High-frequency electrical stimulation of cutaneous nociceptors differentially affects pain perception elicited by homotopic and heterotopic electrical stimuli.

Animal studies have shown that high-frequency electrical stimulation (HFS) of peripheral C-fiber nociceptors induces both homosynaptic and heterosynaptic long-term potentiation (LTP) within spinal nociceptive pathways. In humans, when HFS is applied onto the skin to activate nociceptors, single electrical stimuli are perceived more intense at the HFS site compared with a control site, a finding that was interpreted as a perceptual correlate of homosynaptic LTP. The present study aimed to investigate if after HFS the pain elicited by electrical stimuli delivered at the skin next to the HFS site is perceived as more intense compared with the pain at a control site (contralateral arm). To test this, HFS was applied to one of the two ventral forearms of 24 healthy participants. Before and after HFS, single electrical stimuli were delivered through the HFS electrode, through an identical electrode next to the HFS electrode and an identical electrode at the contralateral arm. After HFS, the pain elicited by the single electrical stimuli was reduced at all three sites, with the largest reduction at the HFS site. Nevertheless, electrical stimuli delivered to the skin next to the HFS site were perceived as more intense than control stimuli. This result indicates that higher pain ratings to electrical stimuli after HFS at the HFS site cannot solely be interpreted as a perceptual correlate of homosynaptic changes. Furthermore, we show for the first time, in humans, that HFS can reduce pain elicited by single electrical stimuli delivered through the same electrode.NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) of cutaneous nociceptors can reduce pain perception to single electrical stimuli delivered through the same electrode. Moreover, single electrical stimuli delivered to the skin next to the site at which HFS was applied are perceived as more intense compared with that at the contralateral control site, indicating the presence of heterosynaptic effects for electrical stimuli.

Rating the Intensity of a Laser Stimulus, but Not Attending to Changes in Its Location or Intensity Modulates the Laser-Evoked Cortical Activity.

Top-down attention towards nociceptive stimuli can be modulated by asking participants to pay attention to specific features of a stimulus, or to provide a rating about its intensity/unpleasantness. Whether and how these different top-down processes may lead to different modulations of the cortical response to nociceptive stimuli remains an open question. We recorded electroencephalographic (EEG) responses to brief nociceptive laser stimuli in 24 healthy participants while they performed a task in which they had to compare two subsequent stimuli on their Spatial location (Location task) or Intensity (Intensity Task). In two additional blocks (Location + Ratings, and Intensity + Ratings) participants had to further provide a rating of the perceived intensity of the stimulus. Such a design allowed us to investigate whether focusing on spatial or intensity features of a nociceptive stimulus and rating its intensity would exert different effects on the EEG responses. We did not find statistical evidence for an effect on the signal while participants were focusing on different features of the signal. We only observed a significant cluster difference in frontoparietal leads at approximately 300-500 ms post-stimulus between the magnitude of the signal in the Intensity and Intensity + Rating conditions, with a less negative response in the Intensity + Rating condition in frontal electrodes, and a less positive amplitude in parietal leads. We speculatively propose that activity in those electrodes and time window reflects magnitude estimation processes. Moreover, the smaller frontal amplitude in the Intensity + Rating condition can be explained by greater working memory engagement known to reduce the magnitude of the EEG signal. We conclude that different top-down attentional processes modulate responses to nociceptive laser stimuli at different electrodes and time windows depending on the underlying processes that are engaged.

Intense pain influences the cortical processing of visual stimuli projected onto the sensitized skin.

Sensitization is a form of implicit learning produced by the exposure to a harmful stimulus. In humans and other mammals, sensitization after skin injury increases the responsiveness of peripheral nociceptors and enhances the synaptic transmission of nociceptive input in the central nervous system. Here, we show that sensitization-related changes in the central nervous system are not restricted to nociceptive pathways and, instead, also affect other sensory modalities, especially if that modality conveys information relevant for the sensitized body part. Specifically, we show that after sensitizing the forearm using high-frequency electrical stimulation (HFS) of the skin, visual stimuli projected onto the sensitized forearm elicit significantly enhanced brain responses. Whereas mechanical hyperalgesia was present both 20 and 45 minutes after HFS, the enhanced responsiveness to visual stimuli was present only 20 minutes after HFS. Taken together, our results indicate that sensitization involves both nociceptive-specific and multimodal mechanisms, having distinct time courses.

Understanding the mechanisms through which spatial attention acts on nociception.

Previous studies have shown that spatial attention can influence the magnitude of brain responses to nociceptive inputs. In their recent article (Franz M, Nickel MM, Ritter A, Miltner WH, Weiss T. J Neurophysiol 113: 2760-2768, 2015), Franz and colleagues expand this observation by showing that spatial attention is further able to modify the chronometry of nociceptive processing by modulating the latency and temporal jitter of the recorded responses. The mechanisms through which attention could possibly modulate nociceptive processing are discussed here, with a particular focus on novel findings and future perspectives.

Are fibromyalgia patients cognitively impaired? Objective and subjective neuropsychological evidence.

OBJECTIVE: Patients with fibromyalgia (FM) syndrome often report a cluster of cognitive disorders that strongly interferes with their work and daily life, but the relationship between impaired cognitive function and self-reported dysfunction remains unclear. We aimed to investigate the presence of cognitive impairments in patients with FM and to analyze the relationship between the impairments and their evaluation by the patients through a comparison with a group of healthy controls. METHODS: In total, 30 FM patients and 30 healthy controls performed a neuropsychological and clinical evaluation of short-term, long-term, and working memory; executive function; and self-evaluation of cognitive impairment and depressive and anxiety symptoms. To thoroughly investigate executive function, we adopted the Miyake model that identifies 4 domains: shifting, inhibition, updating, and access. RESULTS: Our results confirmed the presence of impairments of attention, long-term memory, working memory, and shifting and updating executive functions in FM patients compared with healthy controls. These impairments are reflected in patient reports independently of depressive symptoms. CONCLUSION: The use of a self-reported questionnaire in clinical practice would provide a first and easy screen for the presence of cognitive impairment in FM patients and, in most cases, obviate the need for a time-consuming full neuropsychological test battery.

Gray matter alterations in chronic pain: A network-oriented meta-analytic approach.

Several studies have attempted to characterize morphological brain changes due to chronic pain. Although it has repeatedly been suggested that longstanding pain induces gray matter modifications, there is still some controversy surrounding the direction of the change (increase or decrease in gray matter) and the role of psychological and psychiatric comorbidities. In this study, we propose a novel, network-oriented, meta-analytic approach to characterize morphological changes in chronic pain. We used network decomposition to investigate whether different kinds of chronic pain are associated with a common or specific set of altered networks. Representational similarity techniques, network decomposition and model-based clustering were employed: i) to verify the presence of a core set of brain areas commonly modified by chronic pain; ii) to investigate the involvement of these areas in a large-scale network perspective; iii) to study the relationship between altered networks and; iv) to find out whether chronic pain targets clusters of areas. Our results showed that chronic pain causes both core and pathology-specific gray matter alterations in large-scale networks. Common alterations were observed in the prefrontal regions, in the anterior insula, cingulate cortex, basal ganglia, thalamus, periaqueductal gray, post- and pre-central gyri and inferior parietal lobule. We observed that the salience and attentional networks were targeted in a very similar way by different chronic pain pathologies. Conversely, alterations in the sensorimotor and attention circuits were differentially targeted by chronic pain pathologies. Moreover, model-based clustering revealed that chronic pain, in line with some neurodegenerative diseases, selectively targets some large-scale brain networks. Altogether these findings indicate that chronic pain can be better conceived and studied in a network perspective.

Beyond the "Pain Matrix," inter-run synchronization during mechanical nociceptive stimulation.

Pain is a complex experience that is thought to emerge from the activity of multiple brain areas, some of which are inconsistently detected using traditional fMRI analysis. One hypothesis is that the traditional analysis of pain-related cerebral responses, by relying on the correlation of a predictor and the canonical hemodynamic response function (HRF)- the general linear model (GLM)- may under-detect the activity of those areas involved in stimulus processing that do not present a canonical HRF. In this study, we employed an innovative data-driven processing approach- an inter-run synchronization (IRS) analysis- that has the advantage of not establishing any pre-determined predictor definition. With this method we were able to evidence the involvement of several brain regions that are not usually found when using predictor-based analysis. These areas are synchronized during the administration of mechanical punctate stimuli and are characterized by a BOLD response different from the canonical HRF. This finding opens to new approaches in the study of pain imaging.

Massive modulation of brain areas after mechanical pain stimulation: a time-resolved FMRI study.

To date, relatively little is known about the spatiotemporal aspects of whole-brain blood oxygenation level-dependent (BOLD) responses to brief nociceptive stimuli. It is known that the majority of brain areas show a stimulus-locked response, whereas only some are characterized by a canonical hemodynamic response function. Here, we investigated the time course of brain activations in response to mechanical pain stimulation applied to participants' hands while they were undergoing functional magnetic resonance imaging (fMRI) scanning. To avoid any assumption about the shape of BOLD response, we used an unsupervised data-driven method to group voxels sharing a time course similar to the BOLD response to the stimulus and found that whole-brain BOLD responses to painful mechanical stimuli elicit massive activation of stimulus-locked brain areas. This pattern of activations can be segregated into 5 clusters, each with a typical temporal profile. In conclusion, we show that an extensive activity of multiple networks is engaged at different time latencies after presentation of a noxious stimulus. These findings aim to motivate research on a controversial topic, such as the temporal profile of BOLD responses, the variability of these response profiles, and the interaction between the stimulus-related BOLD response and ongoing fluctuations in large-scale brain networks.

Theta burst stimulation applied over primary motor and somatosensory cortices produces analgesia unrelated to the changes in nociceptive event-related potentials.

Continuous theta burst stimulation (cTBS) applied over the primary motor cortex (M1) can alleviate pain although the neural basis of this effect remains largely unknown. Besides, the primary somatosensory cortex (S1) is thought to play a pivotal role in the sensori-discriminative aspects of pain perception but the analgesic effect of cTBS applied over S1 remains controversial. To investigate cTBS-induced analgesia we characterized, in two separate experiments, the effect of cTBS applied either over M1 or S1 on the event-related brain potentials (ERPs) and perception elicited by nociceptive (CO2 laser stimulation) and non-nociceptive (transcutaneous electrical stimulation) somatosensory stimuli. All stimuli were delivered to the ipsilateral and contralateral hand. We found that both cTBS applied over M1 and cTBS applied over S1 significantly reduced the percept elicited by nociceptive stimuli delivered to the contralateral hand as compared to similar stimulation of the ipsilateral hand. In contrast, cTBS did not modulate the perception of non-nociceptive stimuli. Surprisingly, this side-dependent analgesic effect of cTBS was not reflected in the amplitude modulation of nociceptive ERPs. Indeed, both nociceptive (N160, N240 and P360 waves) and late-latency non-nociceptive (N140 and P200 waves) ERPs elicited by stimulation of the contralateral and ipsilateral hands were similarly reduced after cTBS, suggesting an unspecific effect, possibly due to habituation or reduced alertness. In conclusion, cTBS applied over M1 and S1 reduces similarly the perception of nociceptive inputs originating from the contralateral hand, but this analgesic effect is not reflected in the magnitude of nociceptive ERPs.

Parcellation of the cingulate cortex at rest and during tasks: a meta-analytic clustering and experimental study.

Anatomical, morphological, and histological data have consistently shown that the cingulate cortex can be divided into four main regions. However, less is known about parcellations of the cingulate cortex when involved in active tasks. Here, we aimed at comparing how the pattern of clusterization of the cingulate cortex changes across different levels of task complexity. We parcellated the cingulate cortex using the results of a meta-analytic study and of three experimental studies. The experimental studies, which included two active tasks and a resting state protocol, were used to control the results obtained with the meta-analytic parcellation. We explored the meta-analytic parcellation by applying a meta-analytic clustering (MaC) to papers retrieved from the BrainMap database. The MaC is a meta-analytic connectivity driven parcellation technique recently developed by our group which allowed us to parcellate the cingulate cortex on the basis of its pattern of co-activations during active tasks. The MaC results indicated that the cingulate cortex can be parcellated into three clusters. These clusters covered different percentages of the cingulate parenchyma and had a different density of foci, with the first cluster being more densely connected. The control experiments showed different clusterization results, suggesting that the co-activations of the cingulate cortex are highly dependent on the task that is tested. Our results highlight the importance of the cingulate cortex as a hub, which modifies its pattern of co-activations depending on the task requests and on the level of task complexity. The neurobiological meaning of these results is discussed.

Functional anatomy of cortical areas characterized by Von Economo neurons.

Von Economo's neurons (VENs) are large, bipolar or corkscrew-shaped neurons located in layers III and V of the frontoinsular and the anterior cingulate cortices. VENs are reported to be altered in pathologies such as frontotemporal dementia and autism, in which the individual's self control is seriously compromised. To investigate the role of VENs in the active human brain, we have explored the functional connectivity of brain areas containing VENs by analyzing resting state functional connectivity (rsFC) in 20 healthy volunteers. Our results show that cortical areas containing VENs form a network of frontoparietal functional connectivity. With the use of fuzzy clustering techniques, we find that this network comprises four sub-networks: the first network cluster resembles a "saliency detection" attentional network, which includes superior frontal cortex (Brodmann's Area, BA 10), inferior parietal lobe, anterior insula, and dorsal anterior cingulate cortex; the second cluster, part of a "sensory-motor network", comprises the superior temporal, precentral and postcentral areas; the third cluster consists of frontal ventromedial and ventrodorsal areas constituted by parts of the "anterior default mode network"; and the fourth cluster encompasses dorsal anterior cingulate cortex, dorsomedial prefrontal, and superior frontal (BA 10) areas, resembling the anterior part of the "dorsal attentional network". Thus, the network that emerges from analyzing functional connectivity among areas that are known to contain VENs is primarily involved in functions of saliency detection and self-regulation. In addition, parts of this network constitute sub-networks that partially overlap with the default mode, the sensory-motor and the dorsal attentional networks.

Impulsivities and Parkinson's disease: delay aversion is not worsened by Deep Brain Stimulation of the subthalamic nucleus.

Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN) improves motor symptoms in Parkinson's disease (PD), but can exert detrimental effects on impulsivity. These effects are especially related to the inability to slow down when high-conflict choices have to be made. However, the influence that DBS has on delay aversion is still under-investigated. Here, we tested a group of 21 PD patients on and off stimulation (off medication) by using the Cambridge Gamble Task (CGT), a computerized task that allows the investigation of risk-related behaviours and delay aversion, and psychological questionnaires such as the Barratt Impulsiveness Scale (BIS), the Sensitivity to Punishment and to Reward Questionnaire (SPSRQ), and the Quick Delay Questionnaire (QDQ). We found that delay aversion scores on the CGT were no higher when patients were on stimulation as compared to when they were off stimulation. In contrast, PD patients reported feeling more impulsive in the off stimulation state, as revealed by significantly higher scores on the BIS. Higher scores on the sensitivity to punishment subscale of the SPSRQ highlighted that possible punishments influence patients' behaviours more than possible rewards. Significant correlations between delay aversion scores on the CGT and QDQ delay aversion subscale suggest that these two instruments can be used in synergy to reach a convergent validity. In conclusion, our results show that not all impulsivities are detrimentally affected by DBS of the STN and that the joint use of experimental paradigms and psychological questionnaires can provide useful insights in the study of impulsivity.

Shared "core" areas between the pain and other task-related networks.

The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been challenged. Alternative views now propose that the activity of the primary and secondary somatosensory cortices (SI, SII), the insula and cingulate cortex may be related to a basic defensive system through which significant potentially dangerous events for the body's integrity are detected. By reviewing the role of the SI, SII, the cingulate and the insular cortices in the perception of nociceptive and tactile stimuli, in attentional, emotional and reward tasks, and in interoception and memory, we found that all these task-related networks overlap in the dorsal anterior cingulate cortex, the anterior insula and the dorsal medial thalamus. A thorough analysis revealed that the 'pain-related' network shares important functional similarities with both somatomotor-somatosensory networks and emotional-interoceptive ones. We suggest that these shared areas constitute the central part of an adaptive control system involved in the processing and integration of salient information coming both from external and internal sources. These areas are activated in almost all fMRI tasks and have been indicated to play a pivotal role in switching between externally directed and internally directed brain networks.

Meta-analytic clustering of the insular cortex: characterizing the meta-analytic connectivity of the insula when involved in active tasks.

The human insula has been parcellated on the basis of resting state functional connectivity and diffusion tensor imaging. Little is known about the organization of the insula when involved in active tasks. We explored this issue using a novel meta-analytic clustering approach. We queried the BrainMap database asking for papers involving normal subjects that recorded activations in the insular cortex, retrieving 1305 papers, involving 22,872 subjects and a total of 2957 foci. Data were analyzed with several different methodologies, some of which expressly designed for this work. We used meta-analytic connectivity modeling and meta-analytic clustering of data obtained from the BrainMap database. We performed cluster analysis to subdivide the insula in areas with homogeneous connectivity, and density analysis of the activated foci using Voronoi tessellation. Our results confirm and extend previous findings obtained investigating the resting state connectivity of the anterior-posterior and left-right insulae. They indicate, for the first time, that some blocks of the anterior insula play the role of hubs between the anterior and the posterior insulae, as confirmed by their activation in several different paradigms. This finding supports the view that the network to which the anterior insula belongs is related to saliency detection. The insulae of both sides can be parcellated in two clusters, the anterior and the posterior: the anterior is characterized by an attentional pattern of connectivity with frontal, cingulate, parietal, cerebellar and anterior insular highly connected areas, whereas the posterior is characterized by a more local connectivity pattern with connections to sensorimotor, temporal and posterior cingulate areas. This antero-posterior subdivision, better characterized on the right side, results sharper with the connectivity based clusterization than with the behavioral based clusterization. The circuits belonging to the anterior insula are very homogeneous and their blocks in multidimensional scaling of MACM-based profiles are in central position, whereas those belonging to the posterior insula, especially on the left, are located at the periphery and sparse, thus suggesting that the posterior circuits bear a more heterogeneous connectivity. The anterior cluster is mostly activated by cognition, whereas the posterior is mostly activated by interoception, perception and emotion.

Unawareness of deficits in Alzheimer's disease: role of the cingulate cortex.

Unawareness of deficits is a symptom of Alzheimer's disease that can be observed even in the early stages of the disease. The frontal hypoperfusion associated with reduced awareness of deficits has led to suggestions of the existence of a hypofunctioning prefrontal pathway involving the right dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate gyri and limbic structures. Since this network plays an important role in response inhibition competence and patients with Alzheimer's disease who are unaware of their deficits exhibit impaired performance in response inhibition tasks, we predicted a relationship between unawareness of deficits and cingulate hypofunctionality. We tested this hypothesis in a sample of 29 patients with Alzheimer's disease (15 aware and 14 unaware of their disturbances), rating unawareness according to the Awareness of Deficit Questionnaire-Dementia scale. The cognitive domain was investigated by means of a wide battery including tests on executive functioning, memory and language. Neuropsychiatric aspects were investigated using batteries on behavioural mood changes, such as apathy and disinhibition. Cingulate functionality was assessed with functional magnetic resonance imaging, while patients performed a go/no-go task. In accordance with our hypotheses, unaware patients showed reduced task-sensitive activity in the right anterior cingulate area (Brodmann area 24) and in the rostral prefrontal cortex (Brodmann area 10). Unaware patients also showed reduced activity in the right post-central gyrus (Brodmann area 2), in the associative cortical areas such as the right parietotemporal-occipital junction (Brodmann area 39) and the left temporal gyrus (Brodmann areas 21 and 38), in the striatum and in the cerebellum. These findings suggest that the unawareness of deficits in early Alzheimer's disease is associated with reduced functional recruitment of the cingulofrontal and parietotemporal regions. Furthermore, in line with previous findings, we also found apathy and disinhibition to be prominent features of the first behavioural changes in unaware patients.

Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus modality.

The repetition of nociceptive stimuli of identical modality, intensity, and location at short and constant interstimulus intervals (ISIs) determines a strong habituation of the corresponding EEG responses, without affecting the subjective perception of pain. To understand what determines this response habituation, we (i) examined the effect of introducing a change in the modality of the repeated stimulus, and (ii) dissected the relative contribution of bottom-up, stimulus-driven changes in modality and top-down, cognitive expectations of such a change, on both laser-evoked and auditory-evoked EEG responses. Multichannel EEG was recorded while participants received trains of three stimuli (S1-S2-S3, a triplet) delivered to the hand dorsum at 1-sec ISI. S3 belonged either to the same modality as S1 and S2 or to the other modality. In addition, participants were either explicitly informed or not informed of the modality of S3. We found that introducing a change in stimulus modality produced a significant dishabituation of the laser-evoked N1, N2, and P2 waves; the auditory N1 and P2 waves; and the laser- and auditory-induced event-related synchronization and desynchronization. In contrast, the lack of explicit knowledge of a possible change in the sensory modality of the stimulus (i.e., uncertainty) only increased the ascending portion of the laser-evoked and auditory-evoked P2 wave. Altogether, these results indicate that bottom-up novelty resulting from the change of stimulus modality, and not top-down cognitive expectations, plays a major role in determining the habituation of these brain responses.

Reward pathways in Parkinson's disease: clinical and theoretical implications.

AIMS: The mesolimbic and mesocortical circuits are particularly involved in reward-related behavior in humans. Because these systems may be in some way altered in Parkinson's disease (PD), it is likely that some psychiatric manifestations of PD, such as hedonistic homeostatic dysregulation and pathological gambling, as well as impulsive decision making, may be ascribed to their involvement. The aim of the current article was to review recent literature on this topic in order to analyze whether these disturbances share a common ground and whether actual theoretical frameworks on addiction prove a useful tool for their interpretation. METHODS: Data were identified on searches of MEDLINE/PubMed databases from relevant articles published up until March 2007. RESULTS: All clinical manifestations (hedonistic homeostatic dysregulation, pathological gambling and impulsive decision making) seem to share a common multifaceted ground in which factors related to antiparkinsonian therapy, premorbid personality and progression of disease interact. Theoretical interpretations and conclusions drawn from experimental studies may help to shed light on the underlying pathological mechanisms. CONCLUSIONS: Further studies are needed to analyze why, despite a common ground, only some patients develop those neuropsychiatric complications described here.