, in vivo insights into noradrenergic arousal circuitry have been constrained by the fundamental inaccessibility of the human brain for invasive studies. Functional magnetic resonance imaging (fMRI) studies performed during site-specific pharmacological manipulations of arousal levels may be used to study brain arousal circuitry. Dexmedetomidine is an anesthetic that alters the level of arousal by selectively targeting α2 adrenergic receptors on LC neurons, resulting in reduced firing rate and norepinephrine release. Thus, we hypothesized that dexmedetomidine-induced altered arousal would manifest with reduced functional connectivity between the LC and key brain regions involved in the regulation of arousal. To test this hypothesis, we acquired resting-state fMRI data in right-handed healthy volunteers 18-36 years of age (n = 15, 6 males) at baseline, during dexmedetomidine-induced altered arousal, and recovery states. As previously reported, seed-based resting-state fMRI analyses revealed that the LC was functionally connected to a broad network of regions including the reticular formation, basal ganglia, thalamus, posterior cingulate cortex (PCC), precuneus, and cerebellum. Functional connectivity of the LC to only a subset of these regions (PCC, thalamus, and caudate nucleus) covaried with the level of arousal. Functional connectivity of the PCC to the ventral tegmental area/pontine reticular formation and thalamus, in addition to the LC, also covaried with the level of arousal. We propose a framework in which the LC, PCC, thalamus, and basal ganglia comprise a functional arousal circuitry.SIGNIFICANCE STATEMENT Electrophysiological studies of locus ceruleus (LC) neurons have long suggested a role for noradrenergic mechanisms in mediating arousal. However, the fundamental inaccessibility of the human brain for invasive studies has limited a precise understanding of putative brain regions that integrate with the LC to regulate arousal. Our results suggest that the PCC, thalamus, and basal ganglia are key components of a LC-noradrenergic arousal circuit.

Distinct Patterns of Temporal and Directional Connectivity among Intrinsic Networks in the Human Brain.

To determine the spatiotemporal relationships among intrinsic networks of the human brain, we recruited seven neurosurgical patients (four males and three females) who were implanted with intracranial depth electrodes. We first identified canonical resting-state networks at the individual subject level using an iterative matching procedure on each subject's resting-state fMRI data. We then introduced single electrical pulses to fMRI pre-identified nodes of the default network (DN), frontoparietal network (FPN), and salience network (SN) while recording evoked responses in other recording sites within the same networks. We found bidirectional signal flow across the three networks, albeit with distinct patterns of evoked responses within different time windows. We used a data-driven clustering approach to show that stimulation of the FPN and SN evoked a rapid (<70 ms) response that was predominantly higher within the SN sites, whereas stimulation of the DN led to sustained responses in later time windows (85-200 ms). Stimulations in the medial temporal lobe components of the DN evoked relatively late effects (>130 ms) in other nodes of the DN, as well as FPN and SN. Our results provide temporal information about the patterns of signal flow between intrinsic networks that provide insights into the spatiotemporal dynamics that are likely to constrain the architecture of the brain networks supporting human cognition and behavior.SIGNIFICANCE STATEMENT Despite great progress in the functional neuroimaging of the human brain, we still do not know the precise set of rules that define the patterns of temporal organization between large-scale networks of the brain. In this study, we stimulated and then recorded electrical evoked potentials within and between three large-scale networks of the brain, the default network (DN), frontoparietal network (FPN), and salience network (SN), in seven subjects undergoing invasive neurosurgery. Using a data-driven clustering approach, we observed distinct temporal and directional patterns between the three networks, with FPN and SN activity predominant in early windows and DN stimulation affecting the network in later windows. These results provide important temporal information about the interactions between brain networks supporting human cognition and behavior.

Just a thought: How mind-wandering is represented in dynamic brain connectivity.

The neuroscience of mind-wandering has begun to flourish, with roles of brain regions and networks being defined for various components of spontaneous thought. However, most of brain activity does not represent immediately occurring thoughts. Instead, spontaneous, organized network activity largely reflects "intrinsic" functions that are unrelated to the current experience. There remains no consensus on how brain networks represent mind-wandering in parallel to functioning in other ongoing, predominantly unconscious processes. Commonly, in network analysis of functional neuroimaging data, functional connectivity (FC; correlated time series) between remote brain regions is considered over several minutes or longer. In contrast, dynamic functional connectivity (dFC) is a new, promising approach to characterizing spontaneous changes in neural network communication on the faster time-scale at which intra-individual fluctuations in thought contents may occur. Here I describe how a potential relationship between mind-wandering and FC has traditionally been considered in the literature, and I review methods and results pertaining to the study of the dFC-mind-wandering relationship. While acknowledging challenges to the dFC approach and to behaviorally capturing fluctuations in inner experiences, I describe a framework for describing spontaneous thoughts in terms of brain-network activity patterns that are comprised of connections weighted by time-varying relevance to conscious and unconscious processing. This perspective suggests preferential roles of certain anatomical communication avenues (e.g., via the default mode network) in mind-wandering, while also implying that a region's connectivity fluctuates over time in its immediate degree of relevance to conscious contents, ultimately allowing novelty and diversity of thought.

Dynamic Brain Network Correlates of Spontaneous Fluctuations in Attention.

Human attention is intrinsically dynamic, with focus continuously shifting between elements of the external world and internal, self-generated thoughts. Communication within and between large-scale brain networks also fluctuates spontaneously from moment to moment. However, the behavioral relevance of dynamic functional connectivity and possible link with attentional state shifts is unknown. We used a unique approach to examine whether brain network dynamics reflect spontaneous fluctuations in moment-to-moment behavioral variability, a sensitive marker of attentional state. Nineteen healthy adults were instructed to tap their finger every 600 ms while undergoing fMRI. This novel, but simple, approach allowed us to isolate moment-to-moment fluctuations in behavioral variability related to attention, independent of common confounds in cognitive tasks (e.g., stimulus changes, response inhibition). Spontaneously increasing tap variance ("out-of-the-zone" attention) was associated with increasing activation in dorsal-attention and salience network regions, whereas decreasing tap variance ("in-the-zone" attention) was marked by increasing activation of default mode network (DMN) regions. Independent of activation, tap variance representing out-of-the-zone attention was also time-locked to connectivity both within DMN and between DMN and salience network regions. These results provide novel mechanistic data on the understudied neural dynamics of everyday, moment-to-moment attentional fluctuations, elucidating the behavioral importance of spontaneous, transient coupling within and between attention-relevant networks.

Modulation of cognitive cerebello-cerebral functional connectivity by lateral cerebellar continuous theta burst stimulation.

Network connectivity measured with resting state functional magnetic resonance imaging (rsfMRI) has revealed the contribution of distinct cerebellar lobules to an array of brain wide networks sub-serving motor and cognitive processes. As distinct cerebellar lobules form relatively accessible nodes of different brain networks, this raises the possibility for site-specific modulation of network connectivity using non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS). Continuous theta burst transcranial magnetic stimulation (cTBS) induces long-lasting inhibition of cortical areas. Although previous studies have shown that cTBS of the lateral cerebellum modulates motor cortical excitability and improves symptoms in several movement disorders, the effect on cognitive domains has not been examined. We explored the immediate effects of cTBS in a sham-controlled study on the strength of intrinsic functional connectivity between cerebellar and cortical motor and cognitive regions in 12 participants. Lateral cerebellar cTBS significantly decreased functional connectivity with frontal and parietal cognitive regions, while connectivity with motor regions remained unaltered. Sham stimulation had no effect on either motor or cognitive connectivity. These results show that inhibitory cerebellar stimulation reduces intrinsic functional connectivity between different cortical areas, in keeping with the known connectivity pattern of the cerebellum. The results highlight the plasticity of cerebello-cerebral networks and indicate for the first time that this functional connectivity can be downregulated using an inhibitory neurostimulation paradigm. This may shed light on the pathophysiology of network dysfunction and is a potential treatment for cognitive and movement disorders.

Individual Differences in Temporal Summation of Pain Reflect Pronociceptive and Antinociceptive Brain Structure and Function.

Temporal summation of pain (TSP), the perception of increasingly greater pain evoked by repetitive noxious stimuli, is highly variable between individuals. Individuals with facilitated pain processing and/or reduced pain-modulatory capabilities are regarded as pronociceptive, whereas individuals with reduced pain processing capacity are characterized as antinociceptive. Brodmann area (BA) 3a of the primary somatosensory cortex is part of an ascending pathway from the sensory thalamus that mediates TSP. Descending pain modulation involves projections from the subgenual anterior cingulate cortex (sgACC) to the periaqueductal gray to the rostral ventromedial medulla (RVM). Here, we tested the hypothesis that pronociceptive individuals have an enhanced TSP response compared with antinociceptive individuals, marked by facilitated ascending nociceptive processing and/or reduced capacity for descending pain modulation. Eighty healthy humans were tested with a TSP protocol and underwent structural and resting-state functional magnetic resonance imaging. We found large interindividual differences in TSP responses, which were positively correlated with functional connectivity (FC) between individuals' right sensory thalamus with their BA 3a (thal-BA 3a), and with cortical thickness in their insula and medial prefrontal cortex. In contrast, TSP was negatively correlated with FC between individuals' RVM with their sgACC (RVM-sgACC). When subjects were grouped as pronociceptive or antinociceptive based on whether they had greater thal-BA 3a or RVM-sgACC FC respectively, pronociceptive subjects showed greater TSP responses. Furthermore, TSP was positively correlated with the extent of imbalance toward ascending nociceptive processing. Our study indicates that individuals with enhanced TSP have facilitated ascending nociceptive processing and reduced pain-modulatory capacities. SIGNIFICANCE STATEMENT: This study provides novel evidence that an individual's propensity to experience amplified pain with repeated stimuli [i.e., temporal summation of pain (TSP)] reflects attributes of their "pain connectome," namely stronger ascending nociceptive and weaker descending pain-modulatory components. Understanding the individual neural mechanisms underlying TSP within individuals has implications for developing personalized pain-management strategies for chronic pain.

Association between resting-state brain functional connectivity and muscle sympathetic burst incidence.

The insula (IC) and cingulate are key components of the central autonomic network and central nodes of the salience network (SN), a set of spatially distinct but temporally correlated brain regions identified with resting-state (task free) functional MRI (rsMRI). To examine the SN's involvement in sympathetic outflow, we tested the hypothesis that individual differences in intrinsic connectivity of the SN correlate positively with resting postganglionic muscle sympathetic nerve activity (MSNA) burst incidence (BI) in subjects without and with obstructive sleep apnea (OSA). Overnight polysomnography, 5-min rsMRI, and fibular MSNA recording were performed in 36 subjects (mean age 57 yr; 10 women, 26 men). Independent component analysis (ICA) of the entire cohort identified the SN as including bilateral IC, pregenual anterior cingulate cortex (pgACC), midcingulate cortex (MCC), and the temporoparietal junction (TPJ). There was a positive correlation between BI and the apnea-hypopnea index (AHI) (P < 0.001), but dual-regression analysis identified no differences in SN functional connectivity between subjects with no or mild OSA (n = 17) and moderate or severe (n = 19) OSA. Correlation analysis relating BI to the strength of connectivity within the SN revealed large (i.e., spatial extent) and strong correlations for the left IC (P < 0.001), right pgACC/MCC (P < 0.006), left TPJ (P < 0.004), thalamus (P < 0.035), and cerebellum (P < 0.013). Indexes of sleep apnea were unrelated to BI and the strength of SN connectivity. There were no relationships between BI and default or sensorimotor network connectivity. This study links connectivity within the SN to MSNA, demonstrating several of its nodes to be key sympathoexcitatory regions.

Intrinsic functional connectivity of periaqueductal gray subregions in humans.

The periaqueductal gray matter (PAG) is a key brain region of the descending pain modulation pathway. It is also involved in cardiovascular functions, anxiety, and fear; however, little is known about PAG subdivisions in humans. The aims of this study were to use resting-state fMRI-based functional connectivity (FC) to parcellate the human PAG and to determine FC of its subregions. To do this, we acquired resting-state fMRI scans from 79 healthy subjects and (1) used a data-driven method to parcellate the PAG, (2) used predefined seeds in PAG subregions to evaluate PAG FC to the whole brain, and (3) examined sex differences in PAG FC. We found that clustering of the left and right PAG yielded similar patterns of caudal, middle, and rostral subdivisions in the coronal plane, and dorsal and ventral subdivisions in the sagittal plane. FC analysis of predefined subregions revealed that the ventolateral(VL)-PAG was supfunctionally connected to brain regions associated with descending pain modulation (anterior cingulate cortex (ACC), upper pons/medulla), whereas the lateral (L) and dorsolateral (DL) subregions were connected with brain regions implicated in executive functions (prefrontal cortex, striatum, hippocampus). We also found sex differences in FC including areas implicated in pain, salience, and analgesia including the ACC and the insula in women, and the MCC, parahippocampal gyrus, and the temporal pole in men. The organization of the human PAG thus provides a framework to understand the circuitry underlying the broad range of responses to pain and its modulation in men and women.