Gender differences in cell volume fraction (CVF): a structural parameter reflecting the energy efficiency of maintaining the resting membrane potential.

The cell volume fraction (CVF) of the human brain is high (~82%) and is preserved across healthy aging while the brain declines in volume. These two observations, supported by several independent techniques, suggest that CVF is an important structural parameter. A new biophysical model is presented that incorporates CVF into the Goldman equation of classical membrane electrophysiology. The Goldman equation contains few structural constraints beyond two compartments separated by a semipermeable membrane supporting ion gradients. As potassium is the most permeable ion in the resting state, the resting membrane potential is determined by the potassium ion gradient. This biophysical model indicates that the sodium-potassium ion pumps use less energy at high CVF to maintain the resting membrane potential, explaining the high value of CVF and its conservation with healthy aging. CVF is measured to be statistically significantly higher in the brains of males compared with females, suggesting a structural requirement for higher energy efficiency in the larger male brain to support the greater number of neurons and synapses. As CVF can be measured in humans using quantitative sodium MRI and has potential implications for brain health, CVF may be a quantitative parameter that is useful for assessment of brain health, especially in patients with diseases such as dementia and psychiatric disease that do not have anatomical correlates detectable by clinical proton MRI.

High-resolution sodium imaging using anatomical and sparsity constraints for denoising and recovery of novel features.

PURPOSE: To develop and evaluate a novel method for reconstruction of high-quality sodium MR images from noisy, limited k-space data. THEORY AND METHODS: A novel reconstruction method was developed for reconstruction of high-quality sodium images from noisy, limited k-space data. This method is based on a novel image model that contains a motion-compensated generalized series model and a sparse model. The motion-compensated generalized series model enables effective use of anatomical information from a proton image for denoising and resolution enhancement of sodium data, whereas the sparse model enables high-resolution reconstruction of sodium-dependent novel features. The underlying model estimation problems were solved efficiently using convex optimization algorithms. RESULTS: The proposed method has been evaluated using both simulation and experimental data obtained from phantoms, healthy human volunteers, and tumor patients. Results showed a substantial improvement in spatial resolution and SNR over state-of-the-art reconstruction methods, including compressed sensing and anatomically constrained reconstruction methods. Quantitative tissue sodium concentration maps were obtained from both healthy volunteers and brain tumor patients. These tissue sodium concentration maps showed improved lesion fidelity and allowed accurate interrogation of small targets. CONCLUSION: A new method has been developed to obtain high-resolution sodium images with good SNR at 3 T. The proposed method makes effective use of anatomical prior information for denoising, while using a sparse model synergistically to recover sodium-dependent novel features. Experimental results have been obtained to demonstrate the feasibility of achieving high-quality tissue sodium concentration maps and their potential for improved detection of spatially heterogeneous responses of tumor to treatment.

Quantitative sodium MR imaging: A review of its evolving role in medicine.

Sodium magnetic resonance (MR) imaging in humans has promised metabolic information that can improve medical management in important diseases. This technology has yet to find a role in clinical practice, lagging proton MR imaging by decades. This review covers the literature that demonstrates that this delay is explained by initial challenges of low sensitivity at low magnetic fields and the limited performance of gradients and electronics available in the 1980s. These constraints were removed by the introduction of 3T and now ultrahigh (≥7T) magnetic field scanners with superior gradients and electronics for proton MR imaging. New projection pulse sequence designs have greatly improved sodium acquisition efficiency. The increased field strength has provided the expected increased sensitivity to achieve resolutions acceptable for metabolic interpretation even in small target tissues. Consistency of quantification of the sodium MR image to provide metabolic parametric maps has been demonstrated by several different pulse sequences and calibration procedures. The vital roles of sodium ion in membrane transport and the extracellular matrix will be reviewed to indicate the broad opportunities that now exist for clinical sodium MR imaging. The final challenge is for the technology to be supplied on clinical ≥3T scanners.

Toward 20 T magnetic resonance for human brain studies: opportunities for discovery and neuroscience rationale.

An initiative to design and build magnetic resonance imaging (MRI) and spectroscopy (MRS) instruments at 14 T and beyond to 20 T has been underway since 2012. This initiative has been supported by 22 interested participants from the USA and Europe, of which 15 are authors of this review. Advances in high temperature superconductor materials, advances in cryocooling engineering, prospects for non-persistent mode stable magnets, and experiences gained from large-bore, high-field magnet engineering for the nuclear fusion endeavors support the feasibility of a human brain MRI and MRS system with 1 ppm homogeneity over at least a 16-cm diameter volume and a bore size of 68 cm. Twelve neuroscience opportunities are presented as well as an analysis of the biophysical and physiological effects to be investigated before exposing human subjects to the high fields of 14 T and beyond.

Hemodynamic Features of Symptomatic Vertebrobasilar Disease.

BACKGROUND AND PURPOSE: Atherosclerotic vertebrobasilar disease is an important cause of posterior circulation stroke. To examine the role of hemodynamic compromise, a prospective multicenter study, Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS), was conducted. Here, we report clinical features and vessel flow measurements from the study cohort. METHODS: Patients with recent vertebrobasilar transient ischemic attack or stroke and ≥50% atherosclerotic stenosis or occlusion in vertebral or basilar arteries (BA) were enrolled. Large-vessel flow in the vertebrobasilar territory was assessed using quantitative MRA. RESULTS: The cohort (n=72; 44% women) had a mean age of 65.6 years; 72% presented with ischemic stroke. Hypertension (93%) and hyperlipidemia (81%) were the most prevalent vascular risk factors. BA flows correlated negatively with percentage stenosis in the affected vessel and positively to the minimal diameter at the stenosis site (P<0.01). A relative threshold effect was evident, with flows dropping most significantly with ≥80% stenosis/occlusion (P<0.05). Tandem disease involving the BA and either/both vertebral arteries had the greatest negative impact on immediate downstream flow in the BA (43 mL/min versus 71 mL/min; P=0.01). Distal flow status assessment, based on an algorithm incorporating collateral flow by examining distal vessels (BA and posterior cerebral arteries), correlated neither with multifocality of disease nor with severity of the maximal stenosis. CONCLUSIONS: Flow in stenotic posterior circulation vessels correlates with residual diameter and drops significantly with tandem disease. However, distal flow status, incorporating collateral capacity, is not well predicted by the severity or location of the disease.

Feasibility of 39-potassium MR imaging of a human brain at 9.4 Tesla.

PURPOSE: To demonstrate the feasibility of performing 39-potassium MR imaging of a human brain. METHODS: 39-Potassium magnetic resonance imaging of a human brain was performed at 9.4 T using a flexible twisted projection imaging acquisition with a nominal isotropic spatial resolution of 10 mm in 40 min using a single-tuned birdcage radiofrequency coil. Co-registered sodium imaging with a nominal isotropic spatial resolution of 3.5 mm was performed on the same subject in 10 min. RESULTS: The 39-potassium flexible twisted projection imaging imaging had a signal-to-noise ratio of 5.2 in brain paranchyma. This qualitative imaging showed the expected features when compared to co-registered high- and low-resolution sodium imaging of the same subject. CONCLUSION: Potassium MR images may offer complementary information to that of sodium MR images by sampling the intracellular rather that interstitial environment. Quantification will require additional improvement in signal-to-noise ratio to produce clinically useful bioscales as are developing for sodium MR imaging.

Neuropsychological Test Performance Differentiates Subgroups of Individuals With Adult Moyamoya Disease: A Cross-Sectional Clinical Study.

BACKGROUND AND OBJECTIVES: Moyamoya disease (MMD) is a rare noninflammatory disorder involving progressive intracranial vasculopathy and impaired cerebral blood flow in the anterior circulation, resulting in stroke and cognitive impairment. We aimed to characterize cognitive impairment and the possible predictive value of sociodemographic and clinical characteristics of adults with MMD. METHODS: This cross-sectional study examined neurocognitive performance in a group of 42 consecutive adult patients (mean age = 40.52 years; 69% female) referred for a presurgical neuropsychological evaluation. Neuropsychological functioning was assessed with a comprehensive battery, and cognitive dysfunction was defined as 1.5 SDs below the mean. Neurocognitive performance correlated with clinical/demographic characteristics and disease markers. RESULTS: Most patients (91%) had a history of stroke, and 45% had cognitive deficits, most notably on measures of attention/speed (48%), executive functioning (47%), visuoconstruction (41%), and memory (31%-54%). Only higher educational attainment and poor collateral blood flow in the right hemisphere differentiated cognitively impaired (n = 19) and intact groups (n = 23), and MMD-related characteristics (eg, disease duration, stroke history) did not differentiate the 2 groups. CONCLUSION: Consistent with previous work, frontal-subcortical cognitive deficits (eg, deficits in mental speed, attention, executive functioning) were found in nearly half of patients with MMD and better cognitive performance was associated with factors related to cognitive reserve. Angiographic metrics of disease burden (eg, Suzuki rating, collateral flow) and hemodynamic reserve were not consistently associated with poorer cognitive outcomes, suggesting that cognition is a crucial independent factor to assess in MMD and has relevance for treatment planning and functional status.

PCr/ATP ratio mapping of the human head by simultaneously imaging of multiple spectral peaks with interleaved excitations and flexible twisted projection imaging readout trajectories at 9.4 T.

Quantitative (31)P magnetic resonance imaging of the whole human brain is often time-consuming even at low spatial resolution due to the low concentrations, long T(1) relaxation times, and low detection sensitivity of phosphorus metabolites. We report herein the results of combining the increased detection sensitivity of an ultra-high field 9.4 T scanner designed for human imaging with a new pulse sequence termed simultaneously imaging of multiple spectral peaks with interleaved excitations and flexible twisted projection imaging readout trajectories to rapidly sample multiple resonances in the (31)P spectrum. The phosphocreatine and γ-adenosine triphosphate images, obtained simultaneously from the entire human head, are demonstrated at 1.5 cm isotropic nominal resolution in a total acquisition time of 33 min. The phosphocreatine/γ-adenosine triphosphate ratio calculated for brain parenchyma (1-2) and the superficial temporalis muscle (3-5) are in agreement with literature values.

My starting point: the discovery of an NMR method for measuring blood oxygenation using the transverse relaxation time of blood water.

This invited personal story, covering the period from 1979 to 2010, describes the discovery of the dependence of the transverse relaxation time of water in blood on the oxygenation state of hemoglobin in the erythrocytes. The underlying mechanism of the compartmentation of the different magnetic susceptibilities of hemoglobin in its different oxygenation states also explains the mechanism that underlies blood oxygenation level dependent contrast used in fMRI. The story begins with the initial observation of line broadening during ischemia in small rodents detected by in vivo 31P NMR spectroscopy at high field. This spectroscopic line broadening or T2* relaxation effect was demonstrated to be related to the oxygenation state of blood. The effect was quantified more accurately using T2 values measured by the Carr-Purcell-Meiboom-Gill method. The effect was dependent on the integrity of the erythrocytes to compartmentalize the different magnetic susceptibilities produced by the changing spin state of the ferrous iron of hemoglobin in its different oxygenation states between the erythrocytes and the suspending solution. The hematocrit and magnetic field dependence, the requirement for erythrocyte integrity and lack of T1 dependence confirmed that the magnetic susceptibility effect explained the oxygenation state dependence of T2* and T2. This T2/T2* effect was combined with T1 based measurements of blood flow to measure oxygen consumption in animals. This blood oxygenation assay and its underlying magnetic susceptibility gradient mechanism was published in the biochemistry literature in 1982 and largely forgotten. The observation was revived to explain evolving imaging features of cerebral hematoma as MR imaging of humans increased in field strength to 1.5 T by the mid 1980s. Although the imaging version of this assay was used to measure a global metabolic rate of cerebral oxygen consumption in humans at 1.5-T by 1991, the global measurement had little clinical value. By contrast, a decade after the spectroscopic observation, imaging experiments performed on rodents at 7 T by Ogawa and colleagues identified the extravascular T2* imaging characteristics of the blood oxygenation effect and, most importantly, associated that change with brain functional states. Ogawa appropriately branded this blood oxygenation level dependent mechanism as BOLD contrast. This mechanism was subsequently shown to be the basis of localized MR signal changes associated with local brain function. This connection led to the fMRI revolution in human brain mapping.

Preserving the accuracy and resolution of the sodium bioscale from quantitative sodium MRI during intrasubject alignment across longitudinal studies.

Emerging applications of sodium bioscales derived from quantitative sodium magnetic resonance imaging assess temporal changes in regional sodium concentration over intervals that vary from hours (monitoring tissue viability in stroke) to weeks (monitoring brain tumor treatment during radiation therapy) or even years (monitoring progression of neurodegenerative disease). Accurate interpretation of such quantitative data requires precise registration between magnetic resonance imaging sessions to avoid session-to-session changes in partial volume effects between normal tissue (∼38 mM sodium concentration), lesions (variable sodium concentration), and cerebrospinal fluid (∼144 mM sodium concentration). The existing Automated Image Registration algorithm is shown to be suitable for rapid, accurate, and precise determination of the transform that aligns sodium magnetic resonance images. Implementation of this transform during image reconstruction from the k-space data is shown to produce smaller errors than conventional image-domain interpolation. Experimental results at 9.4 T and 3.0 T demonstrating this registration approach to sodium data illustrate preservation of quantification accuracy during alignment of sodium magnetic resonance images acquired from the same subject during different imaging sessions.

Clinically constrained optimization of flexTPI acquisition parameters for the tissue sodium concentration bioscale.

The rapid transverse relaxation of the sodium magnetic resonance signal during spatial encoding causes a loss of image resolution, an effect known as T(2)-blurring. Conventional wisdom suggests that spatial resolution is maximized by keeping the readout duration as short as possible to minimize T(2)-blurring. Flexible twisted projection imaging performed with an ultrashort echo time, relative to T(2), and a long repetition time, relative to T(1), has been shown to be effective for quantitative sodium magnetic resonance imaging. A minimized readout duration requires a very large number of projections and, consequentially, results in an impractically long total acquisition time to meet these conditions. When the total acquisition time is limited to a clinically practical duration (e.g., 10 min), the optimal parameters for maximal spatial resolution of a flexible twisted projection imaging acquisition do not correspond to the shortest possible readout. Simulation and experimental results for resolution optimized acquisition parameters of quantitative sodium flexible twisted projection imaging of parenchyma and cerebrospinal fluid are presented for the human brain at 9.4 and 3.0T. The effect of signal loss during data collection on sodium quantification bias and image signal-to-noise ratio are discussed.

Detection of intracranial in-stent restenosis using quantitative magnetic resonance angiography.

BACKGROUND AND PURPOSE: In-stent restenosis (ISR) after angioplasty/stenting for intracranial stenosis has been reported in up to 25% to 30% of patients. Detection and monitoring of ISR relies primarily on serial catheter angiography, because noninvasive imaging methods are typically hampered by stent-related artifact. We examined the value of serial vessel flow measurements using quantitative magnetic resonance angiography (QMRA) in detection of ISR. MATERIAL AND METHODS: Records of patients undergoing stenting for intracranial symptomatic stenosis >50% between 2005 and 2009 were retrospectively reviewed. Angiographic images were graded by a blinded neurointerventionalist for stenosis pretreatment, immediately after treatment, and during follow-up. Flow in the affected vessel measured by QMRA was recorded; > 25% reduction in flow was considered indicative of an adverse change. Clinical data regarding neurological outcome were also collected. RESULTS: Twenty-eight patients underwent stenting during the time interval studied. Of these, 12 patients (mean age, 55.5 years; 8 female) had contemporaneous angiography and QMRA and were analyzed. Median follow-up was 9 months. Six patients (50%) demonstrated angiographic restenosis 2 to 12 months after treatment; all had an analogous decrease in flow in the vessel of interest. Of 3 patients with more severe flow decrement (> 50%), 2 experienced stroke. None of the patients without angiographic ISR demonstrated a flow decrease on QMRA. CONCLUSIONS: In this preliminary series, flow decrease on QMRA is highly predictive of angiographic ISR. Additionally, the degree of flow decrement correlates with symptomatic ISR. QMRA may provide a useful noninvasive tool for serial monitoring after intracranial stenting.

Feasibility of mapping the tissue mass corrected bioscale of cerebral metabolic rate of oxygen consumption using 17-oxygen and 23-sodium MR imaging in a human brain at 9.4 T.

The reduction of molecular oxygen to water is the final step of oxidative phosphorylation that couples adenosine triphosphate production to the reoxidation of reducing equivalents formed during the oxidation of glucose to carbon dioxide. This coupling makes the cerebral metabolic rate of oxygen consumption (CMRO(2)) an excellent reflection of the metabolic health of the brain. A multi-nuclear magnetic resonance (MR) imaging based method for CMRO(2) mapping is proposed. Oxygen consumption is determined by applying a new three-phase metabolic model for water generation and clearance to the changing 17-oxygen ((17)O) labeled water MR signal measured using quantitative (17)O MR imaging during inhalation of (17)O-enriched oxygen gas. These CMRO(2) data are corrected for the regional brain tissue mass computed from quantitative 23-sodium MR imaging of endogenous tissue sodium ions to derive quantitative results of oxygen consumption in micromoles O(2)/g tissue/minute that agree with literature results reported from positron emission tomography. The proposed technique is demonstrated in the human brain using a 9.4 T MR scanner optimized for human brain imaging.

Quantitative sodium imaging with a flexible twisted projection pulse sequence.

The quantification of sodium MR images from an arbitrary intensity scale into a bioscale fosters image interpretation in terms of the spatially resolved biochemical process of sodium ion homeostasis. A methodology for quantifying tissue sodium concentration using a flexible twisted projection imaging sequence is proposed that allows for optimization of tradeoffs between readout time, signal-to-noise ratio efficiency, and sensitivity to static field susceptibility artifacts. The gradient amplitude supported by the slew rate at each k-space radius regularizes the readout gradient waveform design to avoid slew rate violation. Static field inhomogeneity artifacts are corrected using a frequency-segmented conjugate phase reconstruction approach, with field maps obtained quickly from coregistered proton imaging. High-quality quantitative sodium images have been achieved in phantom and volunteer studies with real isotropic spatial resolution of 7.5 x 7.5 x 7.5 mm(3) for the slow T(2) component in approximately 8 min on a clinical 3-T scanner. After correcting for coil sensitivity inhomogeneity and water fraction, the tissue sodium concentration in gray matter and white matter was measured to be 36.6 +/- 0.6 micromol/g wet weight and 27.6 +/- 1.2 micromol/g wet weight, respectively.

Vital signs and cognitive function are not affected by 23-sodium and 17-oxygen magnetic resonance imaging of the human brain at 9.4 T.

PURPOSE: To evaluate the effect of 23-sodium ((23)Na) and 17-oxygen ((17)O) magnetic resonance imaging (MRI) at 9.4 (T) on vital signs and cognitive function of the human brain. MATERIALS AND METHODS: Vital sign and cognitive function measurements from healthy volunteers (N = 14) positioned outside and at isocenter of a 9.4 T scanner before and after (23)Na and (17)O MRI were compared for changes due to exposure to the static magnetic field and to the gradient switching and radiofrequency radiation during MRI. RESULTS: Exposure to the 9.4 T static magnetic field and (23)Na and (17)O MRI at 105.92 MHz and 54.25 MHz, respectively, did not have a statistically significant (P > 0.05) effect on the vital signs or cognitive function of healthy normal adults. CONCLUSION: (23)Na and (17)O MRI of the human brain at 9.4 T does not have any readily demonstrated health risks reflected in vital signs or change in cognitive performance.

Investigating the consistency of brain activation using individual trial analysis of high-resolution fMRI in the human primary visual cortex.

Conventional functional magnetic resonance imaging using blood oxygenation level dependent contrast requires signal averaging and statistical methods to detect activation. Signal averaging implicitly assumes that brain activation in response to a stimulus is reproducible on the scale of the imaging voxel. This assumption is examined in the absence of averaging by analyzing individual trials of individual voxels that approach the size of the functional unit, the cortical column, in the human primary visual cortex. In the absence of spatial and temporal averaging, even highly active voxels demonstrate inconsistent activation to the same repeated stimulus despite consistent behavioral responses. This observation implies a variable selection of suitable cortical columns from a population of available functional units to produce consistent perception of the stimulus. The implication of this observation for neuroplasticity and behavioral consistency at the level of functional units is discussed.

Characterization and correction of system delays and eddy currents for MR imaging with ultrashort echo-time and time-varying gradients.

Reconstruction of high-quality MR images requires precise knowledge of the dynamic gradient magnetic fields used to perform spatial encoding. System delays and eddy currents can perturb the gradient fields in both time and space and significantly degrade the image quality for acquisitions with an ultrashort echo time or with rapidly varying readout gradient waveforms. A technique for simultaneously characterizing and correcting the system delay and linear- and zero-order eddy currents of an MR system is proposed. A single set of calibration scans were used to compute a set of system constants that describe the effects of system delays and eddy currents to enable accurate reconstruction of data collected before uncorrected eddy currents have decayed. The ability of the proposed technique to reproducibly characterize small fixed delays (<50 micros) and short-time constant (<1 ms) eddy currents is demonstrated.

Motion reduction for quantitative brain sodium MR imaging with a navigated flexible twisted projection imaging sequence at 9.4 T.

Quantitative measurement of the tissue sodium concentration (TSC) provides a metric for tissue cell volume fraction for monitoring tumor responses to therapy and neurodegeneration in the brain as well as applications outside the central nervous system such as the fixed charge density in cartilage. Despite the low detection sensitivity of the sodium MR signal compared to the proton signal and the requirement for a long repetition time to minimize longitudinal magnetization saturation, acquisition time has been reduced to less than 10 min for a nominal isotropic voxel size of 3.3 mm with the improved acquisition efficiency of twisted projection imaging (TPI) at 9.4 T. However, patient motion can degrade the accuracy of the quantification even within these acquisition times. Our goal has been to improve the robustness of quantitative sodium MR imaging by minimizing the impact of motion that may occur even in cooperative patients. We present a method to spatially encode a lower resolution navigator echo after encoding the free induction decay signal for the quantitative image at no time penalty. Both the imaging and navigator data are sampled with flexTPI readout trajectories. Navigator images are generated at a higher temporal resolution (∼1 min) albeit at lower spatial resolution (8 mm) than the quantitative high-resolution images. The multiple volumes of navigator echo images are then aligned to extract the translational and rotational motion parameters assuming rigid-body motion. These parameters are used to align the k-space data during the acquisition of each volume of the quantitative images. Our results show significantly reduced image blurring with this method when the subject's head moved randomly by up to 7° between the navigator acquisitions.

Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging.

PURPOSE: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival. EXPERIMENTAL DESIGN: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas (n = 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival. RESULTS: RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases back toward normal as infiltrating tumor cells were killed, or decreases as cancer cells continued to infiltrate and extend tumor margins. These highly variable tumor responses showed no correlation with time-to-progression or overall survival. CONCLUSIONS: These bioscales indicate that fractionated chemoradiotherapy of glioblastomas produces variable responses with low cell killing efficiency. These parameters are sensitive to real-time changes within the treatment volume while remaining stable elsewhere, highlighting the potential to individualize therapy earlier in management, should alternative strategies be available.

An FMRI study of saccadic and smooth-pursuit eye movement control in patients with age-related macular degeneration.

PURPOSE: To compare the cortical networks that underlie oculomotor function in patients with age-related macular degeneration (AMD) with those in normally sighted control subjects, using functional magnetic resonance imaging (fMRI). METHODS: Six patients with bilateral geographic retinal atrophy due to AMD (age range, 55-83 years) were recruited for the study. The visual acuities of the patients ranged from 20/76 (0.58 logMAR) to 20/360 (1.26 logMAR). An additional six younger (age range, 22-31 years) and six older (age range, 54-78 years) normally sighted individuals were recruited as control subjects. fMRI data were acquired on a 3.0-Tesla, scanner while subjects performed visually guided saccade (VGS) and smooth-pursuit (SmP) tasks. RESULTS: Contrasts between VGS and fixation on a stationary target identified a network of activation that included the frontal eye fields (FEFs), supplementary eye fields (SMA/SEFs), prefrontal cortex (PFC), intraparietal sulci (IPS), and the areas of the visual cortex (MT/V5, V2/V3, and V1) in control subjects and patients. A similar network was identified for comparisons between SmP and periods of fixation. Marked variability was observed in the performance of both tasks across all patients. For both tasks, the patients generally showed increased PFC and IPS activation, with decreased activation in visual cortex compared with the control subjects. The patients showed significantly increased activation of the FEFs and SMA/SEFs in the SmP task, compared with the control subjects. CONCLUSIONS: These data suggest that performance of both eye movement tasks required greater involvement of the cortical regions generally implicated in attention and effort in patients with AMD.