Vigilance to Painful Laser Stimuli is Associated with Increased State Anxiety and Tense Arousal.

Introduction: Pain is frequently accompanied by enhanced arousal and hypervigilance to painful sensations. Here, we describe our findings in an experimental vigilance task requiring healthy participants to indicate when randomly timed moderately painful stimuli occur in a long train of mildly painful stimuli. Methods: During a continuous performance task with painful laser stimuli (CPTpain), 18 participants rated pain intensity, unpleasantness, and salience. We tested for a vigilance decrement over time using classical metrics including correct targets (hits), incorrectly identified non-targets (false alarms), hit reaction time, and false alarm reaction time. We measured state anxiety and tense arousal before and after the task. Results: We found a vigilance decrement across four 12.5-minute blocks of painful laser stimuli in hits [F3,51=2.91; p=0.043; time block 1>block 4 (t=2.77; p=0.035)]. Both self-report state anxiety (tpaired,17=3.34; p=0.0039) and tense arousal (tpaired,17=3.20; p=0.0053) increased after the task. We found a vigilance decrement during our laser pain vigilance task consistent with vigilance decrements found in other stimulus modalities. Furthermore, state anxiety positively correlated with tense arousal. Discussion: CPTpain acutely increased tense arousal and state anxiety, consistent with previous results implicating the reciprocal interaction of state anxiety and acute painful sensations and the role of pain in augmenting tense arousal. These results may indicate a psychological process which predisposes the hypervigilant to developing greater acute pain, resulting in positive feedback, greater pain and anxiety.

Behavioral, Physiological and EEG Activities Associated with Conditioned Fear as Sensors for Fear and Anxiety.

Anxiety disorders impose substantial costs upon public health and productivity in the USA and worldwide. At present, these conditions are quantified by self-report questionnaires that only apply to behaviors that are accessible to consciousness, or by the timing of responses to fear- and anxiety-related words that are indirect since they do not produce fear, e.g., Dot Probe Test and emotional Stroop. We now review the conditioned responses (CRs) to fear produced by a neutral stimulus (conditioned stimulus CS+) when it cues a painful laser unconditioned stimulus (US). These CRs include autonomic (Skin Conductance Response) and ratings of the CS+ unpleasantness, ability to command attention, and the recognition of the association of CS+ with US (expectancy). These CRs are directly related to fear, and some measure behaviors that are minimally accessible to consciousness e.g., economic scales. Fear-related CRs include non-phase-locked phase changes in oscillatory EEG power defined by frequency and time post-stimulus over baseline, and changes in phase-locked visual and laser evoked responses both of which include late potentials reflecting attention or expectancy, like the P300, or contingent negative variation. Increases (ERS) and decreases (ERD) in oscillatory power post-stimulus may be generalizable given their consistency across healthy subjects. ERS and ERD are related to the ratings above as well as to anxious personalities and clinical anxiety and can resolve activity over short time intervals like those for some moods and emotions. These results could be incorporated into an objective instrumented test that measures EEG and CRs of autonomic activity and psychological ratings related to conditioned fear, some of which are subliminal. As in the case of instrumented tests of vigilance, these results could be useful for the direct, objective measurement of multiple aspects of the risk, diagnosis, and monitoring of therapies for anxiety disorders and anxious personalities.

Missed targets, reaction times, and arousal are related to trait anxiety and attention to pain during an experimental vigilance task with a painful target.

Although hypervigilance may play a role in some clinical pain syndromes, experimental vigilance toward painful stimuli has been studied infrequently. We evaluated vigilance toward pain by using a continuous performance task (CPT), in which subjects responded to moderately intense painful target stimuli, occurring in a train of mildly painful nontargets. We assessed nondetected targets (misses), reaction times (RTs), and psychological activation (tense arousal). During time on task in CPTs of other sensory modalities, there is an increase in misses and RTs (vigilance decrement). We hypothesized that our CPT would influence vigilance performance related to pain, anxiety, and limitation of attentional resources. The results showed a decrement in vigilance over time as misses increased, although RTs were unchanged. While mind-wandering did not influence vigilance performance, intrinsic attention to pain drove both hit RTs and number of misses. This resulted in pain-focused subjects performing worse on the CPT pain task with slower RTs and more misses per block. During the CPT, the change in stimulus salience was related to the change in pain intensity, while pain unpleasantness correlated with tense arousal. CPT performance during experimental vigilance to pain and psychological activation were related to trait anxiety, as measured by the Spielberger State-Trait Anxiety Inventory and neuroticism, as measured by the NEO five factor inventory. Trait anxiety and neuroticism may play important roles in an individual's predisposition to dwell on pain and interpret pain as threatening.NEW & NOTEWORTHY Subjects detected moderately painful target stimuli in a train of mildly painful nontarget stimuli, which resulted in vigilance performance metrics including missed targets, reaction times, and psychological activation. These performance metrics were related to intrinsic attention to pain and trait anxiety. Subjects with high trait anxiety and neuroticism scores, with a predisposition to attend to pain, had greater tense arousal and poorer vigilance performance, which may be important psychological aspects of vigilance to pain.

Neural Correlates of Feedback Processing in Visuo-Tactile Crossmodal Paired-Associate Learning.

Previous studies have examined the neural correlates for crossmodal paired-associate (PA) memory and the temporal dynamics of its formation. However, the neural dynamics for feedback processing of crossmodal PA learning remain unclear. To examine this process, we recorded event-related scalp electrical potentials for PA learning of unimodal visual-visual pairs and crossmodal visual-tactile pairs when participants performed unimodal and crossmodal tasks. We examined event-related potentials (ERPs) after the onset of feedback in the tasks for three effects: feedback type (positive feedback vs. negative feedback), learning (as the learning progressed) and the task modality (crossmodal vs. unimodal). The results were as follows: (1) feedback type: the amplitude of P300 decreased with incorrect trials and the P400/N400 complex was only present in incorrect trials; (2) learning: progressive positive voltage shifts in frontal recording sites and negative voltage shifts in central and posterior recording sites were identified as learning proceeded; and (3) task modality: compared with the unimodal PA learning task, positive voltage shifts in frontal sites and negative voltage shifts in posterior sites were found in the crossmodal PA learning task. To sum up, these results shed light on cortical excitability related to feedback processing of crossmodal PA learning.

Neural correlates of visuo-tactile crossmodal paired-associate learning and memory in humans.

Studies have indicated that a cortical sensory system is capable of processing information from different sensory modalities. However, it still remains unclear when and how a cortical system integrates and retains information across sensory modalities during learning. Here we investigated the neural dynamics underlying crossmodal associations and memory by recording event-related potentials (ERPs) when human participants performed visuo-tactile (crossmodal) and visuo-visual (unimodal) paired-associate (PA) learning tasks. In a trial of the tasks, the participants were required to explore and learn the relationship (paired or non-paired) between two successive stimuli. EEG recordings revealed dynamic ERP changes during participants' learning of paired-associations. Specifically, (1) the frontal N400 component showed learning-related changes in both unimodal and crossmodal tasks but did not show any significant difference between these two tasks, while the central P400 displayed both learning changes and task differences; (2) a late posterior negative slow wave (LPN) showed the learning effect only in the crossmodal task; (3) alpha-band oscillations appeared to be involved in crossmodal working memory. Additional behavioral experiments suggested that these ERP components were not relevant to the participants' familiarity with stimuli per se. Further, by shortening the delay length (from 1300ms to 400ms or 200 ms) between the first and second stimulus in the crossmodal task, declines in participants' task performance were observed accordingly. Taken together, these results provide insights into the cortical plasticity (induced by PA learning) of neural networks involved in crossmodal associations in working memory.

Knowledge gaps and research recommendations for essential tremor.

Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families.

Transcranial magnetic stimulation of the brain: guidelines for pain treatment research.

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.

Differential roles of delay-period neural activity in the monkey dorsolateral prefrontal cortex in visual-haptic crossmodal working memory.

Previous studies have shown that neurons of monkey dorsolateral prefrontal cortex (DLPFC) integrate information across modalities and maintain it throughout the delay period of working-memory (WM) tasks. However, the mechanisms of this temporal integration in the DLPFC are still poorly understood. In the present study, to further elucidate the role of the DLPFC in crossmodal WM, we trained monkeys to perform visuo-haptic (VH) crossmodal and haptic-haptic (HH) unimodal WM tasks. The neuronal activity recorded in the DLPFC in the delay period of both tasks indicates that the early-delay differential activity probably is related to the encoding of sample information with different strengths depending on task modality, that the late-delay differential activity reflects the associated (modality-independent) action component of haptic choice in both tasks (that is, the anticipation of the behavioral choice and/or active recall and maintenance of sample information for subsequent action), and that the sustained whole-delay differential activity likely bridges and integrates the sensory and action components. In addition, the VH late-delay differential activity was significantly diminished when the haptic choice was not required. Taken together, the results show that, in addition to the whole-delay differential activity, DLPFC neurons also show early- and late-delay differential activities. These previously unidentified findings indicate that DLPFC is capable of (i) holding the coded sample information (e.g., visual or tactile information) in the early-delay activity, (ii) retrieving the abstract information (orientations) of the sample (whether the sample has been haptic or visual) and holding it in the late-delay activity, and (iii) preparing for behavioral choice acting on that abstract information.

Behavioral choice-related neuronal activity in monkey primary somatosensory cortex in a haptic delay task.

The neuronal activity in the primary somatosensory cortex was collected when monkeys performed a haptic-haptic DMS task. We found that, in trials with correct task performance, a substantial number of cells showed significant differential neural activity only when the monkeys had to make a choice between two different haptic objects. Such a difference in neural activity was significantly reduced in incorrect response trials. However, very few cells showed the choice-only differential neural activity in monkeys who performed a control task that was identical to the haptic-haptic task but did not require the animal to either actively memorize the sample or make a choice between two objects at the end of a trial. From these results, we infer that the differential activity recorded from cells in the primary somatosensory cortex in correct performance reflects the neural process of behavioral choice, and therefore, it is a neural correlate of decision-making when the animal has to make a haptic choice.

Persistent neuronal firing in primary somatosensory cortex in the absence of working memory of trial-specific features of the sample stimuli in a haptic working memory task.

Previous studies suggested that primary somatosensory (SI) neurons in well-trained monkeys participated in the haptic-haptic unimodal delayed matching-to-sample (DMS) task. In this study, 585 SI neurons were recorded in monkeys performing a task that was identical to that in the previous studies but without requiring discrimination and active memorization of specific features of a tactile or visual memorandum. A substantial number of those cells significantly changed their firing rate in the delay compared with the baseline, and some of them showed differential delay activity. These firing changes are similar to those recorded from monkeys engaged in active (working) memory. We conclude that the delay activity is not necessarily only observed as was generally thought in the situation of active memorization of different features between memoranda after those features have been actively discriminated. The delay activity observed in this study appears to be an intrinsic property of SI neurons and suggests that there exists a neural network in SI (the primary sensory cortex) for haptic working memory no matter whether the difference in features of memoranda needs to be memorized in the task or not. Over 400 SI neurons were also recorded in monkeys well-trained to discriminate two memoranda in the haptic-haptic DMS task for comparison of delay firing of SI neurons between the two different working memory tasks used in this study. The similarity observed in those two situations suggests that working memory uses already-existing memory apparatus by activating it temporarily. Our data also suggest that, through training (repetitive exposure to the stimulus), SI neurons may increase their involvement in the working memory of the memorandum.

Dipole source analyses of laser evoked potentials obtained from subdural grid recordings from primary somatic sensory cortex.

The cortical potentials evoked by cutaneous application of a laser stimulus (laser evoked potentials, LEP) often include potentials in the primary somatic sensory cortex (S1), which may be located within the subdivisions of S1 including Brodmann areas 3A, 3B, 1, and 2. The precise location of the LEP generator may clarify the pattern of activation of human S1 by painful stimuli. We now test the hypothesis that the generators of the LEP are located in human Brodmann area 1 or 3A within S1. Local field potential (LFP) source analysis of the LEP was obtained from subdural grids over sensorimotor cortex in two patients undergoing epilepsy surgery. The relationship of LEP dipoles was compared with dipoles for somatic sensory potentials evoked by median nerve stimulation (SEP) and recorded in area 3B (see Baumgärtner U, Vogel H, Ohara S, Treede RD, Lenz FA. J Neurophysiol 104: 3029-3041, 2010). Both patients had an early radial dipole in S1. The LEP dipole was located medial, anterior, and deep to the SEP dipole, which suggests a nociceptive dipole in area 3A. One patient had a later tangential dipole with positivity posterior, which is opposite to the orientation of the SEP dipole in area 3B. The reversal of orientations between modalities is consistent with the cortical surface negative orientation resulting from superficial termination of thalamocortical neurons that receive inputs from the spinothalamic tract. Therefore, the present results suggest that the LEP may result in a radial dipole consistent with a generator in area 3A and a putative later tangential generator in area 3B.

Dipole source analyses of early median nerve SEP components obtained from subdural grid recordings.

The median nerve N20 and P22 SEP components constitute the initial response of the primary somatosensory cortex to somatosensory stimulation of the upper extremity. Knowledge of the underlying generators is important both for basic understanding of the initial sequence of cortical activation and to identify landmarks for eloquent areas to spare in resection planning of cortex in epilepsy surgery. We now set out to localize the N20 and P22 using subdural grid recording with special emphasis on the question of the origin of P22: Brodmann area 4 versus area 1. Electroencephalographic dipole source analysis of the N20 and P22 responses obtained from subdural grids over the primary somatosensory cortex after median nerve stimulation was performed in four patients undergoing epilepsy surgery. Based on anatomical landmarks, equivalent current dipoles of N20 and P22 were localized posterior to (n = 2) or on the central sulcus (n = 2). In three patients, the P22 dipole was located posterior to the N20 dipole, whereas in one patient, the P22 dipole was located on the same coordinate in anterior-posterior direction. On average, P22 sources were found to be 6.6 mm posterior [and 1 mm more superficial] compared with the N20 sources. These data strongly suggest a postcentral origin of the P22 SEP component in Brodmann area 1 and render a major precentral contribution to the earliest stages of processing from the primary motor cortex less likely.

Prefrontal cortex and somatosensory cortex in tactile crossmodal association: an independent component analysis of ERP recordings.

Our previous studies on scalp-recorded event-related potentials (ERPs) showed that somatosensory N140 evoked by a tactile vibration in working memory tasks was enhanced when human subjects expected a coming visual stimulus that had been paired with the tactile stimulus. The results suggested that such enhancement represented the cortical activities involved in tactile-visual crossmodal association. In the present study, we further hypothesized that the enhancement represented the neural activities in somatosensory and frontal cortices in the crossmodal association. By applying independent component analysis (ICA) to the ERP data, we found independent components (ICs) located in the medial prefrontal cortex (around the anterior cingulate cortex, ACC) and the primary somatosensory cortex (SI). The activity represented by the IC in SI cortex showed enhancement in expectation of the visual stimulus. Such differential activity thus suggested the participation of SI cortex in the task-related crossmodal association. Further, the coherence analysis and the Granger causality spectral analysis of the ICs showed that SI cortex appeared to cooperate with ACC in attention and perception of the tactile stimulus in crossmodal association. The results of our study support with new evidence an important idea in cortical neurophysiology: higher cognitive operations develop from the modality-specific sensory cortices (in the present study, SI cortex) that are involved in sensation and perception of various stimuli.

Statistical modeling and analysis of laser-evoked potentials of electrocorticogram recordings from awake humans.

This article is devoted to statistical modeling and analysis of electrocorticogram (ECoG) signals induced by painful cutaneous laser stimuli, which were recorded from implanted electrodes in awake humans. Specifically, with statistical tools of factor analysis and independent component analysis, the pain-induced laser-evoked potentials (LEPs) were extracted and investigated under different controlled conditions. With the help of wavelet analysis, quantitative and qualitative analyses were conducted regarding the LEPs' attributes of power, amplitude, and latency, in both averaging and single-trial experiments. Statistical hypothesis tests were also applied in various experimental setups. Experimental results reported herein also confirm previous findings in the neurophysiology literature. In addition, single-trial analysis has also revealed many new observations that might be interesting to the neuroscientists or clinical neurophysiologists. These promising results show convincing validation that advanced signal processing and statistical analysis may open new avenues for future studies of such ECoG or other relevant biomedical recordings.

Pain encoding in the human forebrain: binary and analog exteroceptive channels.

The neuronal system signaling pain has often been characterized as a labeled line consisting of neurons in the pain-signaling pathway to the brain [spinothalamic tract (STT)] that respond only to painful stimuli. It has been proposed recently that the STT contains a series of analog labeled lines, each signaling a different aspect of the internal state of the body (interoception) (e.g., visceral-cold-itch sensations). In this view, pain is the unpleasant emotion produced by disequilibrium of the internal state. We now show that stimulation of an STT receiving zone in awake humans (66 patients) produces two different responses. The first is a binary response signaling the presence of painful stimuli. The second is an analog response in which nonpainful and painful sensations are graded with intensity of the stimulus. Compared with the second pathway, the first was characterized by higher pain ratings and stimulus-evoked sensations covering more of the body surface (projected fields). Both painful responses to stimulation were described in terms usually applied to external stimuli (exteroception) rather than to internal or emotional phenomena, which were infrequently evoked by stimulation of either pathway. These results are consistent with those of functional imaging studies that have identified brain regions activated in a binary manner by the application of a specific, painful stimulus while increases in stimulus intensity do not produce increased activation. Such binary pain functions could be involved in pain-related alarm-alerting functions, which are independent of stimulus amplitude.

Attention to pain is processed at multiple cortical sites in man.

Painful cutaneous laser stimuli evoked potentials (LEPs) were recorded over the primary somatosensory (SI), parasylvian, and medial frontal (MF) cortex areas in a patient with subdural electrode grids located over these areas for surgical treatment of epilepsy. The amplitudes of the negative (N2*) and positive (P2**) LEP peaks over SI, parasylvian, and MF cortex were enhanced by attention to (counting stimuli), in comparison with distraction from the stimulus (reading for comprehension). Late positive deflections following the P2** peak (late potential-LP) were recorded over MF and from the lateral premotor regions during attention but not during distraction. These findings suggest that attention gates both early (N2*) and late (P2**) pain-related input to SI, parasylvian, and MF cortical regions while the later components (LP) are specifically related to attention.

Microstimulation in the region of the human thalamic principal somatic sensory nucleus evokes sensations like those of mechanical stimulation and movement.

We explored the region of human thalamic somatic sensory nucleus (ventral caudal, Vc), corresponding to monkey ventral posterior (VP), with threshold microstimulation (TMIS) during stereotactic procedures for the treatment of tremor. Of 122 sites in 116 patients (124 thalami) where mechanical (touch, pressure, and sharp) or movement [movement through the body (movement) and vibration] sensations were evoked, 72 sites were found in the core or in adjacent regions, posterior-inferior (33), inferior (4), and posterior to the core (13). Sites where TMIS evoked touch were less frequently found in the core than those where movement or pressure sensations were evoked. Pressure was more commonly (P < 0.05) evoked than vibration at sites where cells had intraoral receptive fields (RFs). Touch and vibration were more commonly (P < 0.05) evoked than pressure at sites where cells had facial RFs, consistent with the relative density of rapidly adapting (RA) receptors in the mouth and face. Sites described as deep and movement were found superior and anterior in the core, consistent with the location of cells responding to stimulation of muscle afferents. At 72 of 122 sites, TMIS evoked the same sensation at two or more sites in the same plane. Of these sites, 58 are adjacent to each other, in a cluster, consistent with studies of the localization of cells responding to different modalities. These results demonstrate that mechanical and movement sensations can be evoked by stimulation in the region of Vc. The characteristics of these sites suggest that the sensations are evoked by stimulation of pathways specific to cutaneous and deep mechanoreceptors.

Medial lateral extent of thermal and pain sensations evoked by microstimulation in somatic sensory nuclei of human thalamus.

We explored the region of human thalamic somatic sensory nucleus (ventral caudal, Vc) with threshold microstimulation during stereotactic procedures for the treatment of tremor (124 thalami, 116 patients). Warm sensations were evoked more frequently in the posterior region than in the core. Proportion of sites where microstimulation evoked cool and pain sensations was not different between the core and the posterior region. In the core, sites where both thermal and pain sensations were evoked were distributed similarly in the medial two planes and the lateral plane. In the posterior region, however, warm sensations were evoked more frequently in the lateral plane (10.8%) than in the medial planes (3.9%). No mediolateral difference was found for sites where pain and cool sensations were evoked. The presence of sites where stimulation evoked taste or where receptive and projected fields were located on the pharynx were used as landmarks of a plane located as medial as the posterior part of the ventral medial nucleus (VMpo). Microstimulation in this plane evoked cool, warm, and pain sensations. The results suggest that thermal and pain sensations are processed in the region of Vc as far medial as VMpo. Thermal and pain sensations seem to be mediated by neural elements in a region likely including the core of Vc, VMpo, and other nuclei posterior and inferior to Vc.