Disrupting nociceptive information processing flow through transcranial focused ultrasound neuromodulation of thalamic nuclei.

BACKGROUND: MRI-guided transcranial focused ultrasound (MRgFUS) as a next-generation neuromodulation tool can precisely target and stimulate deep brain regions with high spatial selectivity. Combined with MR-ARFI (acoustic radiation force imaging) and using fMRI BOLD signal as functional readouts, our previous studies have shown that low-intensity FUS can excite or suppress neural activity in the somatosensory cortex. OBJECTIVE: To investigate whether low-intensity FUS can suppress nociceptive heat stimulation-induced responses in thalamic nuclei during hand stimulation, and to determine how this suppression influences the information processing flow within nociception networks. FINDINGS: BOLD fMRI activations evoked by 47.5 °C heat stimulation of hand were detected in 24 cortical regions, which belong to sensory, affective, and cognitive nociceptive networks. Concurrent delivery of low-intensity FUS pulses (650 kHz, 550 kPa) to the predefined heat nociceptive stimulus-responsive thalamic centromedial_parafascicular (CM_para), mediodorsal (MD), ventral_lateral (VL_ and ventral_lateral_posteroventral (VLpv) nuclei suppressed their heat responses. Off-target cortical areas exhibited reduced, enhanced, or no significant fMRI signal changes, depending on the specific areas. Differentiable thalamocortical information flow during the processing of nociceptive heat input was observed, as indicated by the time to reach 10% or 30% of the heat-evoked BOLD signal peak. Suppression of thalamic heat responses significantly altered nociceptive processing flow and direction between the thalamus and cortical areas. Modulation of contralateral versus ipsilateral areas by unilateral thalamic activity differed. Signals detected in high-order cortical areas, such as dorsal frontal (DFC) and ventrolateral prefrontal (vlPFC) cortices, exhibited faster response latencies than sensory areas. CONCLUSIONS: The concurrent delivery of FUS suppressed nociceptive heat response in thalamic nuclei and disrupted the nociceptive network. This study offers new insights into the causal functional connections within the thalamocortical networks and demonstrates the modulatory effects of low-intensity FUS on nociceptive information processing.

Low-rank plus sparse compressed sensing for accelerated proton resonance frequency shift MR temperature imaging.

PURPOSE: To improve multichannel compressed sensing (CS) reconstruction for MR proton resonance frequency (PRF) shift thermography, with application to MRI-induced RF heating evaluation and MR guided high intensity focused ultrasound (MRgFUS) temperature monitoring. METHODS: A new compressed sensing reconstruction is proposed that enforces joint low rank and sparsity of complex difference domain PRF data between post heating and baseline images. Validations were performed on 4 retrospectively undersampled dynamic data sets in PRF applications, by comparing the proposed method to a previously described L1 and total variation- (TV-) based CS approach that also operates on complex difference domain data, and to a conventional low rank plus sparse (L+S) separation-based CS reconstruction applied to the original domain data. RESULTS: In all 4 retrospective validations, the proposed reconstruction method outperformed the conventional L+S and L1 +TV CS reconstruction methods with a 3.6× acceleration ratio in terms of temperature accuracy with respect to fully sampled data. For RF heating evaluation, the proposed method achieved RMS error of 12%, compared to 19% for the L+S method and 17% for the L1 +TV method. For in vivo MRgFUS thalamotomy, the peak temperature reconstruction errors were 19%, 31%, and 35%, respectively. CONCLUSION: The complex difference-based low rank and sparse model enhances compressibility for dynamic PRF temperature imaging applications. The proposed multichannel CS reconstruction method enables high acceleration factors for PRF applications including RF heating evaluation and MRgFUS sonication.

Inhalable curcumin: offering the potential for translation to imaging and treatment of Alzheimer's disease.

Curcumin is a promising compound that can be used as a theranostic agent to aid research in Alzheimer's disease. Beyond its ability to bind to amyloid plaques, the compound can also cross the blood-brain barrier. Presently, curcumin can be applied only to animal models, as the formulation needed for iv injection renders it unfit for human use. Here, we describe a novel technique to aerosolize a curcumin derivative, FMeC1, and facilitate its safe delivery to the brain. Aside from the translational applicability of this approach, a study in the 5XFAD mouse model suggested that inhalation exposure to an aerosolized FMeC1 modestly improved the distribution of the compound in the brain. Additionally, immunohistochemistry data confirms that following aerosol delivery, FMeC1 binds amyloid plaques expressed in the hippocampal areas and cortex.

Sensorimotor-independent prefrontal activity during response inhibition.

A network of brain regions involving the ventral inferior frontal gyrus/anterior insula (vIFG/AI), presupplementary motor area (pre-SMA) and basal ganglia has been implicated in stopping impulsive, unwanted responses. However, whether this network plays an equal role in response inhibition under different sensorimotor contexts has not been tested systematically. Here, we conducted an fMRI experiment using the stop signal task, a sensorimotor task requiring occasional withholding of the planned response upon the presentation of a stop signal. We manipulated both the sensory modality of the stop signal (visual versus auditory) and the motor response modality (hand versus eye). Results showed that the vIFG/AI and the preSMA along with the right middle frontal gyrus were commonly activated in response inhibition across the various sensorimotor conditions. Our findings provide direct evidence for a common role of these frontal areas, but not striatal areas in response inhibition independent of the sensorimotor contexts. Nevertheless, these three frontal regions exhibited different activation patterns during successful and unsuccessful stopping. Together with the existing evidence, we suggest that the vIFG/AI is involved in the early stages of stopping such as triggering the stop process while the preSMA may play a role in regulating other cortical and subcortical regions involved in stopping.

Lateralization of temporal lobe epilepsy using resting functional magnetic resonance imaging connectivity of hippocampal networks.

PURPOSE: Early surgical intervention can be advantageous in the treatment of refractory temporal lobe epilepsy (TLE). The success of TLE surgery relies on accurate lateralization of the seizure onset. The purpose of this study was to determine whether resting functional MRI (fMRI) connectivity mapping of the hippocampus has the potential to complement conventional presurgical evaluations in distinguishing left from right TLE. In addition, we sought to determine whether this same network might separate patients with favorable from unfavorable postoperative outcomes. METHODS: Resting fMRI acquisitions were performed on 21 patients with TLE and 15 healthy controls. The patients included seven patients with left TLE and seven patients with right TLE with seizure-free postoperative outcome, and five patients with left TLE and two patients with right TLE with recurring seizures after surgery. Functional connectivity maps to each hippocampus were determined for each subject and were compared between the controls and the seizure-free patients with left TLE and with right TLE. The one network identified was then quantified in the patients with TLE and recurring seizures. KEY FINDINGS: The resting functional connectivity between the right hippocampus and the ventral lateral nucleus of the right thalamus was the most statistically significant network to distinguish between seizure-free patients with left TLE and with right TLE with high sensitivity and specificity. This connectivity was also significantly greater in the seizure-free patients with left TLE than the healthy controls. Finally, six of the seven patients in whom seizures recurred after surgery had connectivity values in this network unlike those who were seizure-free. SIGNIFICANCE: This study identified a region in the ventral lateral nucleus of the right thalamus whose connectivity to the hippocampi separates left from right TLE subjects. This suggests that the quantification of resting-state functional magnetic resonance imaging (MRI) connectivity across this network may be a potential indicator of lateralization of TLE that may be added to other presurgical MRI assessments. Further validation in a larger, independent cohort is required.

Magnetic and optical properties of multifunctional core-shell radioluminescence nanoparticles.

When X-rays irradiate radioluminescence nanoparticles, they generate visible and near infrared light that can penetrate through centimeters of tissue. X-ray luminescence tomography (XLT) maps the location of these radioluminescent contrast agents at high resolution by scanning a narrow X-ray beam through the tissue sample and collecting the luminescence at every position. Adding magnetic functionality to these radioluminescent particles would enable them to be guided, oriented, and heated using external magnetic fields, while their location and spectrum could be imaged with XLT and complementary magnetic resonance imaging. In this work, multifunctional monodispersed magnetic radioluminescent nanoparticles were developed as potential drug delivery carriers and radioluminescence imaging agents. The particles consisted of a spindle-shaped magnetic γ-Fe2O3 core and a radioluminescent europium-doped gadolinium oxide shell. Particles with solid iron oxide cores displayed saturation magnetizations consistent with their ~13% core volume, however, the iron oxide quenched their luminescence. In order to increase the luminescence, we partially etched the iron oxide core in oxalic acid while preserving the radioluminescent shell. The core size was controlled by the etching time which in turn affected the particles' luminescence and magnetic properties. Particles with intermediate core sizes displayed both strong magnetophoresis and luminescence properties. They also served as MRI contrast agents with relaxivities of up to 58 mM-1s-1 (r2) and 120 mM-1s-1 (r2*). These particles offer promising multimodal MRI/fluorescence/X-ray luminescence contrast agents. Our core-shell synthesis technique offers a flexible method to control particle size, shape, and composition for a wide range of biological applications of magnetic/luminescent nanoparticles.

Changes in dietary iron exacerbate regional brain manganese accumulation as determined by magnetic resonance imaging.

Manganese (Mn) is an essential metal required for normal homeostasis. Humans chronically exposed to high Mn levels, however, may exhibit psychomotor signs secondary to increased brain Mn. As Mn and iron (Fe) share several cellular membrane transporters, decreased Fe levels resulting from Fe deficiency or anemia lead to increased brain Mn deposition. Conversely, decreased Mn levels are associated with abnormal brain Fe accumulation. To reduce potential Mn toxicity resulting from brain Mn accumulation, we proposed that increased dietary Fe would attenuate brain Mn deposition. To test this hypothesis, three groups of Sprague-Dawley rats were injected weekly (14 weeks) with Mn (3 mg/kg) and fed normal Fe (TX), Fe-supplemented (FeS), or Fe-deficient (FeD) chow. Control (CN) rats received normal dietary Fe and saline injections. Using magnetic resonance imaging, rats were imaged biweekly for 14 weeks to qualitatively monitor brain Mn and Fe accumulation. Both FeS and FeD had greater brain Mn deposition than TX rats. By week 3, R(1) values, which correlate with Mn deposition, were statistically significantly increased (p < 0.05) in brain stem, cerebellum, cortex, midbrain, and striatum compared with CN or TX animals. By week 14, R(1) values for all brain regions in FeS and FeD animals were statistically significantly increased (p < 0.05). By the end of the study, similar results were obtained for R(2) values, a marker of Fe accumulation. These data suggest that Fe supplementation does not effectively protect and may even exacerbate brain Mn accumulation in mammals subchronically exposed to Mn.

Auditory attraction: activation of visual cortex by music and sound in Williams syndrome.

Williams syndrome is a genetic neurodevelopmental disorder with a distinctive phenotype, including cognitive-linguistic features, nonsocial anxiety, and a strong attraction to music. we preformed functional MRI studies examining brain responses to musical and other types of stimuli in young adults with Williams syndrome and typically developing controls. In Study 1, the Williams syndrome group exhibited unforeseen activations of the visual cortex to musical stimuli, and it was this novel finding that became the focus of two subsequent studies. Using retinotopy, color localizers, and additional sound conditions, we identified specific visual areas in subjects with Williams syndrome that were activated by both musical and nonmusical auditory stimuli. The results, similar to synthetic-like experiences, have implications for cross-modal sensory processing in typical and atypical neurodevelopment.

Has quantitative multimodal imaging of treatment response arrived?

Although there have been dramatic increases in the range and quality of information available from noninvasive imaging methods, their application in clinical trials has been limited. One promising approach is to apply imaging techniques in preclinical studies designed to mimic a corresponding clinical trial in order to inform that trial.

Detection of irregular, transient fMRI activity in normal controls using 2dTCA: comparison to event-related analysis using known timing.

When events occur spontaneously during the acquisition of a series of images, traditional modeling methods for detecting functional MRI activation detection cannot be employed. The two-dimensional temporal clustering algorithm, 2dTCA, has been shown to accurately detect random, transient activations in computer simulations without the use of known event timings. In this study we applied the 2dTCA technique to detect the timings and spatial locations of sparse, irregular, transient activations of the visual, auditory, and motor cortices in 12 normal controls. Experiments with one and two independent types of stimuli were employed. Event-related activation using known timing was compared with event-related activation using 2dTCA-detected timing in individuals and across groups. The 2dTCA algorithm detected the activation from all presented stimuli in every subject. When compared with block-design results using a measure of correlation between activation maps, no significant difference was found between the 2dTCA activation maps and the event-related maps using known timing across all subjects. Therefore, 2dTCA has the potential to be an accurate and more practical method for detection of spontaneous, transient events using fMRI.

Measuring brain manganese and iron accumulation in rats following 14 weeks of low-dose manganese treatment using atomic absorption spectroscopy and magnetic resonance imaging.

Chronic exposure to manganese (Mn) may lead to a movement disorder due to preferential Mn accumulation in the globus pallidus and other basal ganglia nuclei. Iron (Fe) deficiency also results in increased brain Mn levels, as well as dysregulation of other trace metals. The relationship between Mn and Fe transport has been attributed to the fact that both metals can be transported via the same molecular mechanisms. It is not known, however, whether brain Mn distribution patterns due to increased Mn exposure vs. Fe deficiency are the same, or whether Fe supplementation would reverse or inhibit Mn deposition. To address these questions, we utilized four distinct experimental populations. Three separate groups of male Sprague-Dawley rats on different diets (control diet [MnT], Fe deficient [FeD], or Fe supplemented [FeS]) were given weekly intravenous Mn injections (3 mg Mn/kg body mass) for 14 weeks, whereas control (CN) rats were fed the control diet and received sterile saline injections. At the conclusion of the study, both blood and brain Mn and Fe levels were determined by atomic absorption spectroscopy and magnetic resonance imaging. The data indicate that changes in dietary Fe levels (either increased or decreased) result in regionally specific increases in brain Mn levels compared with CN or MnT animals. Furthermore, there was no difference in either Fe or Mn accumulation between FeS or FeD animals. These data suggest that dietary Fe manipulation, whether increased or decreased, may contribute to brain Mn deposition in populations vulnerable to increased Mn exposure.

A functional near-infrared spectroscopy study to detect activation of somatosensory cortex by peripheral nerve stimulation.

INTRODUCTION: Multi-channel near-infrared spectroscopy (NIRS) is a method for non-invasively monitoring of relative concentrations of oxygenated, deoxygenated, and total hemoglobin. This technique has found expanding application in brain mapping and functional imaging. The purpose of this study was to investigate whether activation of somatosensory cortex can be detected without the necessity of the patient's cooperation in performing a task. METHODS: Real-time bilateral parietotemporal cerebral oxygenation was monitored in 12 healthy volunteers. The median nerve at the wrist was electrically stimulated repeatedly at an amplitude below the threshold of discomfort. Interstimulus intervals were randomized between 13 and 31 s to minimize synchronization with respiration or other natural oscillations in cerebral oxygenation. RESULTS: In 8 of the 12 subjects, activation over the contralateral primary somatosensory cortex was detected, correlating significantly with the predicted hemodynamic response function. CONCLUSIONS: To our knowledge, this is the first time functional NIRS has been used to detect activation of somatosensory cortex with peripheral nerve stimulation. While the sensitivity for detection of the functional hemodynamic response was inadequate for clinical diagnostics, these findings are uniquely important in critical care imaging in that the regional blood flow and oxygenation changes can be detected without the requirement of a volitional task. This advancement potentially expands the capability of this modality to be used in brain mapping and in the evaluation of patients with impaired cognitive or motor function at the bedside.

Task demand modulation of steady-state functional connectivity to primary motor cortex.

Correlations in blood oxygen level-dependent (BOLD) MRI signals from separate areas within the human brain have been used as a measure of functional connectivity. Steady-state measures of interregional correlations are particularly useful because they do not depend on the specific design of a task nor on subtracting conditions in a blocked design task. However, the conditions under which such correlations are measured may influence these indices of functional connectivity. The aim of this study was to investigate the influence of task demand on interregional correlations within the motor system. Specifically, tapping rates in audibly paced finger-tapping tasks were controlled and varied between runs in order to observe their effects on interregional correlations to contralateral primary motor cortex (PM). Regions of interest included the supplementary motor area, ipsilateral cerebellum, ipsilateral auditory cortex, and a control region. It was found that tapping rate was a significant factor in determining the mean correlation of some regions to PM, and that correlations measured during tapping in general increased relative to resting state. Furthermore, analysis of the percent of voxels in each region significantly correlated to PM suggested that changes in the mean correlation of that region to PM could be accounted for by changes in the fraction of significantly correlated voxels within a region. This provides insight into the manner in which steady-state correlations are modified in response to different task demands and further evidence that low-frequency fluctuations in BOLD signals reflect functional connectivity.

Hypoglycemia reduces the blood-oxygenation level dependent signal in primary auditory and visual cortex: a functional magnetic resonance imaging study.

Studies of the effects of hypoglycemia on the brain using neurocognitive testing have suggested that mainly complex functions subserved by secondary and tertiary cortex are affected by mild to moderate hypoglycemia and that intensively treated patients with Type I diabetes mellitus (T1DM) may have altered sensitivity to the central nervous system effects of hypoglycemia. Functional magnetic resonance imaging provides a sensitive, regionally-specific probe of possible neurophysiologic changes related to hypoglycemia in the brain. Eleven intensively-treated T1DM patients and 11 matched non-diabetic controls took part in a 2-day protocol in which functional magnetic resonance imaging (MRI) was used to measure changes in the patterns of brain activation produced by simple auditory and visual stimuli in different conditions. On one day, participants were euglycemic the entire time. On the other day, an initial 50-min euglycemic period was followed by a 50-min hypoglycemic period. Results indicated that hypoglycemia reduced the amplitude of the blood-oxygenation level dependent response in primary auditory and visual cortex to simple auditory and visual stimuli. The latency and duration of the transient hemodynamic response function were not affected. Responses to hypoglycemia were similar in diabetic and non-diabetic participants. These results suggest that mild to moderate hypoglycemia may alter the balance of blood flow and oxygen extraction when glucose levels are lowered. Intensively-treated T1DM, with its attendant frequent hypoglycemic episodes, did not seem to alter hypoglycemic responses in primary visual and auditory cortex.

Measurement of thermal diffusivity by magnetic resonance imaging.

Nuclear magnetic resonance (NMR) may be used for monitoring temperature changes within samples based on measurements of relaxation times, the diffusion coefficient of liquids, proton resonance frequency or phase shifts. Such methods may be extended to the explicit measurement of the thermal diffusivity of materials by NMR imaging. A method based on measuring nuclear spin phase shifts or changes in the equilibrium nuclear magnetization has been developed for measuring transient thermal diffusion effects and thermal diffusivity with potential applications in NMR thermotherapy and materials science. In this method, a thermal pulse is applied to a medium, and the resultant temporal variations of the nuclear spin phase or of the magnitude of the nuclear magnetization produced by the thermal pulse are monitored at a spatial distance. The results obtained on common fluids agree well with the data from other methods.

Absolute pitch: music and beyond.

"Perfect pitch," known in the scientific literature as "absolute pitch" (AP), is a rare phenomenon that has fascinated musicians and scientists alike for over a century. There has been a great deal of conflict in the literature between advocates of the two main theories on the etiology of AP: some believe that AP is learned early in life through intensive musical training, whereas others believe AP to be largely innate. Both theories are alike, however, in considering AP to be exclusively a musical phenomenon. We propose a paradigm shift by presenting here a new model of AP, one that is predicated on two principles: (1) that AP may be relatively independent of musical experience; and (2) that there are different types of AP, each of which can be ascribed to discrete neurobiological mechanisms. We also review data from a diverse series of experiments that were designed to test explicitly both the predictions of our model and a series of historical myths about AP. In each case, the data strongly support our model. We conclude with a general discussion on the nature of AP, the relevance of these findings for other areas of research, and future directions of study.

Changes in functional connectivity of human MT/V5 with visual motion input.

The neural basis of human mental function is characterized by interactions between brain regions. Temporal correlations in MR signals between areas may provide one method for investigating these interactions. This approach was used to examine functional connectivity in the motion processing system of the human brain. Correlations between MT/V5 and other brain regions were examined in a resting state (without visual stimulation) and in an active state produced by viewing moving concentric circles. A network of regions consistent with the known functional anatomy of visual processing was correlated with MT/V5 during rest. When subjects were viewing motion, a more limited network was correlated with MT/V5, suggesting MT/V5 was acting in concert with a smaller network specific to the task.

Correlations and dissociations between BOLD signal and P300 amplitude in an auditory oddball task: a parametric approach to combining fMRI and ERP.

A parametric method is proposed to examine the relationship between neuronal activity, measured with event related potentials (ERPs), and the hemodynamic response, observed with functional magnetic resonance imaging (fMRI), during an auditory oddball paradigm. After verifying that the amplitude of the evoked response P300 increases as the probability of oddball target presentation decreases, we explored the corresponding effect of target frequency on the fMRI signal. We predicted and confirmed that some regions that showed activation changes following each oddball are affected by the rate of presentation of the oddballs, or the probability of an oddball target. We postulated that those regions that increased activation with decreasing probability might be responsible for the corresponding changes in the P300 amplitude. fMRI regions that correlated with the amplitude of the P300 wave were supramarginal gyri, thalamus, insula and right medial frontal gyrus, and are presumably sources of the P300 wave. Other regions, such as anterior and posterior cingulate cortex, were activated during the oddball paradigm but their fMRI signal changes were not correlated with the P300 amplitudes. This study thus shows how combining fMRI and ERP in a parametric design identifies task-relevant sources of activity and allows separation of regions that have different response properties.

A comparison of bound and unbound audio-visual information processing in the human cerebral cortex.

Human speech has auditory (heard speech) and visual (seen speech) qualities. The neural representation of audiovisual integration in speech was investigated using functional magnetic resonance imaging (fMRI). Ten subjects were imaged while viewing a face in four different conditions: with speech and mouth movements synchronized, with speech and mouth movements desynchronized, during silent speech, or while viewing a static face. Subtractions of the different sets of images showed that lipreading primarily activated the STG/STS. Synchronized audio-visual speech and desynchronized audio-visual speech activated similar areas. Regions activated more in the synchronized versus the desynchronized conditions were considered to be those involved in cross-modal integration. One dominant activation focus was found near the left claustrum, a subcortical region. A region-of-interest analysis of the STS and parietal areas found no difference between audio-visual conditions. However, this analysis found that synchronized audio-visual stimuli led to a higher signal change in the claustrum region. This study extends previous results, using other sensory combinations, and other tasks, indicating involvement of the claustrum in sensory integration.