Habituation to pain: self-report, electroencephalography, and functional magnetic resonance imaging in healthy individuals. A scoping review and future recommendations.

ABSTRACT: Habituation to pain is a fundamental learning process and important adaption. Yet, a comprehensive review of the current state of the field is lacking. Through a systematic search, 63 studies were included. Results address habituation to pain in healthy individuals based on self-report, electroencephalography, or functional magnetic resonance imaging. Our findings indicate a large variety in methods, experimental settings, and contexts, making habituation a ubiquitous phenomenon. Habituation to pain based on self-report studies shows a large influence of expectations, as well as the presence of individual differences. Furthermore, widespread neural effects, with sometimes opposing effects in self-report measures, are noted. Electroencephalography studies showed habituation of the N2-P2 amplitude, whereas functional magnetic resonance imaging studies showed decreasing activity during painful repeated stimulation in several identified brain areas (cingulate cortex and somatosensory cortices). Important considerations for the use of terminology, methodology, statistics, and individual differences are discussed. This review will aid our understanding of habituation to pain in healthy individuals and may lead the way to improving methods and designs for personalized treatment approaches in chronic pain patients.

Intracranial human recordings reveal association between neural activity and perceived intensity for the pain of others in the insula.

Based on neuroimaging data, the insula is considered important for people to empathize with the pain of others. Here, we present intracranial electroencephalographic (iEEG) recordings and single-cell recordings from the human insula while seven epilepsy patients rated the intensity of a woman's painful experiences seen in short movie clips. Pain had to be deduced from seeing facial expressions or a hand being slapped by a belt. We found activity in the broadband 20-190 Hz range correlated with the trial-by-trial perceived intensity in the insula for both types of stimuli. Within the insula, some locations had activity correlating with perceived intensity for our facial expressions but not for our hand stimuli, others only for our hand but not our face stimuli, and others for both. The timing of responses to the sight of the hand being hit is best explained by kinematic information; that for our facial expressions, by shape information. Comparing the broadband activity in the iEEG signal with spiking activity from a small number of neurons and an fMRI experiment with similar stimuli revealed a consistent spatial organization, with stronger associations with intensity more anteriorly, while viewing the hand being slapped.

Hippocampal activity in working memory tasks: sparse, yet relevant.

Recent studies suggest the hippocampus is involved in working memory (WM). Slotnick (this issue) critically reviewed relevant fMRI findings and concludes WM 'does not activate the hippocampus.' We extend Slotnick's review by discussing observations from human intracranial and lesion research. These studies do suggest hippocampal contributions to WM (beyond novelty encoding), which however are difficult to capture with conventional fMRI. Still, the advent of new fMRI techniques combined with a stronger emphasis on shared hippocampal mechanisms across short- and long-term memory pave an exciting path forward.

Theta-phase dependent neuronal coding during sequence learning in human single neurons.

The ability to maintain a sequence of items in memory is a fundamental cognitive function. In the rodent hippocampus, the representation of sequentially organized spatial locations is reflected by the phase of action potentials relative to the theta oscillation (phase precession). We investigated whether the timing of neuronal activity relative to the theta brain oscillation also reflects sequence order in the medial temporal lobe of humans. We used a task in which human participants learned a fixed sequence of pictures and recorded single neuron and local field potential activity with implanted electrodes. We report that spikes for three consecutive items in the sequence (the preferred stimulus for each cell, as well as the stimuli immediately preceding and following it) were phase-locked at distinct phases of the theta oscillation. Consistent with phase precession, spikes were fired at progressively earlier phases as the sequence advanced. These findings generalize previous findings in the rodent hippocampus to the human temporal lobe and suggest that encoding stimulus information at distinct oscillatory phases may play a role in maintaining sequential order in memory.

Concurrent human TMS-EEG-fMRI enables monitoring of oscillatory brain state-dependent gating of cortico-subcortical network activity.

Despite growing interest, the causal mechanisms underlying human neural network dynamics remain elusive. Transcranial Magnetic Stimulation (TMS) allows to noninvasively probe neural excitability, while concurrent fMRI can log the induced activity propagation through connected network nodes. However, this approach ignores ongoing oscillatory fluctuations which strongly affect network excitability and concomitant behavior. Here, we show that concurrent TMS-EEG-fMRI enables precise and direct monitoring of causal dependencies between oscillatory states and signal propagation throughout cortico-subcortical networks. To demonstrate the utility of this multimodal triad, we assessed how pre-TMS EEG power fluctuations influenced motor network activations induced by subthreshold TMS to right dorsal premotor cortex. In participants with adequate motor network reactivity, strong pre-TMS alpha power reduced TMS-evoked hemodynamic activations throughout the bilateral cortico-subcortical motor system (including striatum and thalamus), suggesting shunted network connectivity. Concurrent TMS-EEG-fMRI opens an exciting noninvasive avenue of subject-tailored network research into dynamic cognitive circuits and their dysfunction.

Combining Gamma With Alpha and Beta Power Modulation for Enhanced Cortical Mapping in Patients With Focal Epilepsy.

About one third of patients with epilepsy have seizures refractory to the medical treatment. Electrical stimulation mapping (ESM) is the gold standard for the identification of "eloquent" areas prior to resection of epileptogenic tissue. However, it is time-consuming and may cause undesired side effects. Broadband gamma activity (55-200 Hz) recorded with extraoperative electrocorticography (ECoG) during cognitive tasks may be an alternative to ESM but until now has not proven of definitive clinical value. Considering their role in cognition, the alpha (8-12 Hz) and beta (15-25 Hz) bands could further improve the identification of eloquent cortex. We compared gamma, alpha and beta activity, and their combinations for the identification of eloquent cortical areas defined by ESM. Ten patients with intractable focal epilepsy (age: 35.9 ± 9.1 years, range: 22-48, 8 females, 9 right handed) participated in a delayed-match-to-sample task, where syllable sounds were compared to visually presented letters. We used a generalized linear model (GLM) approach to find the optimal weighting of each band for predicting ESM-defined categories and estimated the diagnostic ability by calculating the area under the receiver operating characteristic (ROC) curve. Gamma activity increased more in eloquent than in non-eloquent areas, whereas alpha and beta power decreased more in eloquent areas. Diagnostic ability of each band was close to 0.7 for all bands but depended on multiple factors including the time period of the cognitive task, the location of the electrodes and the patient's degree of attention to the stimulus. We show that diagnostic ability can be increased by 3-5% by combining gamma and alpha and by 7.5-11% when gamma and beta were combined. We then show how ECoG power modulation from cognitive testing can be used to map the probability of eloquence in individual patients and how this probability map can be used in clinical settings to optimize ESM planning. We conclude that the combination of gamma and beta power modulation during cognitive testing can contribute to the identification of eloquent areas prior to ESM in patients with refractory focal epilepsy.

Somatotopic mapping of the human breast using 7 T functional MRI.

How are tactile sensations in the breast represented in the female and male brain? Using ultra high-field 7 T MRI in ten females and ten males, we demonstrate that the representation of tactile breast information shows a somatotopic organization, with cortical magnification of the nipple. Furthermore, we show that the core representation of the breast is organized according to the specific nerve architecture that underlies breast sensation, where the medial and lateral sides of one breast are asymmetrically represented in bilateral primary somatosensory cortex. Finally, gradual selectivity signatures allude to a somatotopic organization of the breast area with overlapping, but distinctive, cortical representations of breast segments. Our univariate and multivariate analyses consistently showed similar somatosensory breast representations in males and females. The findings can guide future research on neuroplastic reorganization of the breast area, across reproductive life stages, and after breast surgery.

From coarse to fine: Interactive feature processing precedes local feature analysis in human face perception.

Face perception depends on a dynamic interplay of a "holistic" Interactive Feature Processing (IFP) and a Local Feature Processing (LFP) style. However, it is unclear whether features are processed locally before they are integrated into a holistic percept (Fine-to-Coarse strategy), or whether local feature processing occurs only after a holistic percept is established (Coarse-to-Fine strategy). The present Event-Related Potentials study investigates whether IFP precedes LFP (Coarse-to-Fine) or vice versa (Fine-to-Coarse). Participants matched target features within face pairs (here the eye region), in which distracter features (nose and mouth) called for the same or a different response (congruent and incongruent, respectively). Psychophysical results replicated previous findings. That is, dissimilar target features are locally processed (LFP), which minimizes interference from surrounding incongruent distracters. Conversely, an IFP mode is elicited when similar target features are embedded in dissimilar contexts. In IFP mode, incongruent distracters do interfere with the processing of similar target features, thereby deteriorating task performance. Face inversion, which preserves input properties but disrupts high-level face perception, annihilated these incongruency effects. Psychophysical observations were reflected at the neural level. The IFP and LFP modes of face perception elicited distinct time-courses in occipito-temporal cortex. IFP was affected by inversion as soon as 176 ms post-stimulus onset (coinciding with the N170 peak). In contrast, the first robust indications of LFP occurred 120 ms later, at 296 ms. Thus, the contribution of IFP to high-level face perception appears to temporally precede LFP. Moreover, results showed that the IFP and LFP modes did not only operate in distinct time intervals, but also in different brain areas: activity associated with the IFP mode was right-lateralized, whereas the LPF mode engaged the left hemisphere. In sum, interactive "holistic" encoding of facial features temporally precedes their local analysis. This agrees with models suggesting a Coarse-to-Fine strategy for face perception, in line with generic descriptions of visual perception in which global scene analysis precedes the examination of local details.

Frequency-specific attentional modulation in human primary auditory cortex and midbrain.

Paying selective attention to an audio frequency selectively enhances activity within primary auditory cortex (PAC) at the tonotopic site (frequency channel) representing that frequency. Animal PAC neurons achieve this 'frequency-specific attentional spotlight' by adapting their frequency tuning, yet comparable evidence in humans is scarce. Moreover, whether the spotlight operates in human midbrain is unknown. To address these issues, we studied the spectral tuning of frequency channels in human PAC and inferior colliculus (IC), using 7-T functional magnetic resonance imaging (FMRI) and frequency mapping, while participants focused on different frequency-specific sounds. We found that shifts in frequency-specific attention alter the response gain, but not tuning profile, of PAC frequency channels. The gain modulation was strongest in low-frequency channels and varied near-monotonically across the tonotopic axis, giving rise to the attentional spotlight. We observed less prominent, non-tonotopic spatial patterns of attentional modulation in IC. These results indicate that the frequency-specific attentional spotlight in human PAC as measured with FMRI arises primarily from tonotopic gain modulation, rather than adapted frequency tuning. Moreover, frequency-specific attentional modulation of afferent sound processing in human IC seems to be considerably weaker, suggesting that the spotlight diminishes toward this lower-order processing stage. Our study sheds light on how the human auditory pathway adapts to the different demands of selective hearing.

Facial expressions perceived by the adolescent brain: Towards the proficient use of low spatial frequency information.

Rapid decoding of emotional expressions is essential for social communication. Fast processing of facial expressions depends on the adequate (subcortical) processing of important global face cues in the low spatial frequency (LSF) ranges. However, children below 9 years of age extract fearful expression information from local details represented by high SF (HSF) image content. Our ERP study investigated at which developmental stage this ineffective HSF-driven processing is replaced by the proficient and rapid LSF-driven perception of fearful faces, in which adults are highly skilled. We examined behavioral and neural responses to high- and low-pass filtered faces with a fearful or neutral expression in groups of children on the verge of pre-adolescence (9-10 years), adolescents (14-15 years), and young adults (20-28 years). Our results suggest that the neural emotional face processing network has a protracted maturational course into adolescence, which is related to changes in SF processing. In mid-adolescence, increased sensitivity to emotional LSF cues is developed, which aids the fast and adequate processing of fearful expressions that might signal impending danger.

Proficient use of low spatial frequencies facilitates face memory but shows protracted maturation throughout adolescence.

Face perception is characterized by configural processing, which depends on visual information in the low spatial frequency (LSF) ranges. However, it is unclear whether LSF content is equally important for face memory. The present study investigated how face information in the low and high SF range plays a role in the configural encoding of faces for short-term and long-term recall. Moreover, we examined how SF-dependent face memorization develops in female adolescence, by comparing children (9-10-year-olds), adolescents (12-13-year-olds and 15-16-year-olds), and young adults (21-32-year-olds). Results show that similar to face perception, delayed face recognition was consistently facilitated by LSF content. However, only adults were able to adequately employ configural LSF cues for short-term recall, analogous to the slow maturation of LSF-driven configural face perception reported by previous studies. Moreover, the insensitivity to face inversion of early adolescents revealed their inadequate use of configural face cues regardless of SF availability, corroborating previous reports on an adolescent "dip" in face recognition. Like face perception, face recognition has a protracted maturational course. In (female) adolescence, sensitivity to configural LSF cues is developed, which aids not only configural face perception but also face memorization.

Characterizing object- and position-dependent response profiles to uni- and bilateral stimulus configurations in human higher visual cortex: a 7T fMRI study.

Visual scenes are initially processed via segregated neural pathways dedicated to either of the two visual hemifields. Although higher-order visual areas are generally believed to utilize invariant object representations (abstracted away from features such as stimulus position), recent findings suggest they retain more spatial information than previously thought. Here, we assessed the nature of such higher-order object representations in human cortex using high-resolution fMRI at 7T, supported by corroborative 3T data. We show that multi-voxel activation patterns in both the contra- and ipsilateral hemisphere can be exploited to successfully classify the object category of unilaterally presented stimuli. Moreover, robustly identified rank order-based response profiles demonstrated a strong contralateral bias which frequently outweighed object category preferences. Finally, we contrasted different combinatorial operations to predict the responses during bilateral stimulation conditions based on responses to their constituent unilateral elements. Results favored a max operation predominantly reflecting the contralateral stimuli. The current findings extend previous work by showing that configuration-dependent modulations in higher-order visual cortex responses as observed in single unit activity have a counterpart in human neural population coding. They furthermore corroborate the emerging view that position coding is a fundamental functional characteristic of ventral visual stream processing.

Spatial Frequency Training Modulates Neural Face Processing: Learning Transfers from Low- to High-Level Visual Features.

Perception of visual stimuli improves with training, but improvements are specific for trained stimuli rendering the development of generic training programs challenging. It remains unknown to which extent training of low-level visual features transfers to high-level visual perception, and whether this is accompanied by neuroplastic changes. The current event-related potential (ERP) study showed that training-induced increased sensitivity to a low-level feature, namely low spatial frequency (LSF), alters neural processing of this feature in high-level visual stimuli. Specifically, neural activity related to face processing (N170), was decreased for low (trained) but not high (untrained) SF content in faces following LSF training. These novel results suggest that: (1) SF discrimination learning transfers from simple stimuli to complex objects; and that (2) training the use of specific SF information affects neural processing of facial information. These findings may open up a new avenue to improve face recognition skills in individuals with atypical SF processing, such as in cataract or Autism Spectrum Disorder (ASD).

Frequency-Selective Attention in Auditory Scenes Recruits Frequency Representations Throughout Human Superior Temporal Cortex.

A sound of interest may be tracked amid other salient sounds by focusing attention on its characteristic features including its frequency. Functional magnetic resonance imaging findings have indicated that frequency representations in human primary auditory cortex (AC) contribute to this feat. However, attentional modulations were examined at relatively low spatial and spectral resolutions, and frequency-selective contributions outside the primary AC could not be established. To address these issues, we compared blood oxygenation level-dependent (BOLD) responses in the superior temporal cortex of human listeners while they identified single frequencies versus listened selectively for various frequencies within a multifrequency scene. Using best-frequency mapping, we observed that the detailed spatial layout of attention-induced BOLD response enhancements in primary AC follows the tonotopy of stimulus-driven frequency representations-analogous to the "spotlight" of attention enhancing visuospatial representations in retinotopic visual cortex. Moreover, using an algorithm trained to discriminate stimulus-driven frequency representations, we could successfully decode the focus of frequency-selective attention from listeners' BOLD response patterns in nonprimary AC. Our results indicate that the human brain facilitates selective listening to a frequency of interest in a scene by reinforcing the fine-grained activity pattern throughout the entire superior temporal cortex that would be evoked if that frequency was present alone.

The Effects of Context and Attention on Spiking Activity in Human Early Visual Cortex.

Here we report the first quantitative analysis of spiking activity in human early visual cortex. We recorded multi-unit activity from two electrodes in area V2/V3 of a human patient implanted with depth electrodes as part of her treatment for epilepsy. We observed well-localized multi-unit receptive fields with tunings for contrast, orientation, spatial frequency, and size, similar to those reported in the macaque. We also observed pronounced gamma oscillations in the local-field potential that could be used to estimate the underlying spiking response properties. Spiking responses were modulated by visual context and attention. We observed orientation-tuned surround suppression: responses were suppressed by image regions with a uniform orientation and enhanced by orientation contrast. Additionally, responses were enhanced on regions that perceptually segregated from the background, indicating that neurons in the human visual cortex are sensitive to figure-ground structure. Spiking responses were also modulated by object-based attention. When the patient mentally traced a curve through the neurons' receptive fields, the accompanying shift of attention enhanced neuronal activity. These results demonstrate that the tuning properties of cells in the human early visual cortex are similar to those in the macaque and that responses can be modulated by both contextual factors and behavioral relevance. Our results, therefore, imply that the macaque visual system is an excellent model for the human visual cortex.

Learning of anticipatory responses in single neurons of the human medial temporal lobe.

Neuronal processes underlying the formation of new associations in the human brain are not yet well understood. Here human participants, implanted with depth electrodes in the brain, learned arbitrary associations between images presented in an ordered, predictable sequence. During learning we recorded from medial temporal lobe (MTL) neurons that responded to at least one of the pictures in the sequence (the preferred stimulus). We report that as a result of learning, single MTL neurons show asymmetric shifts in activity and start firing earlier in the sequence in anticipation of their preferred stimulus. These effects appear relatively early in learning, after only 11 exposures to the stimulus sequence. The anticipatory neuronal responses emerge while the subjects became faster in reporting the next item in the sequence. These results demonstrate flexible representations that could support learning of new associations between stimuli in a sequence, in single neurons in the human MTL.

Neural processing of high and low spatial frequency information in faces changes across development: qualitative changes in face processing during adolescence.

Face perception in adults depends on skilled processing of interattribute distances ('configural' processing), which is disrupted for faces presented in inverted orientation (face inversion effect or FIE). Children are not proficient in configural processing, and this might relate to an underlying immaturity to use facial information in low spatial frequency (SF) ranges, which capture the coarse information needed for configural processing. We hypothesized that during adolescence a shift from use of high to low SF information takes place. Therefore, we studied the influence of SF content on neural face processing in groups of children (9-10 years), adolescents (14-15 years) and young adults (21-29 years) by measuring event-related potentials (ERPs) to upright and inverted faces which varied in SF content. Results revealed that children show a neural FIE in early processing stages (i.e. P1; generated in early visual areas), suggesting a superficial, global facial analysis. In contrast, ERPs of adults revealed an FIE at later processing stages (i.e. N170; generated in face-selective, higher visual areas). Interestingly, adolescents showed FIEs in both processing stages, suggesting a hybrid developmental stage. Furthermore, adolescents and adults showed FIEs for stimuli containing low SF information, whereas such effects were driven by both low and high SF information in children. These results indicate that face processing has a protracted maturational course into adolescence, and is dependent on changes in SF processing. During adolescence, sensitivity to configural cues is developed, which aids the fast and holistic processing that is so special for faces.

On the feasibility of concurrent human TMS-EEG-fMRI measurements.

Simultaneously combining the complementary assets of EEG, functional MRI (fMRI), and transcranial magnetic stimulation (TMS) within one experimental session provides synergetic results, offering insights into brain function that go beyond the scope of each method when used in isolation. The steady increase of concurrent EEG-fMRI, TMS-EEG, and TMS-fMRI studies further underlines the added value of such multimodal imaging approaches. Whereas concurrent EEG-fMRI enables monitoring of brain-wide network dynamics with high temporal and spatial resolution, the combination with TMS provides insights in causal interactions within these networks. Thus the simultaneous use of all three methods would allow studying fast, spatially accurate, and distributed causal interactions in the perturbed system and its functional relevance for intact behavior. Concurrent EEG-fMRI, TMS-EEG, and TMS-fMRI experiments are already technically challenging, and the three-way combination of TMS-EEG-fMRI might yield additional difficulties in terms of hardware strain or signal quality. The present study explored the feasibility of concurrent TMS-EEG-fMRI studies by performing safety and quality assurance tests based on phantom and human data combining existing commercially available hardware. Results revealed that combined TMS-EEG-fMRI measurements were technically feasible, safe in terms of induced temperature changes, allowed functional MRI acquisition with comparable image quality as during concurrent EEG-fMRI or TMS-fMRI, and provided artifact-free EEG before and from 300 ms after TMS pulse application. Based on these empirical findings, we discuss the conceptual benefits of this novel complementary approach to investigate the working human brain and list a number of precautions and caveats to be heeded when setting up such multimodal imaging facilities with current hardware.

Task-relevant and accessory items in working memory have opposite effects on activity in extrastriate cortex.

During visual search, the working memory (WM) representation of the search target guides attention to matching items in the visual scene. However, we can hold multiple items in WM. Do all these items guide attention at the same time? Using a new functional magnetic resonance imaging visual search paradigm, we found that items in WM can attain two different states that influence activity in extrastriate visual cortex in opposite directions: whereas the target item in WM enhanced processing of matching visual input, other "accessory" items in memory suppressed activity. These results imply that the representation of task-relevant and (currently) task-irrelevant representations in WM differs, revealing new insights into the organization of human visual WM. The suppressive influence of irrelevant WM items may complement the attention-guiding influence of task-relevant WM items, helping us to focus on task-relevant information without getting distracted by irrelevant memory content.