Stewart Denslow

At the heart of the ventral attention system: The right anterior insula

The anterior insula has been hypothesized to provide a link between attention‐related problem solving and salience systems during the coordination and evaluation of task performance. Here, we test the hypothesis that the anterior insula/medial frontal operculum (aI/fO) provides linkage across systems supporting task demands and attention systems by examining the patterns of functional connectivity during word recognition and spatial attention functional imaging tasks. A shared set of frontal regions (right aI/fO, right dorsolateral prefrontal cortex, bilateral anterior cingulate) were engaged, regardless of perceptual domain (auditory or visual) or mode of response (word production or button press). We present novel evidence that: (1) the right aI/fO is functionally connected with other frontal regions implicated in executive function and not just brain regions responsive to stimulus salience; and (2) that the aI/fO, but not the ACC, exhibits significantly correlated activity with other brain regions specifically engaged by tasks with varying perceptual and behavioral demands. These results support the hypothesis that the right aI/fO aids in the coordination and evaluation of task performance across behavioral tasks with varying perceptual and response demands. Hum Brain Mapp 2009.

A review of functional neuroimaging studies of vagus nerve stimulation (VNS).

Vagus nerve stimulation (VNS) is a new method for preventing and treating seizures, and shows promise as a potential new antidepressant. The mechanisms of action of VNS are still unknown, although the afferent direct and secondary connections of the vagus nerve are well established and are the most likely route of VNS brain effects. Over the past several years, many groups have used functional brain imaging to better understand VNS effects on the brain. Since these studies differ somewhat in their methodologies, findings and conclusions, at first glance, this literature may appear inconsistent. Although disagreement exists regarding the specific locations and the direction of brain activation, the differences across studies are largely due to different methods, and the results are not entirely inconsistent. We provide an overview of these functional imaging studies of VNS. PET (positron emission tomography) and SPECT (single photon emission computed tomography) studies have implicated several brain areas affected by VNS, without being able to define the key structures consistently and immediately activated by VNS. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), with its relatively high spatio-temporal resolution, performed during VNS, can reveal the location and level of the brains immediate response to VNS. As a whole, these studies demonstrate that VNS causes immediate and longer-term changes in brain regions with vagus innervations and which have been implicated in neuropsychiatric disorders. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla. Functional neuroimaging studies have the potential to provide greater insight into the brain circuitry behind the activity of VNS.

Feasibility of Vagus Nerve Stimulation-Synchronized Blood Oxygenation Level-Dependent Functional MRI

Bohning DE, Lomarev MP, Denslow S, et al. Feasibility of vagus nerve stimulation–synchronized blood oxygenation level– dependent functional MRI. Invest Radiol 2001;36:470–479. rationale and objectives. Left cervical vagus nerve stimulation (VNS) by use of an implanted neurocybernetic prosthesis (NCP) system is effective in treating epilepsy, with open data suggesting effectiveness in depression, yet the mechanisms of action are unknown. Our objective was to develop a methodology for performing VNS-synchronized functional magnetic resonance imaging (VNS-fMRI) and then to demonstrate its feasibility for studying VNS effects. methods.In nine patients implanted for treatment of intractable depression, a Macintosh computer was used to detect the signal from the implanted VNS stimulator and then to synchronize fMRI image acquisition with its regular firing. results.With our VNS-fMRI methodology, the blood oxygenation level–dependent response to VNS was shown in brain regions regulated by the vagus nerve: orbitofrontal and parieto-occipital cortex bilaterally, left temporal cortex, the hypothalamus, and the left amygdala. conclusions.Vagus nerve stimulation pulses from an NCP system can be detected externally to determine its firing pattern, thus allowing VNS-fMRI studies of VNS-induced brain activity.

Cellular changes in experimental left heart hypoplasia

Hypoplastic left heart syndrome (HLHS) is a rare but deadly congenital malformation, which can be created experimentally in the chick embryo by left atrial ligation (LAL). The goal of this study was to examine the cellular changes leading to the profound remodeling of ventricular myocardial architecture that occurs in this model. Hypoplasia of left heart structures was produced after 3H‐thymidine prelabeling by partial LAL at stage 24, thereby reducing its volume, and redistributing blood preferentially to the developing right ventricle (RV). Controls included both sham‐operated and intact stage‐matched embryos. Survivors were studied 4 days after the ligation, when the heart organogenesis was essentially complete. Paraffin sections of the hearts were subjected to autoradiography and immunohistochemistry to detect changes in history of cell proliferation and expression of myosin, and growth factors implicated in cardiomyocyte proliferation. Sampling for apoptosis detection using TUNEL assay was done at stages 29 and 34. LAL resulted in decreased levels of proliferation in the left ventricular compact layer and trabeculae. The right ventricular compact layer also showed a slight decrease, but the trabeculae showed no differences. Anti‐myosin staining was significantly reduced in all compartments. The expression levels of growth factors were altered as well. Apoptosis was increased in the right atrioventricular mesenchyme, with no changes in the working myocardium. These data suggest that changes in cardiomyocyte proliferation play a significant role in the pathogenesis of HLHS. Anat Rec 267:137–145, 2002.

Vagus nerve stimulation (VNS) synchronized BOLD fMRI suggests that VNS in depressed adults has frequency/dose dependent effects

Stimulation of the vagus nerve in the neck can reduce seizures in epilepsy patients, and may be helpful in treating depression. PET studies have shown that vagus nerve stimulation (VNS) in epilepsy patients causes acute dose (intensity) dependent changes in regional cerebral blood flow. We sought to use the newly developed VNS synchronized fMRI technique to examine whether VNS BOLD signal changes depend on the frequency of stimulation. Six adults with recurrent depression were scanned inside a 1.5 T MR scanner. Data were acquired at rest, with the VNS device on for 7 s, and also, for comparison, while the patient listened to a tone for 7 s. In two separate back-to-back sessions, the VNS stimulation frequency was set to either 5 or 20 Hz. Data were transformed into Talairach space and then compared by condition. Compared to 5 Hz, 20 Hz VNS produced more acute activity changes from rest in regions similar to our initial VNS synchronized fMRI feasibility study in depression. Brain regions activated by hearing a tone were also greater when VNS was intermittently being applied at 20 Hz than at 5 Hz. In depressed adults, left cervical VNS causes regional brain activity changes that depend on the frequency of stimulation or total dose, or both. In addition to the acute immediate effects of VNS on regional brain activity, this study suggests further that VNS at different frequencies likely has frequency or dose dependent modulatory effects on other brain activities (e.g. hearing a tone).

Mechanisms and State of the Art of Transcranial Magnetic Stimulation

In 1985, Barker et al. built a transcranial magnetic stimulation (TMS) device with enough power to stimulate dorsal roots in the spine. They quickly realized that this machine could likely also noninvasively stimulate the superficial cortex in humans. They waited a while before using their device over a human head, fearing that the TMS pulse might magnetically “erase the hard-drive” of the human brain. Almost 10 years later, in 1994, an editorial in this journal concerned whether TMS might evolve into a potential antidepressant treatment. In the intervening years, there has been an explosion of basic and clinical research with and about TMS. Studies are now uncovering the mechanisms by which TMS affects the brain. It does not “erase the hard-drive” of the brain, and it has many demonstrated research and clinical uses. This article reviews the major recent advances with this interesting noninvasive technique for stimulating the brain, critically reviewing the data on whether TMS has anticonvulsant effects or modulates cortical-limbic loops.

Acute Vagus nerve stimulation using different pulse widths produces varying brain effects

BACKGROUND Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and has been investigated in clinical trials of depression. Little is known about the relationship of VNS parameters to brain function. Using the interleaved VNS /functional magnetic resonance imaging (fMRI) technique, we tested whether variations of VNS pulse width (PW) would produce different immediate brain activation in a manner consistent with single neuron PW studies. METHODS Twelve adult patients with major depression, treated with VNS, underwent three consecutive VNS/fMRI scans, each randomly using one of three PWs (130 micros, 250 micros, or 500 micros). The data were analyzed with SPM2. RESULTS Global activations induced by PWs 250 and 500 were both significantly greater than that induced by PW 130 but not significantly different from each other. For global deactivation, PWs 130 and 250 were both significantly greater than PW 500 but not significantly different from each other. Regional similarities and differences were also seen with the various PWs. CONCLUSIONS The data confirm our hypothesis that VNS at PW 500 globally produces no more activation than does PW 250, and PW 130 is insufficient for activation of some regions. These data suggest that PW is an important variable in producing VNS brain effects.

Right ventricular volumes revisited: A simple model and simple formula for echocardiographic determination

Our objective was to establish a crescentic model of the right ventricle as the basis of a reported 2/3 (Area)(Length) empirical formula for volume. This formula has been investigated by others without cognizance of its connection to a clear geometric model. The particular model, an ellipsoidal shell or difference of ellipsoids, has been investigated by several groups by using different volume formulas. Accordingly, we obtained echocardiographic images in 2 orthogonal planes from 7 patients and 4 volunteers. Specified area and length measurements from these images were used to calculate right ventricular volumes. These volumes were compared with values determined through multislice, magnetic resonance imaging with summation of lumen areas, a widely accepted standard. Obtained high correlations compared favorably with those of previous investigators who used equivalent but less well understood methods. We conclude that the ellipsoidal shell model of the right ventricle provides a simple area-length formula for the determination of lumen volume with echocardiography.

A TMS coil positioning/holding system for MR image-guided TMS interleaved with fMRI

OBJECTIVE Transcranial magnetic stimulation (TMS) can be interleaved with fMRI to visualize regional brain activity in response to direct, non-invasive, cortical stimulation, making it a promising tool for studying brain function. A major practical difficulty is accurately positioning the TMS coil within the MRI scanner for stimulating a particular area of brain cortex. The objective of this work was to design and build a self-contained hardware/software system for MR-guided TMS coil positioning in interleaved TMS/fMRI studies. METHODS A compact, manually operated, articulated TMS coil positioner/holder with 6 calibrated degrees of freedom was developed for use inside a cylindrical RF head coil, along with a software package for transforming between MR image coordinates, MR scanner space coordinates, and positioner/holder settings. RESULTS Phantom calibration studies gave an accuracy for positioning within setups of dx=+/-1.9 mm, dy=+/-1.4 mm, dz=+/-0.8 mm and a precision for multiple setups of dx=+/-0.8 mm, dy=+/-0.1 mm, dz=+/-0.1 mm. CONCLUSIONS This self-contained, integrated MR-guided TMS system for interleaved TMS/fMRI studies provides fast, accurate location of motor cortex stimulation sites traditionally located functionally, and a means of consistent, anatomy-based TMS coil positioning for stimulation of brain areas without overt response.

An increased precision comparison of TMS-induced motor cortex BOLD fMRI response for image-guided versus function-guided coil placement.

Objective:To examine with high precision the differences between function-guided and image-guided transcranial magnetic stimulation (TMS). Method:Using a calibrated TMS coil holder/positioner, interleaved TMS/functional magnetic resonance imaging (fMRI), and individualized anatomy-based regional normalization, we conducted a two-phase study of TMS coil positioning guided by either function (elicited thumb motion) or image-based targeting of the “hand knob,” the anatomy associated with fMRI activation during thumb motion. Results:In every case, image-guided TMS coil placement produced a thumb movement response at thresholds similar to those found under function guidance. Unexpectedly, function-guided coil locations clustered bimodally over central and precentral sulci. Image-guided locations clustered as anticipated toward the targeted gyral crown. Despite these differences, blood oxygenation level-dependent (BOLD) activation locations and magnitude for the two methods displayed no consistent differences in mean or variance between or within subjects. Image guidance produced more consistent coil placement from subject to subject relative to targeted anatomy. Surprisingly, BOLD time courses from image-guided experiments showed significantly slower return to baseline after TMS than was observed under function guidance. Conclusions:The results demonstrate the effectiveness and precision of image-guided positioning of TMS coils combined with a precisely adjustable holder/positioner and regional normalization. Image guidance provides an accurate TMS placement relative to individual anatomy when no external sign is available.