Transient Stimuli Research Articles

NIMG-23. A NOVEL APPROACH TO PERFUSION MRI STUDIES IN BRAIN TUMOR PATIENTS USING ENDOGENOUS DEOXYHEMOGLOBIN AS A CONTRAST AGENT: A PROOF-OF-CONCEPT STUDY

Abstract BACKGROUND Assessment of resting perfusion in brain tumors is clinically relevant and relies on dynamic susceptibility contrast magnetic resonance imaging using gadolinium contrast. Preliminary studies have introduced the use of controlled hemoglobin desaturation by means of a transient hypoxic stimulus during echo-planar imaging(EPI) as a surrogate for gadolinium for resting perfusion assessment in healthy subjects. In this proof of concept study, we investigated whether this approach is feasible in brain tumors and warrant further validation. METHODS A computer controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during EPI acquisition in a heterogenous cohort of tumor patients. The induced blood-oxygen-level-dependent(BOLD) signal changes determined by transit of a bolus of deoxygenated blood in the brain vasculature were used as a surrogate of gadolinium to calculate cerebral blood volume(CBV), cerebral blood flow(CBF) and mean transit time(MTT) using a global arterial input functions obtained through the BOLD signal measured over the middle cerebral artery as previously described by Poublanc et al. Perfusion parameters were calculated in the whole-brain voxel-by-voxel and in automatically segmented region of interest(ROI) using SPM, AFNI, Verbena softwares and MATLAB in-house written scripts. RESULTS Nine patients were included. MTT, rCBV, rCBF were calculated voxel-per-voxel. Obtained maps were overlayed on the co-registered T1 MRI scans and compared to T1CE and FLAIR to identify perfusion patterns in tumor ROIs (contrast enhancement, edema, necrosis). The deoxy-hemoglobin BOLD MRI perfusion were compared to clinical DSC-MRI when available and showed high qualitative agreement. CONCLUSION Transient and precise hemoglobin desaturation by controlled hypoxic gas modulation is safe and repeatable in brain tumor patients. The induced BOLD signal change allows measurement of resting perfusion, which qualitatively closely mimic gadolinium perfusion in different brain tumors. Deoxyhemoglobin-based perfusion warrant further quantitative validation against gadolinium in a larger cohort of heterogenous tumor patients.

NIMG-26. GLIOBLASTOMA TISSUE INVASION MAPPING WITH NOVEL HYPOXIA-TARGETED BLOOD OXYGENATION-LEVEL DEPENDENT MRI

Abstract BACKGROUND Glioblastoma is a devastating incurable malignant primary brain tumor exhibiting an erratic growth pattern and brain tissue invasion exceeding the typically depicted contrast-enhancing lesion on MRI. This behaviour is strongly associated with the presence of aberrant vasculature. Advanced clinical neuroimaging techniques, however, have not provided convincing imaging markers to determine glioblastoma tissue infiltration and monitor treatment effects. We investigated a new imaging technique based on blood oxygenation-level dependent (BOLD) MRI contrast with precise hypoxic respiratory targeting in order to better determine tumor tissue invasion not restricted to the typically depicted focal glioblastoma lesion on contrast-enhanced MRI. METHODS A computer-controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during echo-planar-imaging acquisition in patients with brain tumors.8,9 Data were preprocessed using SPM and in-house written MATLAB scripts. The induced BOLD signal changes were used to calculate %BOLD signal change during hypoxic stimulus with respect to the baseline, contrast to noise (CNR) ratio and goodness-of-fit (Rsquared) for each voxel in the whole-brain and automatically segmented region of interest (contrast-enhancement, necrosis, edema) and overlayed using color-maps onto anatomical high resolution T1. RESULTS Hypoxic targeting during gas modulation could be performed with high reproducibility, caused no discomfort in patients with brain tumors and was able to induce strong signal change during hypoxic stimulus with high contrast-noise ratio and Rsquared. In particular, when compared with other tumors, BOLD hypoxia glioblastoma tissue invasion maps show very distinct hypoxic signal responses in some cases extending beyond the focal -contrast-enhancing- glioblastoma lesion. CONCLUSION The ability to map at voxel level BOLD hypoxia signal patterns may determine a novel therapeutic imaging marker based on structural vascular alterations in the tumour tissue infiltration zone before these become appreciable with standard neuroimaging. This may support a refinement and tailoring of tumor resection and improve follow-up after resection and during treatment i.e. chemoradiotherapy.

Five weeks of intermittent hand exposures to alternating cold and hot stimuli do not modify finger cold-induced vasodilatation response.

We tested the hypothesis that prolonged intermittent hand exposures to transient contrast thermal stimuli would enhance the finger cold-induced vasodilatation (CIVD) response during localized cooling. Eight healthy men participated in a 5-week regimen, during which they immersed, thrice per week, the non-dominant (EXP) hand in 8° and 43°C water, sequentially and at 3-min intervals, for a total period of 60min. The contralateral (i.e., dominant) hand served as the control (CON) hand. Before and after the regimen, subjects conducted two 30-min hand cold (8°C water) provocation trials, one with the EXP hand and the other with the CON hand. In addition, a flow-mediated dilatation test was performed in the brachial artery of the EXP arm. Regardless of the hand tested, the average finger skin temperature [CON hand: pre-trial=10.5 (1.2)°C, post-trial=10.8 (1.3)°C and EXP hand: pre-trial=10.7 (1.1)°C, post-trial 10.9 (1.1)°C; p=0.79], and the incidence of CIVD events [CON hand: pre-trial=1.1 (1.2) events, post-trial=1.2 (1.1) events and EXP hand: pre-trial=1.1 (0.8) events, post-trial=1.1 (0.8) events; p=0.88] were not affected by the 5-week regimen. The sensation of cold-induced pain was transiently alleviated following the regimen (p=0.02). The flow-mediated dilatation response of the EXP brachial artery remained unaltered [pre-trial=5.4 (3.2)%, post-trial=4.7 (3.6)%; p=0.51]. Therefore, five weeks of intermittent hand exposures to alternating cold and hot stimuli do not improve finger temperature responsiveness to sustained localized cold.

Neural mechanisms underlying placebo and nocebo effects in tonic muscle pain

Pain is a highly subjective and multidimensional experience, significantly influenced by various psychological factors. Placebo analgesia and nocebo hyperalgesia exemplify this influence, where inert treatments result in pain relief or exacerbation, respectively. While extensive research has elucidated the psychological and neural mechanisms behind these effects, most studies have focused on transient pain stimuli. To explore these mechanisms in the context of tonic pain, we conducted a study using a 15-minute tonic muscle pain induction procedure, where hypertonic saline was infused into the left masseter of healthy participants. We collected real-time Visual Analogue Scale (VAS) scores and functional magnetic resonance imaging (fMRI) data during the induction of placebo analgesia and nocebo hyperalgesia via conditioned learning. Our findings revealed that placebo analgesia was more pronounced and lasted longer than nocebo hyperalgesia. Real-time pain ratings correlated significantly with neural activity in several brain regions. Notably, the putamen was implicated in both effects, while the caudate and other regions were differentially involved in placebo and nocebo effects. These findings confirm that the tonic muscle pain paradigm can be used to investigate the mechanisms of placebo and nocebo effects and indicate that placebo analgesia and nocebo hyperalgesia may have more distinct than common neural bases.

Design of Thermoresponsive Genetic Controls with Minimal Heat-Shock Response.

As temperature serves as a versatile input signal, thermoresponsive genetic controls have gained significant interest for recombinant protein production and metabolic engineering applications. The conventional thermoresponsive systems normally require the continuous exposure of heat stimuli to trigger the prolonged expression of targeted genes, and the accompanied heat-shock response is detrimental to the bioproduction process. In this study, we present the design of thermoresponsive quorum-sensing (ThermoQS) circuits to make Escherichia coli record transient heat stimuli. By conversion of the heat input into the accumulation of quorum-sensing molecules such as acyl-homoserine lactone derived from Pseudomonas aeruginosa, sustained gene expressions were achieved by a minimal heat stimulus. Moreover, we also demonstrated that we reprogrammed the E. coli Lac operon to make it respond to heat stimuli with an impressive signal-to-noise ratio (S/N) of 15.3. Taken together, we envision that the ThermoQS systems reported in this study are expected to remarkably diminish both design and experimental expenditures for future metabolic engineering applications.

The vestigial pinna-orienting system in humans briefly suppresses superior auricular muscle activity during reflexive orienting toward auditory stimuli.

The vestigial pinna-orienting system in humans is capable of increasing the activity of several auricular muscles in response to lateralized transient auditory stimuli. For example, transient increases in electromyographic activity in the posterior auricular muscle (PAM) to an attention-capturing stimulus have been documented. For the current study, surface electromyograms (EMGs) were recorded from the PAMs and superior auricular muscles (SAMs) of 10 normal-hearing participants. During the experiments, lateralized transient auditory stimuli, such as a crying baby, a shattering vase, or the participant's first names, were presented. These transient stimuli were either presented in silence or when participants actively listened to a podcast. Although ipsilateral PAM activity increased in response to transient stimuli, the SAM displayed the opposite behavior, i.e., a brief, ipsilateral suppression of activity. This suppression of ipsilateral SAM activity was more frequent on the right (75%) than left side (35%), whereas an ipsilateral PAM increase was roughly equal in prevalence on the two sides (left: 90%, right: 95%). During the active listening task, SAM suppression on the right ear was significantly larger in response to ipsilateral stimuli, compared with contralateral ones (P = 0.002), whereas PAM activity increased significantly (P = 0.002). Overall, this study provides evidence of a systematic transient suppression of the SAM during exogenous attention. This could suggest a more complex system than previously assumed, as the presence of synchronized excitatory and inhibitory components in different auricular muscles points toward a coordinated attempt at reflexively orienting the pinna toward a sound.NEW & NOTEWORTHY This study provides evidence that two auricular muscles in humans, the posterior and superior auricular muscles (PAM, SAM), react fundamentally different to lateralized transient auditory stimuli, especially during active listening. Although the PAM reacts with a transient increase in ipsilateral activity, ongoing ipsilateral SAM activity is briefly suppressed at the same time. This indicates the presence of a more complex and nuanced pinna-orienting system, with synchronized excitatory and inhibitory components in humans, than previously suspected.

A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms.

Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions.

Endogenous Acetylcholine Contributes to Flow-Mediated Dilation in Humans

Background & Objective. Flow-mediated dilation (FMD) is a crucial function of the vascular endothelium wherein intraluminal shear stress stimulates endothelium-dependent vasodilation mediated primarily by nitric oxide. Brachial artery FMD (baFMD) is widely evaluated in clinical research as an index of endothelial function, and impaired baFMD is an independent predictor of cardiovascular risk. Despite the physiological and clinical relevance of FMD, the mechanisms by which shear stress is transduced to endothelium-dependent vasodilation (i.e., upstream of nitric oxide production) remain unclear. baFMD corresponds closely with sensitivity to the endothelium-dependent vasodilator acetylcholine (ACh), and preclinical models suggest ACh is released from endothelial cells in response to shear stress. Therefore, the present study tested the hypothesis that activation of muscarinic ACh receptors facilitates baFMD in humans. Methods. baFMD was evaluated using Doppler ultrasound in healthy participants (n=11; 5F/6M; 23±2 y; means ± SE) under control conditions and following local inhibition of muscarinic ACh receptors via intra-arterial atropine infused proximal to the measurement site. baFMD was assessed in response to transient and sustained shear stimuli in separate trials: 1) reactive hyperemia following 5 min of arterial cuff occlusion (RH-FMD) and 2) steady-state rhythmic handgrip exercise at graded intensities (10, 15, 20, & 25% maximal voluntary contraction, MVC) to produce step increases in shear rate (EX-FMD). Blockade effcacy was confirmed via a dose-response to intra-arterial ACh infusion pre and post atropine. Results. Baseline brachial artery diameter and forearm blood flow were similar in all trials (all P>0.05). Atropine reduced peak brachial artery dilation following cuff release (RH-FMD, Δ diameter, atropine: 4.6±0.8 vs. control: 6.5±0.8%, P=0.04) and increased the shear stimulus (shear rate area under the curve, SRAUC: atropine, 29±3 vs. control: 21±3 s−1×103, P=0.01) such that the percent change in brachial diameter was diminished by 35±16% when normalized to SRAUC (baFMD:SRAUC ratio, atropine: 1.7±0.3 vs. control: 3.9±1.0, P=0.02). Similarly, in the EX-FMD trial, atropine reduced brachial artery diameter at all exercise intensities (25% MVC, percent change in diameter: atropine, 10.8±1.4 vs. control, 15.5±1.7%, P=0.04) despite a greater shear stimulus (shear rate: atropine, 10.9±1.1 vs. control, 9.3±0.9 s−1×102, P=0.01). Thus, atropine reduced the slope describing the relationship between brachial artery vasodilation (percent change) and the change in shear rate by 38±8% across all exercise intensities (slope, atropine: 1.3±0.1 vs. control: 2.4±0.4% Δ×s×10−2, P=0.007). As expected, atropine reduced brachial artery vasodilation in response to upstream infusion of ACh (1.5 μg ACh/dl forearm volume/min, Δ diameter, atropine: 2±1 vs. control: 23±4%, P=0.001). Conclusions. The results suggest endogenous ACh facilitates baFMD in response to both transient and sustained shear stimuli, which highlights a novel physiological role of endogenous ACh in vascular regulation in humans and provides insight regarding the basic mechanisms of flow-mediated vasodilation. NIH R01 HL119337 and F31 HL142240. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The structure-function relationship between multifocal pupil perimetry and retinal nerve fibre layer in glaucoma.

Multifocal pupillographic objective perimetry (mfPOP) is a novel method for assessing functional change in diseases like glaucoma. Previous research has suggested that, in contrast to the pretectally-mediated melanopsin response of intrinsically photosensitive retinal ganglion cells, mfPOP responses to transient onset stimuli involve the extrastriate cortex, and thus the main visual pathway. We therefore investigate the correlation between peripapillary retinal nerve fibre layer (pRNFL) thickness and glaucomatous visual field changes detected using mfPOP. Parallel analyses are undertaken using white on white standard automated perimetry (SAP) for comparison. Twenty-five glaucoma patients and 24 normal subjects were tested using SAP, 3 mfPOP variants, and optical coherence tomography (OCT). Arcuate clusters of the SAP and mfPOP deviations were weighted according to their contribution to published arcuate divisions of the retinal nerve fibre layer. Structure-function correlation coefficients (r) were computed between pRNFL clock-hour sector thickness measurements, and the local visual field sensitivities from both SAP and mfPOP. The strongest correlation was observed in the superior-superotemporal disc sector in patients with worst eye SAP MD < -12dB: r = 0.93 for the mfPOP LumBal test (p < 0.001). Correlations across all disc-sectors were strongest in these same patients in both SAP and mfPOP: SAP r = 0.54, mfPOP LumBal r = 0.55 (p < 0.001). In patients with SAP MD ≥ -6dB in both eyes, SAP correlations across all sectors were higher than mfPOP; mfPOP correlations however, were higher than SAP in more advanced disease, and in normal subjects. For both methods the largest correlations with pRNFL thickness corresponded to the inferior nasal field of more severely damaged eyes. Head-to-head comparison of mfPOP and SAP showed similar structure-function relationships. This agrees with our recent reports that mfPOP primarily stimulates the cortical drive to the pupils.

359 Low-Intensity Focused Ultrasound to Human Dorsal Anterior Cingulate Cortex and Insula Attenuates Measures of Central Sensitization

INTRODUCTION: Central sensitization is the abnormal amplified response to pain and is associated with chronic pain. Increased insula and dorsal anterior cingulate cortex (dACC) activity is associated with central sensitization. Low-intensity focused ultrasound (LIFU) is a novel form of non-invasive neuromodulation that can precisely target the anterior insula (AI), posterior insula (PI) and dACC. METHODS: N = 18 healthy participants underwent conditioned pain modulation (CPM) and temporal summation of pain (TSP) tasks before and after 10 minutes of LIFU or sham stimulations. For CPM, the conditioning stimulus (CS) was a cold pressor test to the left hand and the test stimulus (TS) was a brief transient heat stimulus to the dorsum of the right hand. For TSP, 10 transient heat stimuli (&gt;0.33 Hz) were administered to the dorsum of the right hand. The primary outcome measure for both tasks was perceived pain ratings (0-9). Electrodermal response and electrocardiogram was collected to evaluate the effect of LIFU on autonomic reactivity. RESULTS: LIFU to PI increased CPM 0.5 ± 0.181 compared to sham (p = 0.024). LIFU to PI also significantly reduced perceived pain during the TSP task compared to sham (p &lt; 0.001). We also found a significant difference between dACC and sham conditions during TSP by -0.55 ± 0.05 (p &lt; 0.001). LIFU to the AI increases frequency domain measures of heart-rate variability. CONCLUSIONS: LIFU to the insula and dACC affects pain processing in measures of central sensitization. This demonstrates the neuromodulation abilities of LIFU and is a promising tool to develop noninvasive clinical therapies for chronic pain conditions.

Predicting early auditory evoked potentials using a computational model of auditory-nerve processing.

Non-invasive electrophysiological measures, such as auditory evoked potentials (AEPs), play a crucial role in diagnosing auditory pathology. However, the relationship between AEP morphology and cochlear degeneration remains complex and not well understood. Dau [J. Acoust. Soc. Am. 113, 936-950 (2003)] proposed a computational framework for modeling AEPs that utilized a nonlinear auditory-nerve (AN) model followed by a linear unitary response function. While the model captured some important features of the measured AEPs, it also exhibited several discrepancies in response patterns compared to the actual measurements. In this study, an enhanced AEP modeling framework is presented, incorporating an improved AN model, and the conclusions from the original study were reevaluated. Simulation results with transient and sustained stimuli demonstrated accurate auditory brainstem responses (ABRs) and frequency-following responses (FFRs) as a function of stimulation level, although wave-V latencies remained too short, similar to the original study. When compared to physiological responses in animals, the revised model framework showed a more accurate balance between the contributions of auditory-nerve fibers (ANFs) at on- and off-frequency regions to the predicted FFRs. These findings emphasize the importance of cochlear processing in brainstem potentials. This framework may provide a valuable tool for assessing human AN models and simulating AEPs for various subtypes of peripheral pathologies, offering opportunities for research and clinical applications.

Mechanical stimulation and electrophysiological monitoring at subcellular resolution reveals differential mechanosensation of neurons within networks

A growing consensus that the brain is a mechanosensitive organ is driving the need for tools that mechanically stimulate and simultaneously record the electrophysiological response of neurons within neuronal networks. Here we introduce a synchronized combination of atomic force microscopy, high-density microelectrode array and fluorescence microscopy to monitor neuronal networks and to mechanically characterize and stimulate individual neurons at piconewton force sensitivity and nanometre precision while monitoring their electrophysiological activity at subcellular spatial and millisecond temporal resolution. No correlation is found between mechanical stiffness and electrophysiological activity of neuronal compartments. Furthermore, spontaneously active neurons show exceptional functional resilience to static mechanical compression of their soma. However, application of fast transient (∼500 ms) mechanical stimuli to the neuronal soma can evoke action potentials, which depend on the anchoring of neuronal membrane and actin cytoskeleton. Neurons show higher responsivity, including bursts of action potentials, to slower transient mechanical stimuli (∼60 s). Moreover, transient and repetitive application of the same compression modulates the neuronal firing rate. Seemingly, neuronal networks can differentiate and respond to specific characteristics of mechanical stimulation. Ultimately, the developed multiparametric tool opens the door to explore manifold nanomechanobiological responses of neuronal systems and new ways of mechanical control.

Trained recurrent neural networks develop phase-locked limit cycles in a working memory task.

Neural oscillations are ubiquitously observed in many brain areas. One proposed functional role of these oscillations is that they serve as an internal clock, or 'frame of reference'. Information can be encoded by the timing of neural activity relative to the phase of such oscillations. In line with this hypothesis, there have been multiple empirical observations of such phase codes in the brain. Here we ask: What kind of neural dynamics support phase coding of information with neural oscillations? We tackled this question by analyzing recurrent neural networks (RNNs) that were trained on a working memory task. The networks were given access to an external reference oscillation and tasked to produce an oscillation, such that the phase difference between the reference and output oscillation maintains the identity of transient stimuli. We found that networks converged to stable oscillatory dynamics. Reverse engineering these networks revealed that each phase-coded memory corresponds to a separate limit cycle attractor. We characterized how the stability of the attractor dynamics depends on both reference oscillation amplitude and frequency, properties that can be experimentally observed. To understand the connectivity structures that underlie these dynamics, we showed that trained networks can be described as two phase-coupled oscillators. Using this insight, we condensed our trained networks to a reduced model consisting of two functional modules: One that generates an oscillation and one that implements a coupling function between the internal oscillation and external reference. In summary, by reverse engineering the dynamics and connectivity of trained RNNs, we propose a mechanism by which neural networks can harness reference oscillations for working memory. Specifically, we propose that a phase-coding network generates autonomous oscillations which it couples to an external reference oscillation in a multi-stable fashion.

Using Galvanic Vestibular Stimulation to Induce Post-Roll Illusion in a Fixed-Base Flight Simulator.

INTRODUCTION: The illusions of head motion induced by galvanic vestibular stimulation (GVS) can be used to compromise flight performance of pilots in fixed-base simulators. However, the stimuli used in the majority of studies fail to mimic disorientation in realistic flight because they are independent from the simulated aircraft motion. This study investigated the potential of bilateral-bipolar GVS coupled to aircraft roll in a fixed-base simulator to mimic vestibular spatial disorientation illusions, specifically the "post-roll illusion" observed during flight.METHODS: There were 14 nonpilot subjects exposed to roll stimuli in a flight simulator operating in a fixed-base mode. GVS was delivered via carbon rubber electrodes on the mastoid processes. The electrical stimulus was driven by the high-pass filtered aircraft roll rate to mimic the semicircular canals' physiological response. The post-roll test scenarios excluded outside visual cues or instruments and required subjects to actively maintain a constant bank angle after an abrupt stop following a passive prolonged roll maneuver. The anticipated outcome was an overshot in roll elicited by the GVS signal.RESULTS: The responses across subjects showed large variability, with less than a third aligning with the post-roll illusion. Subjective ratings suggest that the high-pass filtered GVS stimuli were mild and did not induce a clear sense of roll direction. However, uncontrolled head movements during stimulation might have obscured the intended effects of GVS-evoked illusory head movements.CONCLUSION: The mild and transient GVS stimuli used in this study, together with the uncontrolled head movements, did not convincingly mimic the post-roll illusion.Houben MMJ, Stuldreher IV, Forbes PA, Groen EL. Using galvanic vestibular stimulation to induce post-roll illusion in a fixed-base flight simulator. Aerosp Med Hum Perform. 2024; 95(2):84-92.

Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial.

The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat-evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.

Mechanically Triggered Polymer Deconstruction through Mechanoacid Generation and Catalytic Enol Ether Hydrolysis.

Polymers that amplify a transient external stimulus into changes in their morphology, physical state, or properties continue to be desirable targets for a range of applications. Here, we report a polymer comprising an acid-sensitive, hydrolytically unstable enol ether backbone onto which is embedded gem-dichlorocyclopropane (gDCC) mechanophores through a single postsynthetic modification. The gDCC mechanophore releases HCl in response to large forces of tension along the polymer backbone, and the acid subsequently catalyzes polymer deconstruction at the enol ether sites. Pulsed sonication of a 61 kDa PDHF with 77% gDCC on the backbone in THF with 100 mM H2O for 10 min triggers the subsequent degradation of the polymer to a final molecular weight of less than 3 kDa after 24 h of standing, whereas controls lacking either the gDCC or the enol ether reach final molecular weights of 38 and 27 kDa, respectively. The process of sonication, along with the presence of water and the existence of gDCC on the backbone, significantly accelerates the rate of polymer chain deconstruction. Both acid generation and the resulting triggered polymer deconstruction are translated to bulk, cross-linked polymer networks. Networks formed via thiol-ene cross-linking and subjected to unconstrained quasi-static uniaxial compression dissolve on time scales that are at least 3 times faster than controls where the mechanophore is not covalently coupled to the network. We anticipate that this concept can be extended to other acid-sensitive polymer networks for the stress-responsive deconstruction of gels and solvent-free elastomers.

Low-Intensity Focused Ultrasound to the Human Dorsal Anterior Cingulate Attenuates Acute Pain Perception and Autonomic Responses.

The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low-frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.

Neural Oscillations and Multisensory Processing.

Neural oscillations play a role in sensory processing by coordinating synchronized neuronal activity. Synchronization of gamma oscillations is engaged in local computation of feedforward signals and synchronization of alpha-beta oscillations is engaged in feedback processing over long-range areas. These spatially and spectrally segregated bi-directional signals may be integrated by a mechanism of cross-frequency coupling. Synchronization of neural oscillations has also been proposed as a mechanism for information integration across multiple sensory modalities. A transient stimulus or rhythmic stimulus from one modality may lead to phase alignment of ongoing neural oscillations in multiple sensory cortices, through a mechanism of cross-modal phase reset or cross-modal neural entrainment. Synchronized activities in multiple sensory cortices are more likely to boost stronger activities in downstream areas. Compared to synchronized oscillations, asynchronized oscillations may impede signal processing, and may contribute to sensory selection by setting the oscillations in the target-related cortex and the oscillations in the distractor-related cortex to opposite phases.

Dynamic alpha power modulations and slow negative potentials track natural shifts of spatio-temporal attention.

Alpha power modulations and slow negative potentials have previously been associated with anticipatory processes in spatial and temporal top-down attention. In typical experimental designs, however, neural responses triggered by transient stimulus onsets can interfere with attention-driven activity patterns and our interpretation of such. Here, we investigated these signatures of spatio-temporal attention in a dynamic paradigm free from potentially confounding stimulus-driven activity using electroencephalography. Participants attended the cued side of a bilateral stimulus rotation and mentally counted how often one of two remembered sample orientations (i.e., the target) was displayed while ignoring the uncued side and non-target orientation. Afterwards, participants performed a delayed match-to-sample task, in which they indicated if the orientation of a probe stimulus matched the corresponding sample orientation (previously target or non-target). We observed dynamic alpha power reductions and slow negative waves around task-relevant points in space and time (i.e., onset of the target orientation in the cued hemifield) over posterior electrodes contralateral to the locus of attention. In contrast to static alpha power lateralization, these dynamic signatures correlated with subsequent memory performance (primarily detriments for matching probes of the non-target orientation), suggesting a preferential allocation of attention to task-relevant locations and time points at the expense of reduced resources and impaired performance for information outside the current focus of attention. Our findings suggest that humans can naturally and dynamically focus their attention at relevant points in space and time and that such spatio-temporal attention shifts can be reflected by dynamic alpha power modulations and slow negative potentials.

The relationship between perseverative thinking, proactive control, and inhibition in psychological distress: a study in a women’s cohort

Cognitive control is a core feature of several mental disorders. A recent account poses that health problems may derive from proactive forms of cognitive control that maintain stress representation over time. The working hypothesis of the present study is that psychological distress is caused by the tendency to select a particular maladaptive self-regulation strategy over time, namely perseverative thinking, rather than by transient stimulus–response patterns. To test this hypothesis, we asked 84 women to carry out a battery of standardized questionnaires regarding their tendency to undertake perseverative thinking and their level of psychological distress, followed by cognitive tasks measuring the tendency to use proactive versus reactive control modality and disinhibition. Through a series of mediation analyses, we demonstrate that the tendency to use proactive control correlates with psychological distress and that this relation is mediated by perseverative thinking. Moreover, we show that the relation between low inhibitory control and psychological stress is more strongly mediated by perseverative thinking than impulsiveness, a classical construct that focuses on more transient reactions to stimuli. The present results underline the importance of considering psychological distress as the consequence of a maladaptive way of applying control over time, rather than the result of a general deficit in cognitive control abilities.