David J. Mikulis

A multimodal cortical network for the detection of changes in the sensory environment

Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.

Idiopathic intracranial hypertension: The prevalence and morphology of sinovenous stenosis

Objective: To determine the prevalence and nature of sinovenous obstruction in idiopathic intracranial hypertension (IIH) using auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MR venography (ATECO MRV). Methods: In a prospective controlled study, 29 patients with established IIH as well as 59 control patients underwent ATECO MRV. In a randomized blinded fashion, three readers evaluated the images. Using a novel scoring system, each reader graded the degree of stenosis seen in the transverse and sigmoid sinuses of each patient. Results: There was excellent agreement across the three readers for application of the grading system. Substantial bilateral sinovenous stenoses were seen in 27 of 29 patients with IIH and in only 4 of 59 control patients. Conclusion: Using ATECO MRV and a novel grading system for quantifying sinovenous stenoses, the authors can identify IIH patients with sensitivity and specificity of 93%.

Cortical activation during human volitional swallowing : an event-related fMRI study

Functional magnetic resonance imaging (fMRI) provides a safe, noninvasive method for studying task-related cortical neuronal activity. Because the cerebral cortex is strongly implicated in the control of human swallowing, we sought to identify its functional neuroanatomy using fMRI. In 10 healthy volunteers, a swallow event-related paradigm was performed by injecting 5 ml water bolus into the oral cavity every 30 s. Whole brain functional magnetic susceptibility[Formula: see text]-weighted spiral imaging data were simultaneously acquired over 600 s on a 1.5-T magnetic resonance scanner, utilizing the blood oxygenation level-dependent technique, and correlation maps were generated using both >99% percentile rank and spatial extent thresholding. We observed areas of increased signal change consistently in caudal sensorimotor cortex, anterior insula, premotor cortex, frontal operculum, anterior cingulate and prefrontal cortex, anterolateral and posterior parietal cortex, and precuneus and superiomedial temporal cortex. Less consistent activations were also seen in posterior cingulate cortex and putamen and caudate nuclei. Activations were bilateral, but almost every region, particularly the premotor, insular, and frontal opercular cortices, displayed lateralization to one or the other hemisphere. Swallow-related cortical activity is multidimensional, recruiting brain areas implicated in processing motor, sensory, and attention/affective aspects of the task.

Intracranial arterial wall imaging using high-resolution 3-tesla contrast-enhanced MRI

Background: Conventional arterial imaging focuses on the vessel lumen but lacks specificity because different pathologies produce similar luminal defects. Wall imaging can characterize extracranial arterial pathology, but imaging intracranial walls has been limited by resolution and signal constraints. Higher-field scanners may improve visualization of these smaller vessels. Methods: Three-tesla contrast-enhanced MRI was used to study the intracranial arteries from a consecutive series of patients at a tertiary stroke center. Results: Multiplanar T2-weighted fast spin echo and multiplanar T1 fluid-attenuated inversion recovery precontrast and postcontrast images were acquired in 37 patients with focal neurologic deficits. Clinical diagnoses included atherosclerotic disease (13), CNS inflammatory disease (3), dissections (3), aneurysms (3), moyamoya syndrome (2), cavernous angioma (1), extracranial source of stroke (5), and no definitive clinical diagnosis (7). Twelve of 13 with atherosclerotic disease had focal, eccentric vessel wall enhancement, 10 of whom had enhancement only in the vessel supplying the area of ischemic injury. Two of 3 with inflammatory diseases had diffuse, concentric vessel wall enhancement. Three of 3 with dissection showed bright signal on T1, and 2 had irregular wall enhancement with a flap and dual lumen. Conclusions: Three-tesla contrast-enhanced MRI can be used to study the wall of intracranial blood vessels. T2 and precontrast and postcontrast T1 fluid-attenuated inversion recovery images at 3 tesla may be able to differentiate enhancement patterns of intracranial atherosclerotic plaques (eccentric), inflammation (concentric), and other wall pathologies. Prospective studies are required to determine the sensitivity and specificity of arterial wall imaging for distinguishing the range of pathologic conditions affecting cerebral vasculature.

Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING NoNO Inc and Arbor Vita Corp.

In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single‐cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single‐cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.

An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli

&NA; The anterior cingulate cortex (ACC) and adjacent regions in the medial wall have been implicated in sensory, motor and cognitive processes, including pain. Our previous functional magnetic resonance imaging (fMRI) studies have demonstrated pain‐related activation of the posterior portion of the ACC during transcutaneous electrical nerve stimulation (TENS) and variable patterns of cortical activation with innocuous and noxious thermal stimuli in individual subjects. The present study represents the companion paper to our recent study of pain‐ and thermal‐related cortical activations with the aim to use fMRI to delineate the activations in the ACC and surrounding regions of the medial wall during application of innocuous and noxious thermal stimuli as well as during performance of a motor task in individual subjects. Ten normal subjects were imaged on a conventional 1.5 T GE ‘echospeed’ system. Functional images were obtained from sagittal sections through each hemisphere centered at approximately 3–5 and 7–9 mm from midline. Each subject was imaged during innocuous (cool, warm) and noxious thermal (cold, hot) stimulation of the thenar eminence, and execution of a motor (sequential finger‐thumb opposition) task. Task‐related activations were mostly confined to contralateral and medial ipsilateral images. Although the present results demonstrate intersubject variability in the task‐related activations, some general modality‐specific patterns were apparent: (i) innocuous thermal‐related activations were located mainly in the anterior ACC; (ii) noxious thermal‐related activations were primarily located in the anterior ACC, the ventral portion of the posterior ACC, and the supplementary motor area (SMA); (iii) motor‐related activations were primarily located in the SMA and dorsal portion of the posterior ACC. These results indicate that specific spatial patterns of activation exist within the ACC and surrounding regions of the medial wall for innocuous and noxious thermal stimuli, and that noxious thermal‐ and motor‐related activations appear to be segregated within the ACC. Therefore, we propose a segregation of the ACC into an anterior non‐specific attention/arousal system and a posterior pain system.

Viewing Artworks: Contributions of Cognitive Control and Perceptual Facilitation to Aesthetic Experience.

When we view visual images in everyday life, our perception is oriented toward object identification. In contrast, when viewing visual images as artworks, we also tend to experience subjective reactions to their stylistic and structural properties. This experiment sought to determine how cognitive control and perceptual facilitation contribute to aesthetic perception along with the experience of emotion. Using functional MRI, we show that aesthetic perception activated bilateral insula which we attribute to the experience of emotion. Moreover, while adopting the aesthetic orientation activated the left lateral prefrontal cortex, paintings that facilitated visuospatial exploration activated the left superior parietal lobule. The results suggest that aesthetic experience is a function of the interaction between top-down orienting of attention and bottom-up perceptual facilitation.

Altered central somatosensory processing in chronic pain patients with “hysterical” anesthesia

Objective: The authors hypothesized that central factors may underlie sensory deficits in patients with nondermatomal somatosensory deficits (NDSD) and that functional brain imaging would reveal altered responses in supraspinal nuclei. Background: Patients with chronic pain frequently present with NDSD, ranging from hypoesthesia to complete anesthesia in the absence of substantial pathology and often in association with motor weakness and occasional paralysis. Patients with pain and such pseudoneurologic symptoms can be classified as having both a pain disorder and a conversion disorder (Diagnostic and Statistical Manual of Mental Disorders–IV classification). Methods: The authors tested their hypothesis with functional MRI (fMRI) of brush and noxious stimulation-evoked brain responses in four patients with chronic pain and NDSD. Results: The fMRI findings revealed altered somatosensory-evoked responses in specific forebrain areas. Unperceived stimuli failed to activate areas that were activated with perceived touch and pain: notably, the thalamus, posterior region of the anterior cingulate cortex (ACC), and Brodmann area 44/45. Furthermore, unperceived stimuli were associated with deactivations in primary and secondary somatosensory cortex (S1, S2), posterior parietal cortex, and prefrontal cortex. Finally, unperceived (but not perceived) stimuli activated the rostral ACC. Conclusions: Diminished perception of innocuous and noxious stimuli is associated with altered activity in many parts of the somatosensory pathway or other supraspinal areas. The cortical findings indicate a neurobiological component for at least part of the symptoms in patients presenting with nondermatomal somatosensory deficits.

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: A functional MRI case study

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinsons disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36‐year‐old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High‐frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level‐dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmanns area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico‐basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).