Applications of Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Neuropsychiatry

Applications of Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Neuropsychiatry

4, S147–S162 (1996) 0065 NEUROIMAGE ARTICLE NO. Applications of Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Neuropsychiatry JONATH...

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4, S147–S162 (1996) 0065

NEUROIMAGE ARTICLE NO.

Applications of Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Neuropsychiatry JONATHAN M. LEVIN,* MARJORIE H. ROSS,* GORDON HARRIS,†

AND

PERRY F. RENSHAW*

*Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178; and †Neuroimaging Research Laboratory, New England Medical Center, Boston, Massachusetts 02111

Functional neuroimaging has assumed an important role in the cognitive and clinical neurosciences. Recently, substantial progress has been made toward developing functional magnetic resonance imaging techniques for the examination of cerebral hemodynamic changes that accompany brain function and toward earlier and better diagnosis of brain disease. Dynamic susceptibility contrast (DSC) MRI offers unique information about cerebral hemodynamics both at rest and in response to brain activation. We review the clinical applications of DSC MRI and present our experience with this modality in the evaluation of patients with neuropsychiatric disorders. Our experience suggests that DSC MRI may afford new insights into the diagnosis and treatment of cognitive disorders. r 1996 Academic Press, Inc. The chemical products of cerebral metabolism contained in the lymph which bathes the walls of the arterioles of the brain can cause variations of the calibre of the cerebral vessels; that in this reaction the brain possesses an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations of functional activity. (Roy and Sherrington, 1890)

Functional neuroimaging has assumed an important role in the cognitive neurosciences. Such investigations derive from general principles, first suggested by Roy and Sherrington a century ago, regarding the close coupling of neuronal activity, energy metabolism, and blood flow (Roy and Sherrington, 1890). For over a decade, clinicians and researchers have used a variety of tools to visualize brain function at rest, with activation, and in disease. Until recently, such studies have been the sole province of radiotracer methods. However, in the last few years, extraordinary progress has been made toward developing functional magnetic resonance imaging (fMRI) techniques for the examination of cerebral hemodynamic changes that accompany brain function and toward earlier and better diagnosis of brain disease (Cohen and Bookheimer, 1994; David et al., 1994; Moonen et al., 1990; Prichard and Rosen, 1994; Turner and Jezzard, 1994). The combined efforts

of physicists, radiologists, and neuroscientists have led to novel methodologies which have already yielded clinically relevant results and which hold great promise for revolutionizing the clinical neurosciences. While certain fMRI procedures can be performed on standard clinical scanners, the field has greatly benefited from technological advances in MR physics. Of particular importance has been the development of extremely rapid imaging techniques which utilize novel pulse sequences as well as improved hardware configurations. Pulse sequence development, particularly fast gradient echo imaging techniques (Duyn et al., 1994; Haase et al., 1986; Wehrli, 1991), as implemented on standard clinical scanners, has facilitated image acquisition on the order of a few seconds as compared to a few minutes with conventional sequences. However, the introduction of echo planar imaging (EPI) has had the most profound effect on the development of fMRI. Requiring sophisticated additional hardware not found on most clinical scanners, EPI allows image acquisition in a fraction of a second, with repeated, multislice acquisitions on the order of a second. While the physics involved and the clinical utility of EPI have been reviewed elsewhere (Cohen and Weisskoff, 1991; Edelman et al., 1994; Mansfield, 1984; Stehling et al., 1991; Turner and Jezzard, 1994), its underlying principle involves the use of rapidly changing magnetic field gradients to acquire an entire imaging plane in a single radiofrequency excitation. EPI offers a number of advantages over conventional fast gradient echo sequences, in temporal resolution, signal-to-noise levels, magnetic gradient strength, and overall flexibility (Cohen and Weisskoff, 1991). CEREBRAL BLOOD VOLUME MAPPING The first widely applied fMRI technique, the dynamic susceptibility contrast (DSC MRI) method, may be used to map cerebral blood volume (CBV) (Belliveau et al., 1990; Rosen et al., 1991, 1989; Villringer et al., 1988). It derives from indicator-dilution methods, which require monitoring of the first pass of a rapid bolus injection of

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1053-8119/96 $18.00 Copyright r 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.

FIG. 1. DSC MRI blood volume time sequence. Sequential difference images generated 6 through 13 s after bolus injection of contrast agent demonstrate contrast influx and efflux. Image number refers to seconds following injection. Dark areas reflect contrast pooling.

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a nondiffusible tracer through the cerebral vasculature (Zierler, 1962). While numerous previous methodologies have utilized radiolabeled tracers, DSC MRI takes advantage of the paramagnetic properties of standard MRI contrast agents as a magnetic tracer. These agents have two main effects, a T1 relaxation time shortening effect, which is exploited in conventional MR imaging, and a susceptibility or T2 relaxation time shortening effect. T1 contrast effects generally require close molecular (dipole–dipole) interaction between contrast agent and water protons, as occurs when there is an alteration in the blood–brain barrier (BBB). However, susceptibility effects, the basis for DSC MRI, are of longer range and extend beyond an intact BBB, even while the contrast agent remains in the intravascular space. Susceptibility effects result from the fact that paramagnetic substances disturb the homogeneity of uniform magnetic fields. These local field inhomogeneities cause a loss of coherence of signal from nearby protons and thus a reduction in measured MR signal. Therefore, as a bolus of paramagnetic contrast agent passes through the vasculature, its susceptibility effects cause a transient magnetic field disruption around these vessels and a reduction in signal intensity on T2 (spin echo) or T2* (gradient echo) weighted images. This transient signal loss, proportional to the amount of tracer in a given region, is monitored by rapid imaging during the first pass of the contrast agent (Fig. 1). Since the time course of cerebral vascular passage is on the order of a few seconds, images must be acquired every 0.5–2 s in order to adequately resolve the dynamics of the signal change. With tracer kinetic modeling, the decrease in image signal intensity at each time point may be used to determine relative CBV, either regionally or on a pixel by pixel basis (Belliveau et al., 1990). High-resolution maps of relative CBV are produced by integration of these data over the time course of the first pass of contrast agent through the cerebral vasculature. While rapid gradient echo sequences, available on conventional scanners, can optimize total signal, they focus on larger vessels (Fisel et al., 1991; Kennan et al., 1994). EPI allows the use of capillarysensitive, multislice spin echo sequences, greatly enhancing the flexibility, temporal resolution, and utility of the technique (Levin et al., 1995a; Weisskoff et al., 1993). Such studies can be performed within the context of a routine clinical MR examination in a short period of time. This allows functional images of high spatial and temporal resolution to be acquired in concert and in anatomical registration with conventional MR images. Such an approach can prove to be time and costeffective, avoid the need for coregistration with functional images acquired with other modalities, and obviate the need for production of and exposure to ionizing radiation. Finally, EPI systems are becoming increasingly

available to clinicians as more sites continue to acquire the necessary hardware and software tools. CLINICAL APPLICATIONS OF DSC MRI In the half-decade since it was first successfully employed in humans, several studies have focused on evaluating the utility of DSC MRI for elucidating problems in traditional areas of neurology such as cerebrovascular disease, neurooncology, and epilepsy. More recent studies have begun to explore neuropsychiatric disorders, such as dementia, schizophrenia, and substance abuse, characterizing changes which are associated with cognitive disorders and mental illness. Finally, methodological advances have allowed DSC to measure hemodynamic changes accompanying physiological and pharmacological activations. Cerebrovascular Disease Conventional MRI has profoundly altered our understanding of stroke by allowing precise anatomic localization of cerebral infarction. In addition, MR angiography (MRA) provides a noninvasive view of brain vasculature that cannot be obtained with any other technology. It is noteworthy that even given these powerful tools, fMRI offers the potential for better evaluation of cerebrovascular disease and ischemic brain injury. Conventional MRI can detect ischemic abnormalities, due to changes in brain tissue relaxation times, generally only after several hours (Yuh et al., 1991), at which point there is little optimism regarding therapeutic intervenTABLE 1 Clinical Referrals for Brain Dynamic Susceptibility Contrast MRI McLean Brain Imaging Center 1994–1996 Referral question

No. of referrals

Findings

1. Memory loss

65

2. Rule-out tumor

14

3. HIV/AIDS

12

Probable AD patients have decreased temporal lobe rrCBV. Many but not all tumors have high rrCBV. Radiation necrosis has a very low rrCBV. Multiple discrete foci of decreased rrCBV. Focal rrCBV deficits which correlate with neurocognitive impairments. Multiple discrete foci of decreased rrCBV. Decreased relative frontal lobe rrCBV. Focal decreases in rrCBV.

4. Closed head injury

7

5. Polysubstance abuse

7

6. Schizophrenia

5

7. Stroke

3

Note. rrCBV, relative regional cerebral blood volume; AD, Alzheimer’s disease.

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tion. X-ray computed tomographic changes occur even later (Hakim et al., 1983). A variety of therapeutic modalities, including thrombolytic agents and putative neuroprotective agents, are currently being developed to minimize the effects of acute cerebral ischemia. Given the marked variability of clinical presentation of cerebral ischemia, there is great interest among those involved in this effort to be able to visualize ischemic changes at the earliest possible moment, both to confirm ischemia as well as to monitor the progress of therapy. To this end, DSC MRI has proven useful in mapping focal reductions in CBV which accompany stroke (Edelman et al., 1990). CBV mapping has been used to demonstrate large cortical infarctions within the first 48 h after onset of stroke symptoms. Analysis of time– concentration curves reveals reduction in CBV as well as an increase in contrast agent cerebral transit time

(Warach et al., 1992). DSC imaging using animal models has shown that CBV reduction is seen almost immediately after the induction of ischemia (Hamberg et al., 1993). Moreover, by calculating an arterial input function, DSC MRI may also be potentially useful in the quantitative assessment of both CBV and CBF (Hamberg et al., 1993). Recent work in humans has demonstrated that DSC MRI can be used to detect hemodynamic abnormalities in patients within 6 h after the onset of stroke symptoms and before abnormalities are seen on conventional MRI (Rother et al., 1996). Strategies combining DSC hemodynamic data with diffusion-weighted MRI in an attempt to define the boundaries of early infarction and the ischemic penumbra also appear promising (Sorensen et al., 1996). In addition to acute ischemia, the hemodynamic effects of chronic large vessel cerebrovascular disease, particularly carotid artery disease, are of concern to

FIG. 2. Axial T2-weighted image and corresponding DSC CBV map from a 31-year-old HIV-positive man with new onset mania. Blood volume pooling is seen as white in this and subsequent images. The CBV map illustrates reduced blood volume (darker area) in a large region of T2 hyperintensity. Brain biopsy confirmed the presence of a large temporal lobe lymphoma, which is less vascular than many other central nervous system neoplasms.

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neurologists and neurosurgeons. Tests of cerebrovascular ‘‘reserve,’’ the ability to augment flow to certain vascular beds that may be compromised by vascular stenosis, have been developed using either the intravenous injection of acetazolamide (Diamox) or the inhalation of 5% CO2 to augment CBF due to their cerebral vasodilating properties. Both emission tomographic and ultrasonographic techniques have been successfully used to monitor regional CBF responses to these challenges (Hauge et al., 1983; Sullivan et al., 1987; Vorstrup et al., 1984). Abnormal test results have correlated with increased risk for stroke (Kuroda et al., 1993). As these studies require repeated measurements before and after challenge, fMRI offers the promise of less invasive imaging techniques for measuring CBF and CBV. DSC MRI has been used to demonstrate augmented CBV in normal subjects following acetazolamide injection in a study paradigm requiring less than an hour (Levin et al., 1995a). Studies evaluating the

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utility of this method in assessing cerebrovascular reserve in patients with cerebrovascular disease are currently ongoing. Neurooncology Important issues in neurooncology include accurate diagnosis, biopsy site selection, and often determination of whether a patient’s symptoms are due to tumor recurrence or to the effects of therapy (e.g., radiation necrosis). Such diagnostic problems have been one of the primary clinical indications for brain PET imaging. Therefore, it is not surprising that one of the earliest clinical applications of DSC MRI has been used to create CBV maps in patients with brain tumors (Rosen et al., 1991). Using these maps and pathological correlates, it has been shown that areas of increased CBV represent active tumor, and heterogeneous patterns often suggest that the grade is high (Aronen et al.,

FIG. 3. Axial T2-weighted image and corresponding DSC CBV map from a 78-year-old woman with a subfrontal meningioma. The CBV map shows that the region perfuses and is extremely vascular, with a relative CBV that is 11 times that of unaffected white matter and 3 times that of gray matter.

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1994, 1995). Focal reduction in CBV maps, on the other hand, represent low grade tumor or radiation necrosis. In addition, it may be possible to differentiate tumor types based on CBV characteristics (Maeda et al., 1993). Highly vascular tumors, such as meningiomas, have very high focal CBV, in contrast to neuromas (Maeda et al., 1994) (see Fig. 3). Epilepsy Clinically, a major goal in evaluating intractable epilepsy has been the difficult task of isolating the epileptic locus. Accurate localization provides information that is helpful for both proper diagnosis of epilepsy type, as well as choice of treatment, either pharmacological or surgical. Such localization has entailed using a variety of modalities, from neurological examination and detailed neuropsychological testing to long-term

EEG monitoring with telemetry and invasive EEG monitoring with depth electrodes. Efforts to identify the locus of epileptic activity have also evaluated focal changes in blood flow and metabolism which may either accompany or underlie epileptic activity. Thus, emission tomographic techniques are often employed interictally, and occasionally ictally, to demonstrate areas of altered blood flow and metabolism (Marks et al., 1992; Ryvlin et al., 1992). Conventional MRI is frequently performed in the evaluation of epilepsy. Therefore, development of fMRI techniques that can be incorporated into what is often a routine clinical study has added appeal. To this end, DSC MRI has been used to show significantly increased regional CBV during focal status epilepticus, correlating well with SPECT perfusion and EEG findings (Warach et al., 1994).

FIG. 4. Axial T1-weighted image and corresponding DSC CBV map from a 54-year-old man with a 3-month history of rapidly progressive memory loss. Conventional MRI demonstrates thickening of the cortical ribbon in the temporal lobes. The CBV map shows a loss of normal demarcation between gray and white matter, most prominent in the lateral temporal lobes. Brain biopsy 2 days after imaging was consistent with Creutzfeldt–Jakob disease.

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Dementia Functional MRI may also prove to be an important modality in understanding such cognitive disorders as the dementias, especially with regard to distinguishing among different neuropathological processes. Radiotracer studies have shown marked parietotemporal hypometabolism and hypoperfusion in patients with Alzheimer’s disease (de Leon et al., 1983; Foster et al., 1983; Holman et al., 1992), and significant correlations have been found between these abnormalities and cognitive impairment (Karbe et al., 1994). Recent evidence indicates that these methods may be useful in assessing patients genetically at risk for developing Alzheimer’s disease and potentially for monitoring the efficacy of therapies designed to prevent the disease (Small et al., 1995). Preliminary work with DSC MRI has indicated that CBV maps correlate well with single photon emission

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computed tomography (SPECT) perfusion images in both elderly controls and in patients with Alzheimer’s disease (Johnson et al., 1995). In order to evaluate resting cerebral hemodynamics in these patients using DSC MRI, we have performed a semiquantitative regional analysis of CBV maps in 13 patients with Alzheimer’s disease and in 13 age-matched controls (Harris et al., 1996). In patients with Alzheimer’s disease, we found areas of significantly reduced relative CBV in the temporoparietal cortices (mean reduction 5 17%; P , 0.01), with less reduction in CBV in the sensorimotor cortices (mean reduction 5 9%; P 5 NS), results consistent with emission tomographic work. No significant reduction in relative CBV was noted in control subjects. In addition, discriminant function analysis correctly classified 88.5% of patients with Alzheimer’s disease, although Mini-Mental Status scores did not correlate well with relative CBV (Harris

FIG. 5. Axial proton density image and corresponding DSC CBV map from a 47-year-old man with chronic, progressive multiple sclerosis. The CBV map reveals a focus of decreased CBV corresponding to a large plaque in the left occipital white matter, which was nonenhancing on conventional postcontrast T1 images.

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et al., 1996). Results in a larger number of patients have confirmed these findings (unpublished data). Finally, we have also shown that group differences in principal component scores associated with global and temporoparietal patterns (P 5 0.08 and P 5 0.007, respectively) are highly sensitive and specific for Alzheimer’s disease classification (Maas et al., 1996). Given the cortical atrophy associated with both Alzheimer’s disease and normal aging, the importance of accounting for atrophy in interpreting such studies must be emphasized (Alavi et al., 1993; Herscovitch et al., 1986). The sequential and registered acquisition of high resolution anatomic data and functional data using the DSC MRI technique affords a powerful tool with which to address these issues. Finally, in contrast to these studies of resting hemodynamics, one activation study has demonstrated an intact CBV response to photic stimulation in controls and in patients with Alzheimer’s disease (Mattay et al., 1993).

Compared to emission tomographic methods, DSC MRI does not require the use of radiotracers, provides a higher degree of spatial resolution, and allows the acquisition of a complete data set in less than 5 min. The speed with which EPI can be performed may be of great advantage in demented patients, in whom motion artifact is often a particular problem degrading conventional anatomic as well as functional images. Over time, DSC MRI may offer advantages over emission tomographic imaging for the clinical evaluation of dementia, as well as the evaluation of newer treatment strategies aimed at preventing or slowing the progression of the disease. Schizophrenia The enormous potential of fMRI for the study of individuals with psychiatric disorders has become increasingly appreciated (David et al., 1994; Levin et al.,

FIG. 6. Axial T2-weighted image and corresponding DSC CBV map from a 46-year-old man with a history of closed head injury and postconcussion syndrome. T2-weighted image demonstrates a region of encephalomalacia in the lateral right temporal lobe and gliosis in the left anterotemporal lobe. The CBV map shows bilateral temporal areas of decreased CBV, correlating with his neurocognitive impairment.

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1995b; Moonen, 1995). However, despite the perceived importance of fMRI, relatively few studies of patients have been published, perhaps owing to the limited availability of the imaging technology. In preliminary studies with blood oxygenation level-dependent (BOLD) fMRI, we demonstrated a greater occipital cortical response to photic stimulation in schizophrenic patients compared to age-matched normal control subjects (Renshaw et al., 1994), a finding subsequently confirmed by PET (Taylor et al., 1996). In order to address possible basic abnormalities in regional cerebral vasculature in schizophrenia, we have performed further studies using DSC MRI (Cohen et al., 1995). We compared 10 patients with schizophrenia (mean age 5 32 years) and 10 age-matched control subjects. All schizophrenic patients had maintained a stable clinical course on neuroleptic medication for at least one year. Semiquantitative analysis of regions of caudate, cerebellum, and occipital cortex showed greater relative CBV in schizophrenic patients in all regions,

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suggesting widespread differences in the density, size, or configuration of cerebral blood vessels in these patients. Further studies are needed to assess the influence of neuroleptic medication, and other possible factors related to chronic schizophrenia, on these findings. Physiological and Pharmacological Activation Studies of brain activation have long been the province of emission tomographic techniques. However, this has often entailed grouping data across subjects, emphasizing commonalities in brain function. Functional MRI techniques offer a unique opportunity to investigate function in individual subjects. This was initially demonstrated in 1991, when Belliveau et al. produced the first functional MR images of brain activation with photic stimulation using DSC MRI (Belliveau et al., 1991). Activation studies highlight both the advantages and the limitations of the DSC technique. Employing bolus injections of paramagnetic gadolinium chelates,

FIG. 7. Axial T2-weighted image and corresponding DSC CBV map from a 56-year-old man, 3 weeks following a right middle cerebral artery infarction with neuropsychiatric complications. The CBV map shows large areas of decreased CBV within this vascular territory.

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DSC MRI offers a large change in signal intensity and a high signal to noise ratio, especially when compared to intrinsic contrast fMRI methods, such as the BOLD method (Mattay et al., 1995). However, studies of activation require at least two acquisitions, one at baseline and another during activation, and therefore two or more doses of contrast agent. Newer non-ionic, low-osmolar contrast agents have been approved for use at far greater doses than early generation agents, facilitating repeated bolus studies. However, residual contrast agent effect may result in spuriously elevated measurements of relative CBV, mimicking activation (Levin et al., 1995a). These issues become particularly important as fMRI techniques are utilized to study small and global changes in cerebral hemodynamics, such as occur when measuring drug effect on brain. In order to avoid these effects, we have successfully employed a steady-state method to achieve reproducible sequential measurements as well as measure-

ments of superimposed pharmacological activation (Levin et al., 1995a). We have measured an increase (,21%) in relative CBV following an intravenous injection of the potent vasodilator acetazolamide, a value that agrees well with other, more invasive, methods for measuring CBV. Recently, we have demonstrated a global decrease in relative CBV, as well as a decrease in apparent mean transit time (MTT), soon after the intravenous administration of cocaine (Kaufman et al., 1996). These results suggest the possibility of a decoupling of blood volume and blood flow with a vasoactive agent, highlighting the wealth of data that can be derived from such studies using this technique. Clinical Experience with DSC MRI in Neuropsychiatry Access to echo planar imaging at a large psychiatric hospital has afforded us the opportunity to assess the utility of various fMRI modalities in a unique clinical

FIG. 8. DSC CBV maps from an 83-year-old man without memory impairment and from an 86-year-old man with mild to moderate probable Alzheimer’s disease (AD). Although difficult to appreciate, there is decreased CBV in temporoparietal regions bilaterally in the patient with AD, best demonstrated by quantitative analysis. Moderate atrophy is also present in the patient with AD.

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setting. Aside from the formal studies of dementia and schizophrenia previously mentioned, we have performed DSC CBV mapping on a series of patients referred for a variety of neuropsychiatric disorders. All DSC imaging was performed with a spin echo EPI sequence and the rapid bolus injection of 0.2 mmol/kg gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ). CBV maps were generated by integrating time series data from the first intracerebral pass of contrast agent on a pixel by pixel basis (Belliveau et al., 1990; Harris et al., 1996). Table 1 summarizes our experience in 113 subjects, the majority for work-up of memory loss, as well as several with closed head injury, HIV or AIDS, polysubstance abuse and psychotic disorders. Our findings in patients with tumors and stroke parallel the experience of other investigators using this technique (Aronen et al., 1994; Rother et al., 1996). Our findings in dementia, HIV and AIDS, closed head injury, and polysubstance abuse parallel findings previ-

ously reported only with emission tomographic techniques. Figures 2–11 demonstrate findings in several selected cases. While anecdotal, our experience suggests that this tool may be sensitive in detecting hemodynamic abnormalities in a variety of disorders, including several without conventional MRI correlates. It remains to be seen whether this methodology, and further advances in its quantification, offers the sensitivity and specificity of traditional radiotracer techniques or new hemodynamic information not afforded by other methods. LIMITATIONS OF DSC MRI TECHNIQUES Although slightly more invasive than intrinsic contrast fMRI techniques (e.g., BOLD), DSC MRI provides more robust signal intensity changes as well as unique hemodynamic information (Mattay et al., 1995). However, it is not without its limitations. The primary

FIG. 9. DSC CBV maps from a healthy 32-year-old man and from a 38-year-old male with a long history of schizoaffective disorder and polysubstance abuse. Multifocal areas of markedly decreased CBV are evident in the images from the subject with a history of substance abuse.

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limitation is that any study of activation requires at least two acquisitions, one at baseline and another during activation, and therefore two or more doses of contrast agent. Newer non-ionic, low-osmolar contrast agents have been approved for use at far greater doses than early generation agents, facilitating repeated bolus studies. However, residual contrast agent effect may result in spuriously elevated measurements of relative CBV, mimicking activation unless care is taken to avoid these effects (Levin et al., 1995a). These issues will become particularly important as fMRI techniques are utilized to study small and global changes in cerebral hemodynamics, such as occur when measuring drug effect on brain. EPI itself imposes a number of other potential limitations. Spatial resolution is often more limited and less flexible than when using conventional gradients, although there is improved signal-to-noise (Cohen and Weisskoff, 1991). Furthermore, one feature of EPI that

makes it particularly useful for fMRI, its enhanced sensitivity to susceptibility effects, can also lead to artifacts. These susceptibility artifacts are particularly prominent in brain regions adjacent to air sinuses, such as inferior frontal and temporal regions, often areas of considerable interest (Servan-Schreiber et al., 1995). Other limitations are related to safety and subject comfort, particularly with ultrarapid imaging techniques. Because it relies on extremely rapid changes in magnetic field gradients over time (dB/dT), EPI poses particular problems due to potential magnetic stimulation from induced currents. Muscle twitching and sensory neural stimulation, especially of extremities, have been reported with EPI (Budinger et al., 1991; Cohen et al., 1990). Cardiac stimulation, theoretically a risk, seems to require a much greater dB/dT threshold than that which is currently implemented on EPI systems and approved by the FDA (Cohen and Weisskoff, 1991). In addition, the gradient changes are extremely loud,

FIG. 10. Axial Tc-99m HMPAO SPECT images from a healthy 40-year-old man and a 42-year-old man with cocaine and polysubstance dependence. The latter image shows numerous foci of reduced perfusion (purple–black areas), typical of men with a similar history of substance abuse.

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which can be uncomfortable for some subjects. None of these safety and comfort considerations have proven to be significant. DSC MRI COMPARED WITH EMISSION TOMOGRAPHY Much has been made of the relative ease with which fMRI studies can be performed compared with traditional emission tomographic studies, particularly PET. However, one must keep in mind that they are fundamentally different techniques, capable of acquiring similar yet distinct information. As such, each has specific advantages and disadvantages. Functional MRI provides extremely high spatial resolution (typically 1–3 mm), temporal resolution (subsecond), and is minimally or noninvasive and thus, easily repeatable. The advantages of this high spatial resolution, up to several times that currently achievable with PET and SPECT,

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are obvious when delineating detailed functional neuroanatomy. Equally important, however, is the ability to acquire images rapidly, at least two orders of magnitude more quickly than PET, and within the time frame of the hemodynamic response to functional activation. Additionally, being minimally invasive, without requiring radioactive tracers, fMRI allows safe, repeated testing within individual subjects. Finally, in contrast to PET, these techniques are widely available, often with minor modifications of existing clinical MRI scanners. However, emission tomography can provide unique information regarding brain function not currently available with fMRI. Physiological parameters such as rates of glucose and oxygen metabolism, as well as absolute quantification of cerebral blood flow and volume, are currently the province of PET, while both PET and SPECT can provide information about neurotransmitter receptor populations and other ligand-specific

FIG. 11. Tc-99m HMPAO SPECT image and DSC CBV map from different men with a similar history of substance abuse. The SPECT image shows numerous foci of reduced perfusion (purple–black areas) and the CBV map shows multiple areas of decreased CBV, pointing out the similarity of findings with these two modalities in this patient population.

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data. These unique data are often of particular importance, and it is clear that radiotracer methods will continue to play a pivotal role in understanding brain function. Furthermore, these techniques are more mature, and the data obtained may be interpreted in a more straightforward manner, than fMRI results. With correlative studies, such methods will be an important resource in more fully understanding and characterizing the information obtained with fMRI techniques. Finally, the relative sensitivity of emission tomographic techniques and fMRI to small changes in regional cortical and subcortical activation remains to be determined. CONCLUSION In a remarkably short period of time, fMRI techniques have matured to the point where their clinical application is apparent. The various techniques, all minimally invasive and readily repeatable, offer unique information regarding brain function. Our experience with DSC MRI suggests that this tool may be quite sensitive in detecting cerebral hemodynamic abnormalities in a variety of neuropsychiatric disorders. It seems likely that fMRI will be a mainstay for both clinical and research applications of functional neuroimaging in the near future. The benefits of fMRI, especially in an era of aggressive cost containment, will need to be critically weighed against the expense. Nonetheless, fMRI has opened an important new window on evaluating brain function. Appreciation for the its diversity and potential will benefit those in the clinical practice of the neurosciences. ACKNOWLEDGMENTS This work was supported, in part, with funds provided by Bracco Diagnostics and the National Institute on Drug Abuse (DA-09448). The expert technical assistance provided by Camper D. English and Robert F. Lewis is gratefully acknowledged. We thank Anne Smith, RT, and Eileen Connolly, RT, for their help in performing these imaging studies.

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