fects to the development of indicator fractionation and clearance methods such as autoradiography, hydrogen clearance, and positron emission tomography (PET), the clinical and experimental need for a ready means of CBF assessment has been complemented by the efforts to de velop such quantification techniques (Bell, 1984). Nev ertheless, the ultimate goal of a totally noninvasive method that enables the mapping of CBF with high tem poral and spatial resolution over the wide range of rel evant blood flows has not been attained.The advantage of using a magnetic resonance imaging (MRI) based perfusion imaging method is that, in addi tion to its noninvasiveness, the option of using other nuclear magnetic resonance techniques (e.g., diffusion weighted imaging, metabolite spectroscopy, tissue relax ometry) is available. This allows the combined longitu dinal assessment of tissue perfusion, morphologic fea tures, metabolism, and function, thus providing a more complete understanding of the developing pathophysi ologic mechanism. The sensitivity of nuclear magnetic resonance to the movement of spins in flowing liquids was noted at an early stage (Singer, 1959) and has led to the important radiologic technique of magnetic reso nance (MR) angiography (Potchen et al., 1993). Efforts to image perfusion, on the other hand, have been dogged by the relatively low volume and velocity of moving spins in capillary beds. The pioneering work of Le Bihan et al. (1986) and Turner (1988), who used the dephasing of randomly perfusing water protons (intravoxel incoher ent motion) in magnetic field gradients as an index of 702 F. CALAMANTE ET AL.tissue perfusion, was thwarted by the inadequacy of the hardware available to provide sufficient image dynamic range for useful quantification of perfusion. In the suc ceeding years, two distinct MRI techniques have arisen, each with well-supported claims to provide a quantitative assessment of CBF. These methods differ with regard to their respective use of an exogenous and endogenous MRI-visible tracer. The first of the techniques, dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI), is not entirely noninvasive, requiring injec tion of a contrast agent toxic in high dosages, whereas the second, arterial spin labeling (ASL), uses radiofre quency (RF) pulses to magnetically label moving spins in flowing blood. PERFUSION IMAGING USING MR CONTRAST AGENTSThe use of exogenous MR contrast agents for the study of cerebral perfusion has long been recognized (Villringer et aI., 1988; Rosen et aI., 1990). These con trast agents also provide information about different physiologic parameters related to CBF, cerebral blood volume (CBV) and the mean transit time (MTT) ... through a volume of tissue. This technique, usually re ferred to as DSC-MRI, involves the injection of a bolus of contrast agent (typically 0. 1 to 0.3 mmol/kg body weight) and the rapid measurement of the MRI signal loss caused by spin dephasing (i.e., decrease in T2 and T 2 *) during its fast passage through the tissue (V...

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OBJECTIVE -In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis.RESEARCH DESIGN AND METHODS -We studied type 1 diabetic (n ϭ 106) and control subjects (n ϭ 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis.RESULTS -Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P Ͻ 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P Ͻ 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P Ͻ 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P Ͻ 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia.CONCLUSIONS -This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity. Diabetes Care 32:445-450, 2009

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) have been associated with neuroplasticity, but most physiological studies have evaluated only the immediate effects of the stimulation on neurochemical markers. Furthermore, although it is known that baseline excitability state plays a major role in rTMS outcomes, the role of spontaneous neural activity in metaplasticity has not been investigated. The first aim of this study was to evaluate and compare the long-term effects of high-and low-frequency rTMS on the markers of neuroplasticity such as BDNF and GluR1 subunit of AMPA receptor. The second aim was to assess whether these effects depend on spontaneous neural activity, by comparing the neurochemical alterations induced by rTMS in anesthetized and awake rats. Ten daily sessions of high-or low-frequency rTMS were applied over the rat brain, and 3 d later, levels of BDNF, GluR1, and phosphorylated GluR1 were assessed in the hippocampus, prelimbic cortex, and striatum. We found that high-frequency stimulation induced a profound effect on neuroplasticity markers; increasing them in awake animals while decreasing them in anesthetized animals. In contrast, low-frequency stimulation did not induce significant long-term effects on these markers in either state. This study highlights the importance of spontaneous neural activity during rTMS and demonstrates that high-frequency rTMS can induce long-lasting effects on BDNF and GluR1 which may underlie the clinical benefits of this treatment in neuroplasticity-related disorders.

SUMMARYPurpose: Quantitative measurement of hippocampal volume using structural magnetic resonance imaging (MRI) is a valuable tool for detection and lateralization of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE). We compare two automated hippocampal volume methodologies and manual hippocampal volumetry to determine which technique is most sensitive for the detection of hippocampal atrophy in mTLE. Methods: We acquired a three-dimensional (3D) volumetric sequence in 10 patients with left-lateralized mTLE and 10 age-matched controls. Hippocampal volumes were measured manually, and using the software packages Freesurfer and FSL-FIRST. The sensitivities of the techniques were compared by determining the effect size for average volume reduction in patients with mTLE compared to controls. The volumes and spatial overlap of the automated and manual segmentations were also compared.Results: Significant volume reduction in affected hippocampi in mTLE compared to controls was detected by manual hippocampal volume measurement (p < 0.01, effect size 33.2%), Freesurfer (p < 0.01, effect size 20.8%), and FSL-FIRST (p < 0.01, effect size 13.6%) after correction for brain volume. Freesurfer correlated reasonably (r = 0.74, p << 0.01) with this manual segmentation and FSL-FIRST relatively poorly (r = 0.47, p << 0.01). The spatial overlap between manual and automated segmentation was reduced in affected hippocampi, suggesting the accuracy of automated segmentation is reduced in pathologic brains. Discussion: Expert manual hippocampal volumetry is more sensitive than both automated methods for the detection of hippocampal atrophy associated with mTLE. In our study Freesurfer was the most sensitive to hippocampal atrophy in mTLE and could be used if expert manual segmentation is not available.

Obstructive sleep apnea is associated with abnormalities in neuropsychologic function, and defects in respiratory control may contribute to pathogenesis. Abnormalities may be reflected in structural brain changes. Twenty-seven male untreated patients with severe sleep apnea without comorbidities, and 24 age-matched control subjects, had T1-weighted brain imaging in a high-resolution magnetic resonance scanner. Twenty-three patients with sleep apnea had repeat imaging after 6 months of continuous positive airways pressure treatment. No areas of gray matter volume change were found in patients using an optimized voxel-based morphometry technique, at p < 0.05 adjusted for multiple comparisons (despite the method being sensitive to changes in gray matter fraction of 0.17 or less in all voxels). Furthermore, no differences were seen in bilateral hippocampal, temporal lobe, or whole brain volumes, assessed by manual tracing of anatomical borders. No longitudinal changes were seen in gray matter density or regional volumes after treatment, but whole brain volume decreased slightly. We have found no gray matter volume deficits nor focal structural changes in severe obstructive sleep apnea. Whole brain volume decreases without focal changes after 6 months of continuous positive airways pressure treatment.

The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo. Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders.

Human proprioception is essential for motor control, yet its central processing is still debated. Previous studies of passive movements and illusory vibration have reported inconsistent activation patterns related to proprioception, particularly in high-order sensorimotor cortices. We investigated brain activation specific to proprioception, its laterality, and changes following stroke. Twelve healthy and three stroke-affected individuals with proprioceptive deficits participated. Proprioception was assessed clinically with the Wrist Position Sense Test, and participants underwent functional magnetic resonance imaging scanning. An event-related study design was used, where each proprioceptive stimulus of passive wrist movement was followed by a motor response of mirror ­copying with the other wrist. Left (LWP) and right (RWP) wrist proprioception were tested separately. Laterality indices (LIs) were calculated for the main cortical regions activated during proprioception. We found proprioception-related brain activation in high-order sensorimotor cortices in healthy participants especially in the supramarginal gyrus (SMG LWP z = 4.51, RWP z = 4.24) and the dorsal premotor cortex (PMd LWP z = 4.10, RWP z = 3.93). Right hemispheric dominance was observed in the SMG (LI LWP mean 0.41, SD 0.22; RWP 0.29, SD 0.20), and to a lesser degree in the PMd (LI LWP 0.34, SD 0.17; RWP 0.13, SD 0.25). In stroke-affected participants, the main difference in proprioception-related brain activation was reduced laterality in the right SMG. Our findings indicate that the SMG and PMd play a key role in proprioception probably due to their role in spatial processing and motor control, respectively. The findings from stroke-­affected individuals suggest that decreased right SMG function may be associated with decreased proprioception. We recommend that clinicians pay particular attention to the assessment and rehabilitation of proprioception following right hemispheric lesions.