Magnetic resonance imaging using deoxyhemoglobin contrast versus positron emission tomography in the assessment of brain function

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NeuroPsychopharmamL

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1995. Vol. 19. pp. 351-366 0 1995 Elsetier Science Ltd Britah 0278

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MAGNETIC RESONANCE IMAGING USING DEOXPHEMOGLOBIN CONTRAST VERSUS POSITRON EMISSION TOMOGRAPHY IN THE ASSESSMENT OF BRAIN FUNCTION

PRADEEP RAJAGOPALANI, K. RANGA KRISHNANI, THEODORE J. PASSEI and JAMES R. MACFALL2 IDepartments of Psychiatry and *Radiology Duke University Medical Center, Durham, NC, USA

(Final form, September 1994)

1. 2. 3. 4. 5. 6. 7.

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Abstract Introduction PETasaModel Principles of Magnetic Resonance Imaging Principles of MR Functional Brain Imaging Future Applications of Functional MRI Future Directions Conclusion References

Rajagopalan, Pradeep, K. Ranga Krishnan, Theodore J. Passe and James R. Macfall: Magnetic Resonance Imaging Using Deoxyhemoglobin Contrast versus Positron Emission Tomography in the Assessment of Brain Function. Prog. Neuro-Psychopharmacol. & Biol. Psychlat. 1995, 19(3): 351-366. 1. Function of the brain can be assessed through radiologic imaging to determine physiology of underlying tissue. 2. Until recently, positron emission tomography has been the standard tool with which to study function. 3. In the past few years, several investigators have attempted to use magnetic resonance imaging, which has better resolution and is less expensive, to provide functional information 4. A noninvasive technique termed BOLD (blood oxygen level dependent) has become a popular area of research to determine physiologic change that occurs in the brain in resting as well as activated states. 5. Thls article reviews what information PET has given us with regard to function of the brain, followed by a discussion of the principle of functional MRI of the brain with emphasis on what has been done in this field as well as future application of the technique. w:

brain, function, imaging, magnetic resonance, oxygen, positron emission tomography, resolution.

. Akhsdms

Alzheimer’s Disease (AD), blood oxygen level dependent (BOLD), computed tomography (CT), deoxyhemoglobin (deoxyhb), magnetic resonance imaging (MRI), obsessive-compulsive disorder (OCD), oxyhemoglobin (oxyhb), positron emission tomography (PET), re gional cerebral blood flow (rCBF).

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1. introduction Imaging of the brain, using various radiologic tools such as CT and MRI, has been used as a diagnostic tool in the field of medicine for many years. Using these techniques, anatomic structure can be well depicted and static abnormalities such as tumors, infarct and hemorrhage are relatively simple to diagnose as long as they appear different than surrounding normal tissue. However, although medical imaging is quite good at representing normal and abnormal anatomic structure, representations of functional information regarding the brain have been more difficult to obtain. Function, as it relates to biology, can be thought of as the physiologic property of a system, organ, tissue or cell. Structure underlies function, but is not necessarily the optimal vehicle for its depiction (Brady et al., 1992). More recently (1980’s and 90’s), imaging techniques have come about to try and study the physiologic mechanisms that contribute to normal as well as abnormal brain function. Nuclear medicine, EEG and positron emission tomography (PET) were the initial methods used to study functional information. PET has especially been useful in dete rmining regional blood flow, oxygen extraction fractions, total blood volume, glucose consumption rates and glucose metabolism in certain areas of the brain (Faulstich and Sullivan, 1991; Fox et al., 1986; Fox et al., 1987; Guze et al., 1991b). More recently, PET imaging has been used to study differences in blood flow and metabolism in certain disease states. Although the informational content of images obtained using these modalities can be high, their relatively low spatial resolution places limits on their application to problems seen daily in medical practice (Brady et al., 1992). More recently, nuclear magnetic resonance (MR) imaging has entered the field of functional study of the brain. MRI can generate much higher resolution images and can provide functional information in part because of the large number of parameters that can effect MR image contrast (proton density, Tl and T2 relaxation, chemical shift, flow, magnetic susceptibility and diffusion). Each of these parameters can be exploited to assess various functional activities of the brain. Assessment of cerebral hemodynamics has previously been demonstrated with serial imaging during first pass transit of MR contrast agents - the susceptibility induced signal loss that accompanies transit of agent through the region of interest is proportional to the tissue blood volume of that region (Rosen et al., 1991). Using this method, maps of blood volume have been generated which compare favorably with the former PET studies. There have been more recent reports without the use of contrast agents of the measurement of cerebral blood flow changes that occur during various task activations. These MR methods take advantage of the body’s own endogenous contrast agent, deoxyhemoglobm (Bandettini et at., 1992; Constable et al., 1993; Frahm et al., 1992; Ogawa et al., 1992; Turner et al., 1993). Refinements in fast MR imaging to decrease motion artifacts and improve spatial resolution further are making this method even more applicable to study brain function in more clinically related situations. The purpose of this paper is to introduce and describe functional MR imaging using the endogenous contrast agent, deoxyhemoglobin.

The potential applications for this method with regard to clinical states as well as

the advantages and disadvantages of the technique with regard to other imaging modalities will also be looked at. Finally, the future of functional MR imaging will be discussed with regard to improvements in technology. First, previous work that has been done to study brain function using PET imaging will be presented.

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2. FET Positron emission tomography has been used in the exploration of brain metabolism in health and disease for almost two decades (Robinson and Harbert, 1992). PET is a nuclear medical technique that takes advantage of the fact that certain radioactive nuclei emit a positron when they decay that in turn results in the simultaneous emission of a pair of photons that travel in opposite directions (Correia, 1992). These photons can then be detected by special radiation detection devices. This allows the computation of the concentration of radioisotope regionally in an organ and may therefore yield quantitative physiological information that can be presented in image form (Correia, 1992). The most widely applied type of study with PET uses deoxyglucose labelled with fluorine-18 as an indicator of regional cerebral metabolism. Other studies measure the local uptake of oxygen-15 as an indirect indicator of regional cerebral blood flow since in the normal brain oxygen uptake and blood flow are closely linked (Robinson and Harbert, 1992). Using these methods the physiology of many disease states, including psychiatric disorders, may be revealed. In temporal lobe epilepsy for which surgical resection of the epileptogenic zone is a therapeutic option, PET studies show that glucose metabolism and blood flow were increased at the epileptogenic focus during seizures, and subsequently reduced there during interictal states (Chugani, 1992). Here, the application of PET may increase the chance of successful operation without the need for chronic EEG monitoring.

PET can

also be used to select patients who have suffered a stroke for surgical revascularization procedures, or for intensive drug therapy and rehabilitation based on where abnormalities are seen with respect to glucose consumption and local blood flow (Heiss et al., 1983; Ackerman et al., 1981). PET studies have also shown that glucose uptake in malignant tumors parallels the degree of malignancy and neovascularization and that prognosis appears to be inversely related to tumor uptake of glucose (Patronas et al., 1982). This information can be used to differentiate between residual necrosis and recurrent disease after initial treatment (Patronas et al., 1982). PET is also currently being used to study metabolic changes that occur in certain neuropsychiatric diseases such as schizophrenia, Huntington’s chorea and Alzheimer’s disease. Studies of schizophrenia have suggested reduced glucose metabolism in the frontal areas in patients with this disease (Wik and Wiesel, 1991). Friston et al. (1992) used PET to show that increasing severity of psychopathology in schizophrenia was associated with increased regional cerebral blood flow in the left medial temporal region, mesencephalic, thalamic and left striatal structures, the highest correlation being in the left parahippocampal region. More recently, the investigation of cerebral metabolism in psychoses has concentrated on receptor studies using compounds such as carbon-11-labelled methyl spiperone, which binds to D2 receptors, and have shown a substantial difference between schizophrenic patients and control subjects (Coppens et al., 1991). However, Martinot et al. (1991) suggest that there is no quantitative abnormality of striatal D2 dopamine receptors in schizophrenia.

Focal reduction in glucose metabolism in the caudate nucleus and putamen has been

observed in Huntington’s chorea using PET (Mazziotta et al ., 1985). With regard to Alzheimer’s Disease (AD), Guze et al. (1991a) have shown symmetrical reduction of regional oxygen uptake and local blood flow in the parietal and adjacent sections of temporal and occipital lobes, with the frontal lobes less severely involved. More recent studies on Alzheimer’s have suggested that the reductions in metabolism seen with PET progress with severity and extent as the disease itself shows clinical progression (Guze et al., 1991a; Sakamoto, 1990). There have also been PET studies done on Alzheimer’s disease looking at glucose metabolism as a measure of energy metabolism in the brain (which is closely coupled to brain function) as

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well as to differentiate it from other psychiatric disorders (Murphy et al., 1993; Karbe et al., 1992; Guze et al, 1991b; Heiss et al., 1991; Jagust et al., 1991; Grady et al., 1990). Disturbances in glucose metabolism appear in AD once again in the parietotemporal association cortex and later in the frontal lobe, whereas primary cortical areas, basal ganglia, thalamus, brainstem and cerebellum are relatively spared (Heiss et al., 1991). It is this typical pattern that can distinguish Alzheimers from other forms of dementia. It has also been demonstrated that patients with Parkinson’s disease showed no significant change in regional cerebral metabolic rates for glucose (Karbe et al., 1992). Guze et al. (1991b) demonstrated that there was significant differences in the local cerebral glucose metabolic rate in both unipolar and bipolar depression when compared with Alzheimer’s dementia. These data suggest that PET may be useful in the differential diagnosis of dementia vs. depression and Parkinson’s disease. Finally, Grady et al. (1990) suggested that glucose metabolism studies could be used to classify different subgroups of Alzheimer’s patients based on where hypometabolism was seen. The advantage of PET imaging lies mainly in its ability to study metabolism and blood flow in the brain. In addition, the radiopharmaceuticals used in PET can be constructed so that they are almost identical chemically and physically to naturally occurring substrates (Faulstich and Sullivan, 1991). PET technology can measure biochemical activity at discrete brain regions without disturbing the ongoing physiologic processes of interest (Faulstich and Sullivan, 1991). Finally, PET studies with neumreceptors may guide the synthesis of specific pharmacologic agents to target particular neurotransmttter systems (Faulsttch and Sullivan, 1991). There are also many disadvantages to PET imaging that underlie the fact that the method has not yet reached the mass market of clinical utilization. One reason is the cost of the equipment required to perform PET studies. ln addition to the positron emission camera, the production of suitable positron emitting radiopharmaceuticals requires a cyclotron or a powerful linear accelerator (Robinson and Harbert, 1992). Also the tracers used have short half-lives, which further limits the range of applications in a clinical situation (Robinson and Harbert, 1992). The fact that these tracers are radioactive is also unappealing to many people. There is limited availability of PET technology and the complex nature of the technical aspects of PET studies requires a staff of trained experts to carry out studies (Correia, 1992). Methodological factors such as variations and limitations in scanning techniques and study design, variations and inaccuracies in tracer kinetic models, and diagnostic heterogeneity contribute to contradictory data that have been reported in the psychiatric studies (Faulstich and Sullivan, 1991). For example, the equipment and techniques at the relatively few PET centers vary considerably (Faulstich and Sullivan, 1991). Finally, the spatial resolution of PET is relatively low when compared to MRI. All of these limitations and disadvantages of PET technology have opened the door for magnetic resonance to provide functional information in hopes of beiig able to evaluate brain disorders in the typical clinical environment. 3. p The technique of nuclear magnetic resonance to account for the structure of atomic spectra has been around for many years. The first magnetic resonance (MR) images were published in 1973 by Lauterbur and since then a tremendous amount of progress has been made in improving the quality and reducing the time in which images are produced (Margulis, 1983). One attractive thing about MRI is that it combines the advantages of the other imaging modalities without sharing some of their disadvantages. Like x-ray computed tomography (CT), MR is a computer based imaging modality that displays the body in thin

MRI using DeoxyHb Contrast vs. PET to Assess Brain Function tomographic slices (Bradley, 1985). Unlike CT, which requires ionizing radiation, MR is based on what appears to be a safe interaction between radio waves and hydrogen nuclei (Bradley, 1985). Also, MR can image three planes (axial, coronal, sagittal), whereas CT can only image in two planes (axial, coronal). Like ultrasound (which is also non-ionizing) MR offers a great deal of tissue information (Margulis, 1983). Similar to nuclear medicine, MR has the potential to follow metabolic processes and give information about physiology. MR imaging relies on the magnetic properties of hydrogen nuclei as well as the chemical and physical environment in which the hydrogen protons reside. Physical characteristics of a volume element (voxel) are translated by the computer into a two-dimensional image comprised of picture elements, or pixels (Bradley, 1985). Images produced have a spatial resolution of at least 0.8mm (similar to CT) and a contrast resolution that exceeds 500% in soft tissue which results in outstanding anatomic detail (Margulis, 1983). Other advantages of MR imaging include the fact that the signal obtained and subsequently,imaged is a synthesis of many more parameters than the signal of any other imaging modality. This includes hydrogen density, Tl and T2 relaxation times, chemical shift, flow, magnetic susceptibility and diffusion (Margulis, 1983). Each of these parameters can be manipulated so that optimal information about disease processes is obtained. Also, because it takes approximately SOmsec to register the signal obtained from protons residing in a field, information about motion can be observed (Margulis, 1983). For example, if the hydrogen protons move through the plane of imaging at faster rate, no signal will be recorded - this in itself can provide valuable information about the status of patency of blood vessels (Margulis, 1983). In addition, the number of techniques for obtaining the image is enormous. Saturation recovery, spin echo, and inversion recovery techniques offer many ways of acquiring data. Also, the pulse interval (TR) or spin echo delay (TE) times can be varied to obtain information in various processes (Margulis, 1983). Although MRI is not rivaled in providing valuable morphological information without any known harmful biologic side effects, it does carry with it some disadvantages. For one, the long barrel of the magnet induces claustrophobia in some patients (although the recent development of “open” MRI alleviates this problem somewhat). In addition, any loose metallic objects, ferromagnetic clips and cardiac pacemakers should not be introduced into the magnetic field of the imager (Margulis, 1983). Also, parameters such field strength, slice thickness, echo delay time, and field of view still need to be optimized to produce the best spatial resolution and signal to noise ratio while minimizing motion artifact. In spite of these minor disadvantages, MR imaging appears to be an optimal modality to provide functional information of the brain.

During the late 1980s and early 199Os, methods have come about to attempt to study blood flow and metabolism in the brain using MR imaging. As stated before, blood flow can provide information on the biological function of the brain since the metabolic activity of brain tissue is well correlated with oxygen supply (which depends on blood flow). Several techniques have come about in recent years to aid the assessment of regional brain function using MRI. This includes measurement of water diffusion (Le Biian et al., 1986), temperature (Bleier et al., 1991), and motion (Poncelet et al., 1992). These advancements have extended the anatomic capabilities of conventional MRI methods to the acquisition of tissue function maps of high spatial and temporal resolution (Rosen et al., 1993). Because magnetic susceptibility contrast agents strongly affect tissue signal intensity, dynamic contrastbased studies have shown considerable promise toward providing functional information in preliminary

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studies (Rosen et al., 1991). This method has been aided by two developments; namely, high-speed gradient echo and echo-planar imaging to increase the speed of MR data collection (Rosen et al., 1993). Contrast imaging has been especially useful in studying blood flow, blood volume, and blood oxygenation in normal as well as disease states. The principle behind the use of MR contrast agents to assess cerebral hemodynamics is that the signal loss that accompanies passing of the agent through the region of interest is proportional to the tissue blood volume of that region (Brady et al., 1992). Aronen et al. (1992) used this technique to grade brain tumors as well as assess prognosis. Other studies have provided information as to the temporal and anatomic evaluation of acute stroke as well as the differentiation between Alzheimer’s disease and multiinfarct dementia (Rosen et al., 1993). The first demonstration that the local vascular response to a simple visual task could be mapped by MRI came in 1991 (Belliveau et al.) using contrast imaging. Based on the principle that physiological function, energy metabolism and localized blood supply are linked, Belliveau et al. (1991) used dynamic susceptibilitycontrast h4R imaging of an intravenously administered paramagnetlc contrast agent (gadolinium-DPTA)

to

produce regional cerebral blood volume maps during resting and activated states. These functional maps corresponded well to maps created by PET radionuclide techniques but provided better spatial and temporal

More recently, it has been shown by investigators at Massachusetts General Hospital, the Univ. of Minnesota and the Medical College of Wisconsin that the same thing could be accomplished non-inzmively using the endogenous paramagnetic contrast agent, deoxyhemoglobin. that the magnetic-susceptibility

Thulbom et al. (1982) first observed

effect of paramagnetic deoxyhemoglobin led to a 72 shortening of blood,

therefore establishing the first link between MR signal intensity and the oxygenation state of blood. Then Ogawa et al. (1990a) suggested the phrase Blood Oxygen Level Dependent (BOLD). His group noted numerous dark lines of various sizes in the MR brain images of live mice and rats that correlated with blood vessels (verified by optical microscopy of fixed slices) (Ogawa et al., 1990b). He concluded that these dark lines appeared when the oaramaenetic (magnetic moments due to unpaired electrons -in this case iron) s

content in the red cells increased (i.e. under anoxy conditions) but was not present in the

brain with -(zero

magnetic moment due to oxygen bound iron) v

(i.e. 100% 02

breathed in) (Ogawa et al., 1990b). The principle behind this revolutionary finding is that the magnetic susceptibility change in the blood due to paramagnetic deoxyhemoglobin (deoxyhb) creates static held inhomogeneities which causes irreversible magnetic spin dephasing of the water proton signals ln the blood compared to the surrounding tissue - this causes the blood to appear darker than the surrounding tissue (Ogawa et al., 1990a; Ogawa et al., 1990b). It is thought that the deoxyhb acts to shorten T2* relaxation which is the apparent decay rate of transverse magnetization that is applied to the field (Turner et al., 1993). Ogawa concluded that the contrast seen between the blood vessels and surrounding tissues was determined by the balance of supply (blood flow) and demand (oxygen extraction by tissue) (Ogawa et al., 199Oa). As with PET images, regional blood flow measurements with MR images can be a good physiologic study of the brain since the metabolic activity of brain tissue is well correlated with oxygen supply and therefore to blood flow. One possibility using the method introduced by Ogawa is to use the changes in the level of deoxyhemoglobin to measure regional tissue oxygen consumption which is an important indicator of organ

MRI using DeoxyHb ConLrast vs. PET

Lo Assess

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Function

function (Brady et al., 1992). This can be applied to various disease states to gain information into physiological changes occurring in the brain. More recent reports using this method demonstrate real time regional changes in MR signal in the brain in response to various task activations (Fig. 1). The principle here is that with task activation, there is a regional increase in blood flow. This increase in blood flow (and oxyhb) simultaneous with a reduction in deoxyhb produces regional signal intensity enhancement on MR images in the area of activation (Brady et al., 1992). The observed signal increase represents a transient hyperoxemia due to a large increase in regional blood volume compared to only a mild enhancement of oxygen consumption in that area (Frahm et al., 1993). This increase in blood volume, and simultaneous reduction in deoxyhb, is believed to occur mainly in the venous rather than the arterial part of the blood pool since the oxygen saturation Lnthe arterial blood remains fairly constant (Frahm et al., 1992). Studies that have been carried out include observed changes in the visual cortex during photic stimulation (Frahm et al., 1992; Frahm et al., 1993; Turner et al., 1993; Kwong et al., 1992; Ogawa et al., 1992). Each of these groups was able to create a functional oxygenation map of the calcarine cortex (anatomic location of the human primary visual cortex) using a light source with the signal intensity confined to the visual cortex. The maps created compared favorably with previous PET studies looking at the same thing (Fox et al., 1986; Fox et al., 1987) but again with much better spatial resolution.

Other studies have

tried to map regions of the motor cortex by having patients do various finger movements while being scanned (Bandettini et al., 1992; Constable et al., 1993). Bandettini et al. (1992) had subjects perform finger

Fig, 1. MR images during task activation showing areas of increased signal intensity. (A) Sequential, selfpaced tapping of each finger to thumb, left and right hands (axial cut). (8) Listening to spoken words, reading text (axial cut). Images provided by Peter Bandettini, Medical College of Wisconsin.

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Fig. 1. (C) Listening

to music

FI al.

(COrOnd

cut).

movements to show that the brightest region of signat mtensity in the cortex was in the hemisphere contralateral to the hand performing the task in the primary motor and sensory cortices using both coronal and axial images. Each of these groups reported signal increases in the primary motor and sensory areas functionally associated with the task. Signal increase observed with all these studies ranged from 4 to 25 % depending on magnetic field strength (1.5 tesla to 4 tesla). More recently, several groups have attempted to look at signal increases that occur in the brain with cognitive stimulation (Rao et al., 1993a; Bandettini et al., 1993; Rueckert et al., 1993). These studies attempt to look at speech and language organization in brain through observed increases in signal intensity when presented with more complex mental and cognitive tasks. The problem with cognitive studies is that PET literature shows that there is a much greater increase in blood flow in the motor areas of the brain during voluntary movements than there is in the cognitive areas during mental operations.

Roland et al. (1980) found a 40.4% increase in blood flow to the motor hand area of

the brain during isolated finger movements of the contralateral hand when compared to resting state. This same group found only a 14.9% increase in blood flow to the whole brain during tasks that involved thinking with a maximum increase of 28% to any particular area (Roland and Friberg, 1985; Roland et al., 1987). Therefore, at this time, studies looking at motor tasks are more reliable at 1.5T than studies involving cognitive stimulation.

Advancements in functional MRI that make the method more easily applicable to

cognitive activity will greatly aid in the use of this technique to study pathologic states. 5. wns

of Fun&&&lRI

The recent studies done with BOLD contrast imaging are extremely exciting in that they are non-invasive and are relativeby simple to perform and interpret. Also, MR technology is improving with respect to resolution and accuracy and this should greatly aid the advancement of this technique as a diagnostic modality. Using this method, it should be possible to map out cortical columns of gray matter as well as the cerebellum based on signal increase, depending on the task (visual, motor, speech, language). In order to gain widespread clinical application, functional MR imaging must provide increased diagnostic sensitivity,

MRI using DeoxyHb Contrast

vs. PET to Assess

Brain Function

specificity with respect to disease states and reliability in predicting responses to therapy (Brady et al., 1992). There are many potential applications of this technique. Basically, any oxygen and blood flow studies done with PET can be duplicated with MR using the BOLD contrast method. This includes studying the effects of drugs on blood flow and oxygenation in the brain as well as any disease state that may disturb blood flow. Recently, work has been done by Cuenod et al. (1993) using MN to monitor the brain response to pharmacological receptor activation with choline+ (choline@

drugs. This group found that after injection of arecoline

agonist), signal increase was found in several areas of the brain including the cingulum, basal

forebrain, caudate nuclei and inferior temporal cortex (Cuenod et al., 1993). They concluded that the unmatched combined high spatial and temporal resolution that can be achieved noninvasively in vivo with MR.J holds great promise to study the normal and abnormal brain response to a large variety of brain receptors and pathways (Cuenod et al., 1993). Wenz et al. (1993) have studied the effects of neuroleptic drugs on signal intensity during motor cortex stimulation and found that schizophrenic patients on Clozapin had lowered signal increase relative to controls with motor activation. Two examples of pathologic states in the brain that can be studied are epilepsy and ischemia. Connelly et al. (1993) have done preliminary work on trying to map the cortical activation associated with focal seizures in a patient with epilepsy. They found that functional MRl revealed activated regions (regions where there was an increased signal intensity during seizures) which corresponded to gyri in the structurally abnormal regions of the left hemisphere in the brain (Connelly et al., 1993). With respect to stroke, functional MRI should aim at a rapid detection of infarcted areas in patients as well as to an assessment of related pathophysiologic changes and therapeutic interventions in the early phase (Frahm et al., 1993). Studies are currently being employed in a porcine model to map out regions of ischemic insult in the brain (Hees et al., 1993). Howe et al. (1993) used MR to look at signal changes in tumors and found a decrease in signal intensity in the area of the tumor that could be explained by an overall increase in the concentration of tumor deoxyhb concurrent with a reduction in tumor blood flow. Using the principles of BOLD contrast imaging it should be possible to study changes in neuropsychiatric disease in a similar fashion to previous PET studies. Breiter et al. (1993) have done some preliminary work with obsessive-compulsive

disorder (OCD) and found signal intensity increases in the orbital gyri and

dorsolateral prefrontal cortex during symptom provocation in OCD subjects consistent with published results in the PET literature as well as current pathophysiological models of CCD. They concluded that the differences in functional activity between CXD patients and controls could be interpreted to indicate either differences in neuronal connectivity, or differential use of intact circuitry secondary to state differences in neuronal modulation (Breiter et al., 1993). Here it is shown that functional MR can be useful in understanding the pathophysiological

mechanism involved in OCD. Jenkins et al. (1993) found a dramatic

alteration in the hemodynamic oxygenation response in patients with Huntington’s disease during photic stimulation when compared to controls. As functional MR technology improves and this method becomes more accepted, it should be possible in the near future to apply the technique to other neuropsychiatric diseases such as schizophrenia and depression and aid both in the diagnosis and response to treatment. Although no formal studies have been published, Alzheimer’s disease should be a good pathologic state in which to apply this technique based on previous PET studies that have shown decreased regional cerebral blood flow (rCBF) which correspond fairly well with neuropathological studies of post mortem brains. There

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are several theoretical ways to use BOLD contrast imaging to evaluate Alzheimer’ disease. One possibility would be to identify regions in the brain that differ with regard to signal intensity increase between AD and controls when presented with cognitive stimulation such as visuospatial tasks, memory tasks, and language tasks. This would integrate methods that have already been applied to normal subjects by several investigators (Rao et al., 1993a; Bandettini et al., 1993; Rueckert et al., 1993). Thus far, the low resolution PET scanners have not been able to identify changes in areas outside the neocortex that are presumed to be involved in memory. Because functional MR produces higher spatial and temporal resolution in its images, it should be possible to see signal intensity differences in areas such as the hippocampus, amygdaloid and nucleus basilus of Meynert. If identified early enough, these differences could be used as a marker to predict whether a normal person who is at risk of developing the disease (due to family history) is beginning to show characteristic changes, and interventions could be instituted to reverse the process before clinical symptoms begin. It would also be useful to apply functional MR to study the central effects of drugs in AD patients. The cholinergic hypothesis of AD proposes that a major component of the cognitive dysfunction is the result of cholinergic depletion (Davies and Maloney, 1976). PET studies have looked at the effect of physostigmine (anti-cholinesterase)

on AD patients and found that the drug produced a focal increase in ICBF in the left

posterior parietotemporal region in these people (in which baseline rCBF was decreased) but not of controls (Rapoport, 1991). Besson et al. (1992) administered physostigmine to AD patients and measured blood flow while subjects were at rest and also while performing a recognition memory task using PET. They used a memory test because of the well established role of the cholinergic system in memory function. They found a mean increase of 7.1% of resting rCBF during physostigmine infusion and a mean increase of 11.8% during memory task performance (Besson et al., 1992). They also found a corresponding improvement in memory performance (Besson et al., 1992). Cuenod et al. (1993) used functional MRI to study the effects of arecoline (cholinergic agonist) on rhesus monkeys. They found signal increase in several areas including the cingulum, amygdaloid bodies, and inferior temporal cortex, which are areas implicated in memory function (Cuenod et al., 1993). Low resolution PET has not been able to discriminate these areas outside the neocortex. Soon, it will be possible to perform studies such as these on human subjects. With newer and better pharmacologic treatment coming out for AD, it should be possible in the near future to monitor the regional brain response to these drugs and correlate this with effects on cognitive function. The issues discussed on application of the BOLD imaging technique to Alzheimer’s disease could theoretically be used to study any pathologic state that involves changes in blood flow. The advantage of MR is the high spatial and temporal resolution produced in ik images compared with the much lower resolution seen with PET. An example of the resolution power of MR over PET is provided by Rao et al. (1993b). They were able to distinguish areas of the brain that had increased signal intensity when subjects performed arm movements versus finger movements, something a previous PET study was not able to do @IO et al, 1993b). Because of this increased resolution, more discrete areas of the brain can be studied making it easier to identify patients early in their disease process or even patients at risk of devetoping a disease. Thus, it would be more likely to reverse a process or prevent it from occurring. Another big advantage of the BOLD imaging technique is that it is noninvasive and uses the apparently safe interaction between radio waves and the magnetic properties of tissues. Thus there is no exposure to ionizing radiation (CT) or radioactive contrast agents (PET). As long as one can stand to be in the long bore of a magnet, the experiments are relatively

MRI using DeoxyHb Contrast simple and non-stressful.

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Finally, as has been discussed, this technique can be used to look at many different

aspects of a disease. This includes differentiating stages, looking at areas of possible pathology, and studying the effects of pharmacologic treatment. In addition, MR scanners are more readily available than are PET scanners and the images produced by MR are relatively easy to interpret. The major disadvantage of BOLD contrast imaging is that it is in the infant stage of development.

The

principle was first described by Ogawa in 1996, and since then most of the published data involves changes ln signal intensity seen during task activation (photic, motor, sensory) in normal subjects. These studies will be useful ln eventually being able to map out the entire cortex depending on the task. However, ln order for the method to be used routinely in the study of disease states, more refinements will have to be made with respect to technology. For example, Ogawa et al. (1992) and Turner et al. (1993) each found a greater increase in signal intensity when a 4 tesla magnet was used versus a 1.5 tesla magnet during photlc stimulation. Also, ln images sensitive to oxygen contrast, the noise using the 1.5T magnet is generally in the 2.5 - 3.0% range which makes a 4% increase ln signal intensity more difficult to detect. This requires a lot of statistical processing to analyze data accumulated using a 1.5T system whereas using a 4T system it is possible to calculate subtraction images without the need for in depth statistical processing (Ogawa et al., 1992; Turner et al., 1993). For example, Constable et al. (1993) concluded that simple subtraction of consecutive images was unsatisfactory using a 1.5T system due to motion effects and pixel mlsregistrations.

They therefore had to

employ complicated statistical methods to analyze the data where each pixel in each set of control and activation image pairs generated a number of paired data sets which were then subjected to a student’s paired t-test (Constable et al., 1993). Bandettini et al. (1992) obtained brain activity images by calculating the correlation between the time response of each voxel and an ideal response to the task activation. Turner et al. (1993), using a 4T system, were able to reconstruct images without the use of any phase-correction algorithm and then calculate subtraction images. However, at this field strength, patients may experience vertigo and it is the 1.5T magnet that is generally used for routine clinical application. It would therefore be best to optimize other parameters while using the 1.5T magnet. There is also a controversy as to whether the signal increase that is seen with the various task activations correlates with increased blood flow in capillaries or whether it is occurring in larger vessels in the venous system. This information is important because it may determine the ultimate resolution of the technique (Menon, 1993). The preference would be to see changes in image intensity caused by hemodynamic changes in the local capillary bed of the gray matter because if the changes occur in larger vessels which dram the involved gray matter regions, then they may be fairly nonspecific to the involved areas (Menon, 1993). Ogawa et al. (1993) have actually suggested that at lower field strength (1.5T), a substantial contribution to the signal change is made by noncapillary vessels. The ability to someday map cortical columns of gray matter may depend greatly on the answer to this question, and newer techniques which allow faster acquisition of images (i.e. Echo Planar Imaging) and higher resolution should aid in this purpose. 6. Future

.

Now that the theory is in place for BOLD contrast imaging, the next step is to optimize a technique for conventional hardware in order to produce the best results. This includes maximizing TE (echo decay time), flip angle, field of view, and slice thickness at 1.5T. Work towards this has already been done by Constable et al. (1993) who showed that the effects of activation of visual and motor areas of the brains of normal volunteers could be recorded using conventional MR imaging methods on a standard 1.5T clinical scanner.

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Newer refinements in fast MR imaging techniques (i.e. fast gradient- echo and echo planar imaging) are producing even higher resolution images and reducing motion artifacts. These refinements also make it possible to increase the number of patient examinations performed in a specified time (Brady et al., 1992). Using these same principles with the newer technology, oxygenation related studies of motor and sensory activation as well as of other more complex mental and cognitive tasks should be possible. Another example of the advancement of this technology is provided by Chandra et al. (1993) who used a technique termed RIGR (Reduced-encoding Imaging with Generalized Series Reconstruction) in BOLD MR imaging to increase temporal resolution as well as signal to noise ratio. It is studies such as this that will make this method applicable in the clinical environment in the near future. It would also be helpful to be able to quantify regional blood flow based on deoxyhemoglobin level in a blood vessel during the resting state. Again, this should be possible in the near future.

The BOLD contrast imaging technique is non-invasive and produces no known ill effects. The images produced are relatively easy to interpret and the method can potentially be used in a variety of normal as well as disease processes. Therefore, functional MR imaging using BOLD technology holds great promise in the future to be able to map out cortical columns of gray matter in the brain as well as aid in the diagnosis and treatment of pathologic states.

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Inquiries and reprint requests should be addressed to: K. Ranga Krishnan Department of Psychiatry Duke University Durham, NC 27710 U.S.A.