NEUROIMAGING IN PSYCHIATRY

DIAGNOSTIC DILEMMAS, PART I1

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NEUROIMAGING IN PSYCHIATRY David G. Weight, PhD, and Erin D. Bigler, PhD

Since Freud's early years as a budding young neurologist, the hope for objective diagnosis of psychiatric disorders has been alive and well. From Freud's earliest attempts to differentiate hysterical paralysis, loss of sensation, seizure-like episodes, amnesia, and other mental illnesses from certifiable neurologic disorders clinicians have been faced with critical challenges. Most of our classic textbooks have discussed the distinction between the so-called functional and organic disorders with considerable research energy being directed toward being able to differentiate these disorders by mental status examinations or psychological tests. This has been particularly true of schizophrenia in which syndromal qualities have been addressed by several subsequent editions of The Diagnostic and Statistical Manuals of Mental Disorders. The variance in the diagnostic category has been reduced significantly because dimensions, such as goodpoor premorbid, paranoid-nonparanoid, positive-negative symptoms, and other such factors, have been considered. Requiring time periods for the manifestation of symptoms along with a better classification of the toxic states and the exclusion of many other biologic complications that can result from psychotic states have further tightened the diagnosis. In spite of these developments, the clinician has still looked forward to more objective and commonly accepted diagnostic criteria. With major technological developments in the 1970s, clinicians soon had the ability to view the living brain. This has had a major impact on our evolving theory and diagnoses. Because of the emergence of magnetic resonance imaging (MRI) in the mid-l980s, we can now see a slice of the living brain; this slice mimics almost perfectly a slice seen on postmortem (see Fig. 1). Even the lessaccessible positron emission tomography (PET) scans offered hopes of locating areas of function and dysfunction in the brains of our patients. This further raised the hopes of practicing psychiatrists and psychologists who seek more definitive and objective measures of pathology. Research is proceeding on all

From the Department of Psychology, Brigham Young University; Utah Valley Regional Medical Center (DGW, EDB) Provo, Utah; and LDS Hospital, Salt Lake City (EDB), Utah

THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 21 NUMBER 4 * DECEMBER 1998

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Figure 1. Coronal section of actual postmortem brain (/eft) compared to magnetic resonance imaging (not the same subject; right). Note the clear distinction on this specially weighted MR image between white matter and gray matter, ventricular space, and major anatomic nuclei. (Top left) Postmortem MR section at the level of the anterior horn of the lateral ventricular system. (A) cingulate gyrus; (B) corpus callosum;. (C) ventricular cavity of the anterior horn of the lateral ventricle; (0) septum pallusidum; (€) caudate; (F) putamen; (G)external capsule; (H) gray matter; (I) white matter; (J) temporal horn of lateral ventricle; (K) hippocampus; (L) Sylvia fissure. Coronal section further back of the image presented above. This image clearly representsthe exceptional image quality observed with magnetic resonance imaging and how gross anatomy and MR imaging reflects actual anatomy.

sides in this, the "Decade of the Brain", and we must pause periodically to look at our current state of knowledge and hopes for the future. Research in areas in which the neurologic substrates are well established (dementias, brain injury, vascular disorders, Parkinsons disease, and so forth) have led the way in the use of these technologies for the diagnosis of pathology. Unfortunately, in psychopathology, the research has been plagued by some

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circularity in the protocol. In these instances, we use behavioral symptoms and diagnostic descriptors to identify the experimental groups that will then be either confirmed or disconfirmed by imaging studies. Even in more established biologic disorders, the relationship between structure and behavior has not been as compelling as we would hope. Neuroradiologists continue to describe temporal and frontal atrophy in aging populations as being well within normal limits, whereas a subset of these patients show memory and visual-spatial dysfunction that is clearly characteristic of a dementia process. Nevertheless, our research efforts are leading to significant findings and are totally altering our theoretic explanations of disorders that have historically been explained primarily by psychological conflict, object loss, early developmental patterns, or classical and operant learning. As newer and more available technologies make it possible to observe function, cognitive localization, drug effects, and other such factors, the future seems even more hopeful, despite the many disappointments that abound. This article first briefly describes the neuroimaging procedures that are most accessible and useful to the practicing clinician. Interpretive illustrations of both normal and pathologic images are presented. We offer interpretive strategies along with a view of the current status of imaging products and their potential usefulness in the areas of theory and diagnosis. This is followed by summaries of current research findings of the major areas of psychopathology that have been studied with neuroimaging. BRAIN-IMAGING TECHNIQUES

The history of neuroimaging has been fully discussed and pictorially presented by Ei~enberg.4~” Regarding contemporary neuroimaging that is in clinical use and has efficacy for the mental health practitioner, there really are three main modalities: computerized tomography (CT), MRI, and various types of perfusion studies, typically examining regional cerebral blood flow (rCBF). We truly live in an exciting era, and there will no doubt be monumental changes in clinical neuroimaging as it applies to disorders of a psychiatric and a psychological nature. The future of this type of imaging has been excellently discussed in several recent te~ts.4~. 75,93, lz5 For the purposes of this article, we focus almost exclusively on CT, MR, or perfusion studies. Accordingly, a brief introduction to these methods is appropriate. Computerized Tomography

In CT imaging, a thinly calibrated beam of x-rays is passed through the subject’s head, and this x-ray beam attenuates, depending on the type of tissue encountered. As the x-ray beam emerges from the point opposite its entry, the beam arrives at an image receptor (scintillation crystal) and is recorded. As the x-ray beams are rotated around the subject, a computer algorithm reconstructs the attenuation changes into a two-dimensional image. A standard CT scan is presented in Figure 2 for comparison with MRI images. For the practicing clinician, CT has some significant advantage over the superior images obtained with MRI. In addition to being less expensive, very accessible, and less likely to provoke anxiety symptoms in patients, CT has a major advantage of being able to detect gross pathology in a rapid and efficient manner and is good for detecting recent blood accumulations. It will continue to be a technique of choice for the initial assessment of patients who have acute

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Figure 2. CT and MR comparison in the same patient. (Left side) CT imaging compared with MR imaging (right side) in the same patient. The patient had sustained a neurologic injury, and this is reflected in the slight increase in ventricular size as a sign of some mild, nonspecific atrophy. When injury occurs, it may take days to months to detect atrophic changes. The MR is approximately 2 years after the CT imaging was obtained.

cerebral vascular accidents and head trauma. CT has a disadvantage of being unable to detect changes in important structures, such as hippocampi and basal ganglia, which figure prominently in some of the findings reported in this article. Aside from the ventricular structures that are easiest to measure, few reliable volumetric measurements have been accessible with CT. It does have the additional advantage of having fewer contraindications, such as those found with MRI (i.e., metal clips, pacemakers, intubation, and so forth). CT imaging does offer good correspondence with gross brain structures, just as with MRI (Fig. 2).

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Magnetic Resonance Imaging

MRI is based on the principle that atoms with an odd number of nucleons have a magnetic dipole and tend to align or spin within a directional polar axis in a normal magnetic field. When stimulated with a radio-frequency (RF) wave, the energy absorption is manifested by a change in the orientation of the original alignment, This is the process called resonance. When the RF source is turned off, the energy is released in a process called realization. This release of energy can be detected as RF signals are measured and processed into images (Fig. 2). Traditionally, there are different weightings that have to do with the way and time duration of the application of the magnetic field. These are typically referred to as T1, T2, and mixed-weighted or proton-density images. Such images are presented in Figure 3. MRI has a number of advantages that make it a superior technique in most structural analyses of brain anatomy. Tumors, cysts, hemorrhage, necrosis, and white-matter changes are seen readily with this technique. This makes MRI superior for diagnosing multiple sclerosis and the results of a cerebrovascular accident (CVA). It also has advantages in demonstrating ischemic changes after acute stroke, particularly in structures, such as the cerebellum and brain stem, where artifacts disrupt the image produced by CT. Newer developments show future applications, some of which are reported here. Functional MR Imagery (fMRI) utilizes a process of rapid acquisition sequences that can detect deoxyhemoglobulin. This detection makes it possible to measure focal changes in the blood flow during cerebral activity?] By comparing the brain during periods of both rest and execution of tasks, increases in blood flow can be inferred. Although this technique is primarily experimental, the clinician will ultimately have access to such studies in many hospitals in which MRI technology is available. Neurosurgeons are using fMRI to determine regions and boundaries of localized function to assess loss that can be expected from excising lobes of the brain in partial complex seizures. In this manner, fMRI is being used as a noninvasive in vivo procedure. Such use also makes it possible to evaluate cognitive challenge tasks as well as other forms of cognitive activity during psychotic episodes and the like. Activation images from fMRI can be accumulated across subjects, such that theoretic predictions of localized brain activity can be tested (see Color Plate: Fig. 1). Additionally, magnetic resonance spectroscopy (MRS) makes it possible to obtain data regarding tissue metabolism and biochemistry.lO*This amassing is possible because nuclei have differing resonance patterns as it relates to basic chemical make up of brain tissue. Accordingly, MRS provides a technique to assess such basic biochemical constituents as sodium, chloride, potassium, carbon, phosphorus, fluorine, and other elements. Until now, there has not been much application of MRS to psychiatric diagnoses, but these measures undoubtedly provide useful information about underlying brain biochemistry in a host of disorders. Perfusion Studies

With regards to perfusion studies, the most common acronym given to such studies is single photon emission computed tomography (SPECT). In such images, the resolution is never as exquisite or detailed as that obtained by CT or MRI, but the technique does allow the detection of injected radiopharmaceuticals and their perfusion into different regional brain areas. The study is done while

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A Figure 3. Comparison of standard T,, T2, and proton density weighted MR images depicting how these different weightings highlight different aspects of brain structure and pathology. A, This patient sustained a severe traumatic brain injury when he was bucked from a horse, sustaining a linear skull fracture and bifrontal and temporal lobe contusions. These MR imaging studies demonstrate extensive atrophy of the frontal and temporal poles as well as some generalized atrophy as evident in wasting of the corpus callosum (B). Clinically, this patient had significant problems with impulse control, planning, and judgment; common problems seen in individuals with frontal lobe pathology. Illustration continued on opposite page

the patient is at rest. Having the patient at rest implies that metabolic activity should be uniform across the brain when homologous sites are compared. If there is a problem with the even perfusion of a particular brain region, it should either show up as an asymmetry or show up as a change from what would be considered a normal baseline activity level. This asymmetry or change is well demonstrated in Color Plate: Figure 2. The most apparent advantage to the use of SPECT is that the technique is

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Figure 3 (Continued).

more accessible, goes beyond structural imaging, and infers activation of brain structures. Although an image is produced, this is the result of a mathematical filtering technique used to cancel out background. Scatter and attenuation problems are difficult to resolve and experimentation with different radiopharmaceuticals is being conducted to improve the estimation of pathologic states. Also, each patient must serve as their own control because there are no universal normative standards that can be universally applied to SPECT imaging. Shepstone and Jobst116provide detailed critiques of this technique as it applies to clinical diagnosis. Positron Emission Tomography Studies

Another metabolic imaging technique, positron emission tomography (PET), allows for the investigation of temporal changes as well as for resting changes in brain structure. In PET imaging, a physiologic tracer, usually a radioactive isotope, is injected and then activation patterns are monitored over time. The radioactive tracer can be attached to the glucose or oxygen molecule. In SPECT as well as

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PET imaging, the tissue resolution does not match that seen with CT or MRI, but the metabolic images can be coregistered with CT or MlU. Application is limited because of the expense of the equipment and the need for the equipment to be adjacent to a physics laboratory that has a cyclotron in which the radiopharmaceutical can be prepared. As of this writing, PET imaging is essentially a research technique and not a technique that is in the clinician’s armamentarium. Basic Image Interpretation

As of this writing and as discussed earlier, the three most widely used neuroimaging measures are CT, MRI, and SPECT. There is tremendous potential clinical application of new techniques, such as fMRI and MRS, along with new applications of standard MRI (i.e., diffusion-weighted images) and magnetoencephalography (MEG) (see-Fig.4 for an excellent comparison of the qualities of MR diffusion-weighted images). PET remains a research tool. Various methods for computer-assisted electroencephalography (EEG) and quantitative EEG (QEEG) analysis have received increasing attention in the research literature in evaluating psychopathologic states. Although these technologies offer new dimensions for evaluating brain function and especially epileptiform abnormali-

Figure 4. A, MR scans depict three different weightings that highlight different aspects of anatomy. Using these traditional weightings, no abnormalitieswere observed in this individual who had sustained a head i n j u y However, the SPECT scan, 6,and a diffusionweighted MR scan, C,both show abnormalities in the frontal regions.

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ties, significant problems in interpretation persist and, often, not much useful, clinically accurate information is offered to the clinician. QEEG provides reliable and reproducible measurements with slow-wave power; however, there has been relatively little agreement on how much is excessive. Additionally, good normative databases have not been developed to establish pathology clearly, and the possibility of unpredictable influence resulting from problems with artifacts remains.78Consequently, at present, these findings are not readily useful to the practicing clinician. MEG and PET imaging methods are still very much research tools and are not be discussed here. The reader should look for widespread clinical applications coming from these techniques within the next decade13,14, 49, 56, 75,93, lZ; however, for this article we discuss only CT, MRI, and SPECT, with an occasional reference to PET. The aforementioned references also provide detailed discussion of basic neuroimaging techniques that also are not covered here. Because structural detail is best afforded by MRI, our focus here is on MRI. To introduce the basic concepts associated with image interpretation, we present several normal and pathologic MRI and SPECT cases below. The basic tenet for image interpretation deals with brain symmetry and the homogeneity of brain parenchyma. In a global sense, the contents of the calvarium can be divided into the following components; white matter (WM), gray matter (GM), cerebrospinal fluid (CSF), cerebrovasculature (CV), and meninges (M). Each component possesses distinct characteristics that can be detected with CT and MRI. Because SPECT imaging is, at least indirectly, measuring blood flow characteristics, the perfusion images of SPECT only permit inference about WM, GM, and CSF. Although pathologic identification of abnormalities of a cerebrovascular or meningial origin are important, they are rarely the issue in the psychiatric disorders to be discussed in this article. Accordingly, this article focuses primarily on CT and MRI identification of brain parenchymal abnormalities and perfusion studies of blood irregularities that shed light on potential pathologic findings in certain neuropsychiatric disorders. Typically, the first assumption of clinical analysis in neuroimaging starts with a firm understanding of normal neuroanatomy (Fig. 5). Next, the principle of symmetry is applied to the image analysis. Because the brain is a symmetric structure, nuclei, pathways, and regions of one hemisphere are mirrored in the other. Fig. 6, based on axial MRI views at the level of the third ventricle and anterior horn of the lateral ventricular system, demonstrates how three normal brains match when compared across one another at the same level. This figure nicely demonstrates the general symmetry of the brain in each case. By knowing the appearance of one hemisphere, or the structures within, the other hemisphere or structures can be compared readily. With these standards, significant pathology is readily apparent when viewing a clinical scan. For example, in Figure 7 an MRI scan that is taken from a schizophrenic, paranoid-type patient who also had suffered a right hemisphere cerebrovascular accident. The scan sequence presented in this figure also depicts the case with which MRI can be acquired in planes other than axial (a limitation for CT imaging) as well as different types of weighting that permits better differentiation of certain tissue types. In this patient’s case, the area of damage that represents the structural sequela of the CVA is readily apparent in the frontolateral aspect of the right hemisphere. The art of clinical interpretation of scan information is based on the clinician’s visual perception and the guidelines presented above. However, it is obvious that there is considerably more information in the images. For example, because bilateral structures are generally symmetric, one structure could be quantified and compared with its homologous pair. Likewise, because normal

Figure 5. Sequential axial (horizontal) T,-weighted MR scans from the level of the foramen magnum (upper left-hand corner) to vertex (lower right-hand corner). Note the symmetry of the brain at each level. The white represents CFS fluid-filled spaces.

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Figure 6. Axial MR T,-weighted magnetic resonance imaging studies taken from three different patients, but all at the same level (anterior horn head of the caudate nucleus). This represents the concept of similarity at a particular brain level or region across patients. Deviations from that similarity may signify abnormality (see Fig. 3).

brain anatomy is relatively uniform across individuals, a given patient could be compared with a normative database. Accordingly, much of the recent neuroimaging research has been to quantify various structures so that a quantitative MRI (QMRI) (see Color Plate: Fig. 3) approach can be taken in the evaluation of structural brain The MR scans presented in Color Plate 3 were taken from a patient who sustained a severe traumatic brain injury and are compared with an age-matched normal individual representative of the normal agematched sample. The bar graph depicts the QMRI analysis of the patient’s values compared with the norms for the individuals age. Quantitative analyses such as these provide further detail about the structural abnormalities, particularly how certain structures or areas deviate from normal. Although traditional CT and MRI are techniques for assessing brain structure, SPECT imaging provides some measure of function, typically based on rCBE The physiologic imaging achieved by SPECT is based on the assumption that the resting brain has a certain uniform baseline activation pattern and that deviations from this represent abnormal blood flow patterns.56 Via systemic intravenous injection of a radiopharmaceutical, such as 99m Tc-hexamethylpropyleneamineoxime (HMPAO), rCBF then demonstrates the perfusion of the agent. Any deviation in uptake represents either hypoperfusion (implicating less rCBF such as seen with tissue infarction) or hyperperfusion (such as seen with hyperexcitability at the site of the seizure focus). The same principles apply to SPECT imaging as with CT and MRI; namely, the brain is a symmetric organ, and at rest rCBF should be even across the two hemispheres. This is demonstrated in Color Plate 2. TRAUMATIC BRAIN INJURY

We have elected to initiate the various sections of this article with a brief discussion of traumatic brain injury. There are several reasons for this. First, traumatic brain injury may play an antecedent role in several neuropsychiatric disorders. Having had a brain injury may predispose one to various neuropsy-

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Figure 7. See legend on opposite page

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chiatric conditions, and hence the clinician should be familiar with what is typically observed in neuroimaging studies of those who have had brain injury. A straightforward case of brain injury is seen in Color Plate: Figure 4A. This is an image from a construction worker who fell several feet, striking his head, and sustaining massive frontal contusion. The three-dimensional (3-D) MRI shows the residual burr holes and horseshoe craniotomy sear used to evacuate a hematoma over the frontal region, and the various imaging planes performed in this patient demonstrate the cystic formation in the frontal region brought on by this trauma. The colorized 3-D image of the brain (Color Plate: Fig. 4B), based on a volume acquisition MRI scan, shows the position of structural damage to the brain. Much of contemporary neuroimaging can be done with this 3-D imaging technology. In the case presented in Color Plate 2, a direct comparison is made between MRI and SPECT findings. This image is taken from a patient who sustained a serious traumatic brain injury in a fall down a flight of stairs. She sustained a hemorrhagic contusion to the frontal region. The MRI and SPECT imaging studies were done several months after the injury, and accordingly, this would represent the stable defect. There is a large perfusion defect in the left frontal lobe, and there are some of the classic findings associated with trauma seen in MRI. A review of structural, functional, and behavioral findings from traumatic brain injury is beyond the scope of this article, and the reader is referred to Bigler.I3,l4 ANXIETY DISORDERS

Perhaps nothing is more central to psychopathology than anxiety. Freud’s conflict theories revolved around forms of anxiety that required psychoneurotic defenses and other ego functions to diffuse or distort the effects of the nonspecific arousal that was so distressing and motivating. Biology is generally assumed to serve behavior, and we have long known of the fight-or-flight response30 that has been referenced prominently in many theoretic discussions of human and animal responses to threat and fear. Consequently, anxiety serves an adaptive function if it does not become perpetual and damaging to the very

Figure 7. This series of MR scans were taken from a patient with longstanding histoty of schizophrenia, paranoid type, who had been on neuroleptic medication for approximately 20 years when she suffered a right frontal cerebral vascular accident (CVA). A, Sagittal view demonstrating extensive involvement of the anterior frontal region and some aspects of the temporal lobe on the right. B, Midsagittal view (T,-weighted) demonstrating involvement of the inferior frontal/orbital frontal region. C, Coronal view showing extensive involvement of the right frontal lobe on the T,-weighted coronal image. D, T,-weighted image showing atrophy as well as extensive frontal involvement. Some degree of generalized atrophy appears to be a substrate common to chronic schizophrenia. This is also depicted below (€)on the axial T,-weighted image through the body of the lateral ventricle. Obviously, there is extensive lesion in the right frontal lobe (images presented in the radiologic perspective where rigbt is on the /eft side). The ventricle extends into the lesion, but the ventricle in the left hemisphere is also enlarged, and there are more prominent sulci than would be expected for a woman this age. This is a case where neuroimaging addresses two questions: the nature and extent of the CVA, its location, and the associated structural changes; and the likelihood that longstanding ventricular dilation and cortical atrophy were present.

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biology that it seems designed to protect. Mowers8described the neurotic paradox that has long been observed by practicing clinicians. Some behaviors are ”at one and the same time self perpetuating and self defeating.” The explanation of this paradox appears to be that the individual repeatedly turns to selfdestructive behavior that has the potential to remove the anxiety, even if only briefly. Biologic research might then lead to discovery of the effects of chronic anxiety in individuals who seem unable to modulate this generally adaptive emotion. Research on neurotransmitter systems and the biochemistry of anxiety has certainly made major contributions to theory and treatment. The diagnosis of defective neurotransmitter systems in a given patient, however, often becomes a diagnosis by trial and error. We still seek more objective diagnostic criteria. Obsessive-Compulsive Disorder

The obsessive-compulsivedisorder (OCD)has been one of the more compelling anxiety disorders since the repetitive and the seemingly irrational behaviors seem to border on psychosis. This condition is reported in 2% to 3%of the world populations9,lo6 and typically involves obsessive thinking or ritual behaviors that are thought to dispel temporarily the anxiety consistent with the neurotic paradox. In addition to the distractibility and attention difficulties that anxiety does produce, patients report cognitive changes, including general impairment and deficit in nonverbal and visual-spatial memory. Case studies reporting lesions in the caudate nucleus76,77, 134 led Jenike et a P to conduct a study specifically looking for cerebral or structural abnormalities in the OCD. (To review the location of subcortical structures, see Fig. 1).Although the study had only 10 experimental subjects and 10 control subjects, it was an ambitious project that provided quantitative morphometric MRI data. They essentially concluded that their patients who had OCD had significantly less total white matter but greater total cortex and opercular volumes. Grachev et a153used MRI-based brain seg72 in their attempt to tighten the protocol by reevaluating mentation the data of the Jenike et al.” Segmentation methods are a semiautomated differential analysis that can blindly segment and measure the principal gray- and white-matter structures. They ”found no differences in anterior cingulate, orbitofrontal, or opercular cortical volumes in patients with OCD compared with matched normal control subjects” (p. 181). They did find, however, that the overall cerebral neocortical volume was greater with patients who had OCD. This procedure appeared to measure opercular volumes differently from previous studies. Neuropsychologic measures were found to show that OCD patients who had greater right frontal volumes had worse memory performance. These, however, were unrelated to clinical severity of OCD. The small number of subjects may still make this finding tentative. They found no significant difference in the size of the corpus callosum; however, the OCD patients did have a longer corpus callosum when compared with the control subjects. Peterson et a197 reported that ”worst-ever motor tic symptoms” in Tourette syndrome correlated positively with the length of the corpus callosum ( R = 0.88). Tourettes’ does have OCD features. As is often true in areas of research in which using multiple technologies are used, the findings are not entirely consistent. Kellner et al,” who used a similar-sized sample, found no sigruficant differences between subjects and controls on the head of the caudate, cingulate gyrus thickness, intracaudate/ frontal horn ratios, and area of the corpus callosum. The Jenike et a1” study also found no significant difference in size of the caudate. Notwithstanding, Baxter

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et alll,lzand Rauch et aPol had shown a relatively strong relationship between the caudate nucleus and the pathophysiology in OCD. If the preliminary studies of decreased white-matter volume are observed in replication, this decrease may be further confirmation for nonspecific stress and steroidal effects on white matter and other subcortical structures. The decreased white-matter volume would be consistent with chronic anxiety. Very few studies of functional changes in OCD have been reported. Machlin et alS2reported a study of 10 OCD patients for whom SPECT was used to determine rCBF. They reported that patients had a higher ratio of medial-frontal to whole cortex blood flow that seemed to be generally unrelated to the severity of the symptoms but were negatively correlated with anxiety. No change in orbital-frontal blood flow was found, and they concluded that this was consistent with expected frontal-lobe involvement in OCD. This finding appears consistent with increased frontal volumes and inconsistent with the above reported decreases in white matter and the continuing controversy regarding the role of the basal ganglia in OCD. A few small n studies have been done with panic disorder and SPECT. DeCristofaro et aP9 showed right-left asymmetry in the interior frontal cortex, and they concluded that hippocampal hypoperfusion was characteristic of panic. Kaschka et aP9found several areas of regional activity that differed between panic disorder subjects and the control group. These included the lateral inferior temporal lobes (right and left) and the medial inferior temporal lobes on the left along with the inferior temporal lobes on the right and left. They could not conclude if this regional activity was a result of genuine blood flow difference or benzodiazapene receptor effects. Eighteen patients with generalized anxiety disorder were studied with PET scansz6that reported significant differences in patterns of absolute brain metabolism. These were most evident in the basal ganglia and white matter. Relative metabolism was reportedly greater in the left inferior area of the occipital lobe as well as the right posterior temporal lobe and the right precentral frontal gyrus. They did not find any asymmetry of the parahippocampal gyri. For now, none of the studies appear to be very conclusive. Aside from the fact that studies with a small number of subjects show frontal abnormality that may involve white matter and that structural and functional abnormalities are found in OCD, compelling and reliable data are not yet evident. Subcortical structures appear to be affected, and this may be the result of more generalized anxiety effects to be discussed below. Posttraumatic Stress Disorder Among the anxiety disorders, posttraumatic stress disorder (PTSD) has been at once controversial and important diagnostically. Combat-related posttraumatic stress typically results in flashbacks, nightmares, intrusive memories, changes in memory function, and unusual avoidance patterns and amnesia of war or other traumatic experiences. This appears to be a disorder that is less likely to be developmental in origin and is acquired on the basis of acute stress reactions that then persist. Changes in short-term memory could be the result of poor attention and distractibility as well as brain effects that might implicate the hippocampus. The hippocampus has been reported to be vulnerable to the destructive effects of glucocorticoids secondary to stress. In animal studies, this vulnerability is reportedly due to the loss of neurons and dendritic branching in the hippo-

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campus.112,135 This glucocorticoid toxicity may result from the vulnerability of Iz9 Starkman et allzoconneurons to toxic changes in excitatory aminoacids.llO, ducted an MRI study in which a relationship was found between deficits in short-term memory, reduced hippocampal volume, and increased plasma cortisol levels in Cushings disease. The expectation that human subjects involved in

artillery bombardment and other such trauma would be exposed to extreme stress is an easy assumption to make. Bremner et al” conducted a study of 26 Vietnam combat veterans with PTSD and 22 matched normal control subjects. They found a lateralized effect with smaller right hippocampal volume (8%)in the PTSD group. No differences in the caudate or temporal lobe were noted. Performance on the Weschler Memory Scale was significantly affected by the reduced right hippocampal volume and seemed consistent with the above prediction. Explanation of the lateralized finding is less clear however. A preexisting developmental difference is possible. Explanations based on alteration in sex hormones, seizure disorders, and so forth are beyond the scope of this article. There does not appear to be any clear expectation for asymmetric concentrations of glucocorticoids that would affect one hippocampal structure more than another. There had been a mix of findings in schizophrenia18,*O that show reduced hippocampal volume on the left. Another compelling study1= also found discrepancies in hippocampal volume between monozygotic twins who were discordant for schizophrenia. This would strongly argue for more acquired-stress features producing the changes. It is unclear whether similar mechanisms could operate both in acute and in chronic anxiety states as well as schizophrenia. More recently in a study in which fewer were used, decreased hippocampal volume was again found. A lateralized effect was not reported; however, these researchers reported that the hippocampal volume was correlated quite directly with combat exposure. Pre-existing hippocampal size was not ruled out in this study nor in the above studies. Another studyg0reported a greater incidence (50%) of cavum of the septum pellucidum, which is a small cleft in the callosol-septa1 interface. This occurrence is a finding only seen in 14% of normal MRI scans. This would be a premorbid condition that could increase vulnerability. Few regional blood studies are reported for patients diagnosed with PTSD. A remarkable case study in which PET was used was very recently reported. This study suggests a potential for the use of perfusion studies in psychopathology? A patient was temporarily trapped in the basement of a burning house and apparently escaped without significant smoke inhalation or other harm. The following morning he was reported to be in an anxious and disoriented state and experienced retrograde amnesia of over 6 years. He was also complaining of a significant headache. During a psychiatric hospitalization he reported an early traumatic experience (age 4) involving an automobile accident in which a car burst into flames. He apparently witnessed the drivers screaming and death, and this event reportedly was confirmed by his mother. CT and MRI scans were reported as normal and an extensive PET study was obtained. These were coregistered with MRI and showed major hypometabolism, especially in the bilateral hippocampal structures (see Color Plate: Fig. 5). The hypometabolism was reported to be sigruficantly different, two to three standard deviations below the mean for age and gender-matched controls. Also depicted in Color Plate: 5 is a comparison with a normal and a severely amnesiac patient recovering from a heart attack.83Although a single case study, this raises questions concerning the possibility of a stressful event leading to exascerbation of an earlier traumatic episode that subsequently produces amnesia and atten-

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dant cognitive changes. This would continue to fuel theoretic discussion over the possibility that cases with overt brain damageZ1f1l1 and cases with amnesia attributed to psychogenic states8,119 may both result in similar changes in brain perfusion and cognitive efficiency. Another related finding showed that substance abusers differed from control subjects in regional blood flow to the orbital-frontal cortex and the hippocarnp~s.”~ Although few studies are reported, hippocampal volume and function appears to be implicated. The research is clearly not at the place, however, where a clinician could make use of an MRI to aid in the diagnosis of this condition for an individual case. AlTENTION DEFICIT HYPERACTIVITY DISORDER

This is one of the most commonly diagnosed disorders of children and adults. It is estimated that approximately 5% of school-age children and 40% of 92, Iz3 It tends to clinic referrals have symptoms that might support this di~order.~, be a persistent condition with approximately 50% of subjects continuing to show symptoms through adolescence and into early adulthood.86The principal symptoms involve hyperactivity with inability to delay or inhibit motor res p o n s e ~along ~ with difficulties in sensory detectionIz8and suggestion of prefrontal dysfunction from neuropsychologic studies.Io0There are secondary findings of neglect and deficits in delayed response to tasks. Right-sided dysfunction of the frontal-striatal circuitry has been proposed for attention deficit hyperactivity (ADHD). Older studies in which CT findings were used, have not been particularly convincing regarding ADHD.46Studies with positive findings primarily reported cerebral atrophy. These studies, however, used subjects who had gross abnormalities or neurological impairment or histories of alcohol abuse in adult ADHD patients. Possible contaminants seem evident and CT still does not lend itself to the structural analysis that is available through MRI. In one of the best-conducted studies to date Castellanos et a132studied 57 boys who had ADHD and 55 matched control subjects (aged 5 to 18 years). Volumetric measures of MRI were obtained on basal ganglia as well as cortical structures (left and right), cerebellum, and corpus callosum. The principal findings showed the ADHD group to have a 4.7% smaller total cerebral volume. The caudate nucleus was found to have a significant loss in the expected normal right greater than left asymmetry. Ventricular volumes are expected to change in normal males as they age. This study reports that normal males showed these age changes, whereas the ADHD subjects did not. The study also reported a significantly smaller right globus pallidus and smaller area in the right anterior frontal region. The cerebellum was also found to be smaller and there was a reverse of the normal lateral ventricular asymmetry. They concluded that there was evidence for the “hypothesized dysfunction of the right-sided prefrontal-striatal systems in A D H D (p. 607). Other studies have also reported right greater than left caudate asymmetry.20,48 There does appear to be “converging evidence that a lack of normal asymmetry mediates the expression of ADHD.”32 Several studies have investigated the size of the corpus callosum because possible asymmetry and differences between frontal and posterior brain communication may be implicated in this disorder.62The anterior corpus callosum contains fibers that interconnect with orbitofrontal, prefrontal, premotor, and general right and left The posterior corpus callosum has fibers that

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primarily connect to visual association cortical areas.’ It has been hypothesized6’ that the pathology associated with ADHD should show reduced size in the anterior corpus callosum. The data seem to confirm this hypothesis. A replication of the reported a reduction of the size of the splenium but not the anterior corpus callosum. In both cases it does raise questions about asymmetry between the two hemispheres. Indirect evidence of right hemisphere structural changes may also be supported by PET studies in normal adults. In these studies, only the right hemisphere is activated in vigilance 95 Other studies of adults who had ADHD have tended to show significantly reduced glucose metabolic rates. These areas were thought to include the right thalamus, the right hippocampus, the cingulate, and the right caudate. Although these studies1@are generally consistent with decreases in frontal and striatal brain glucose metabolism such as that seen in the Lou et a179findings, there seem to be contradictions between decreases in somatosensory and occipital areas and increased blood flow in these regions. Again the primary conclusion appears to be that the findings, positive and negative, are associated with brain regions that are expected to mediate symptoms of ADHD. Very few SPECT studies have been performed on ADHD subjects. A study of six patients showed greater hemispheric uptake asymmetry with less activity in the left frontal and left parietal regions compared with control subjects. Greater hemispheric uptake was thought to be consistent with areas that affect control of tensional processes. These findings of diminished modulation of emotion seem to further substantiate that lesions or atrophy of the caudate and 138 not the putamen are most implicated in hypera~tivity.~~, Several studies by Lou et a179-81 used the same population of subjects and cannot be viewed as replications. Their conclusions on a small number of subjects pointed to pure ADHD children as showing 10.7% decrease in blood flow in the striatal regions and the paraventricular region but with no mention of asymmetry. They also reported an increase in the occipital regions compared with the control group. In spite of the limitations of the subjects in the studies, they may be viewed as generally consistent with pathogenesis in ADHD. These abnormalities include the frontal cortex and the striahun, with at least one study showing right greater than left. EmsP concludes that there are two major findings from studies with both adults and adolescents. ”The right frontal cortices, corpora callosa (posterior area in one study and anterior in two studies) and heads of the caudate nuclei, left in one study and right in one study, were found to be smaller in subjects with ADHD than control subjects” (p. 105). The decrease in the metabolism of brain glucose, which has been seen in adults who have ADHD, is not consistent with adolescent findings. Females showed more metabolic deviance than did males who had ADHD. There also appears to be an age factor. The age factor may be consistent with findings of differences in lateralized brain function between males and females (see Color Plate: Figure 1). Again these findings contribute substantially to our theories of anxiety and hyperactivity, although they have not yet provided criteria for discovering clearly measurable structural or functional differences that will aid in the diagnosis of the individual case.

MOOD DISORDERS Mood disorders, because of their great affect on human suffering and risk for self-destructive behavior, continue to be a major diagnostic and treatment

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concern for clinicians. Since emotional tone can be viewed as a continuum, the polar opposites (sad and happy), lead to very different behavioral outcomes and attendant risk factors. Diagnosis has clear implications for treatment, and misdiagnosis can be very costly, particularly in the older populations where neurologic disorders have very different origins and treatment implications. The hope that neuroimaging procedures will aid in these diagnoses is evident. In spite of research findings that strongly argue for neuroscanning as part of the regular treatment protocol in first-episode major depressive disorder in elderly patients,132in a recent study of over 600 elderly patients it was reported no CT scans being utilized in this group.118It appears that clinicians either find scanning not helpful, an unnecessary expense, or merely overlook the risk factors from neurologic complications, particularly in the elderly. We have long known that the bipolar disorder along with schizophrenia 67, Io7; has the most compelling genetic implications of all the mental Kraepelin’s earliest classifications of psychopathology included primarily the bipolar and the schizophrenic disorders. Psychopathology history and its genetic correlates argue very strongly for a neurosubstrate of these disorders, and clearly, most of the research using the new scanning techniques has investigated these conditions. Studies in which CT is used, have necessarily focused on brain structures that are most available to that technology. In a representative study by Gewirtz et a1,52 in first-admission psychotic patients, 40% of this sample showed cortical atrophy when compared with normal subjects. No differentiation could be made between schizophrenia, schizoaffective disorder, bipolar disorder, or psychotic depression. In another large sample of bipolar and chronic schizophrenic patients, choroid plexus calcification was found, and there was a significant association between suicidal behavior and this calcification.1wIn an associated finding, pineal calcification was reported as significantly associated with bipolar electroconvulsive therapy (patients who did not respond to ECT). It is unclear whether these calcification findings are secondary to vascular or stress patterns or some other determinant. With the development of MRI, there was significantly improved capability to see white- and gray-matter variation; this has consequently led to some of our most significant findings. As soon as MRI studies became available, neuroradiologists immediately started reporting cerebral white-matter hyperintensities (WMHI) that appeared to be present in normal aging. These were also reported to be more frequent in hypertensive patients than those with cerebral vascular disease.6*63 In an excellent study by DeCarli et a1,38 the relationship between these WMHI and brain structure, cognitive performance, and glucose metabolism were studied in normal healthy adults. In previous studies it had already been reported that WHMI were related to brain atrophy,”, 87 rCBF,59,85 along with focal neurologic signs,lZ1and some reports of poor neuropsychologic 137 In their study, DeCarli et a138 developed a protocol to test perf~rmance.~~, evaluate WMHI volume beyond a mere counting of hyperintensities. They found that these volumes were “significantly predictive of increased ventricular volume, reduced brain volume, and reduced cognitive scores” (p. 2077). They also found that their normal subjects who had more than 0.5% WMHI also had significantly reduced frontal-lobe metabolism, higher systolic blood pressure, and enlarged ventricular volume. Consistent with these apparent changes in brain structure, they also showed significantly lower scores on neuropsychologic tests that are thought to mediate overall cortical function when compared with age-matched controls. Although all of their subjects were within a normal cerebral-vascular risk range, a relationship between hypertensive measures and the above negative effects were found. This looked very much like an aging

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process when blood pressure is controlled. They concluded that WMHI do occur in healthy individuals but that it also appears to be related to pathologic processes as well. These findings are important since comprehensive volumetric MRI studies of mood disorders are showing these to be some of the most compelling findings (see Fig. 8). In one of the best-controlled studies in which MRI and both bipolar and unipolar depressive disorders were used," it was found that WMHI volumes were significantly different. It was found that younger patients who had bipolar disorder showed the increased volume of W H I . The difference in the older groups may have been compounded by age changes. Overall differences were still significant, however, with bipolar-disordered patients showing a higher volume of abnormal white matter than either control subjects or those who had unipolar disorder. Dupont et alO used a protocol in which they could identify more extensive and diffuse white-matter process beyond that suggested just by the small, highly localized lesions or areas of signal hyperintensity that could be seen visually. Other studies have also found white-matter abnormalities in unipolar disor33, 74 These abnormalities may have been accounted for by the researchers' derZ4, attempts to control for hypertension, whereas other studies had apparently not done this. Dupont et a143also found that those with higher volumes of whitematter disease had family histories more positive for psychiatric disorder and a later age at onset. Cognitive impairment was noted to be consistent with other studies.@

Figure 8. MR scan showing hyperintensities in the brain of a patient with bipolar disorder. (From Aylward EH, Roberts-Twillie JV, Barta PE, et al: Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry 151:690, 1994; with permission.)

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In another large MRI study of 48 severely depressed patients referred for ECT, these subcortical hyperintensities in the periventricular white matter were also observed. This large sample of depressed subjects may have been older, at greater risk of self-destructive behavior, and likely to have had trials on many antidepressant medications since they were all referred for ECT. This study also measured several other structures that have shown abnormalities in the literature. They found no differences between cerebral hemisphere volumes, in the amygdala-hippocampal complex nor in the degree of cortical atrophy or temporal-lobe volume. Neither did these subjects differ in the volumes of the lateral or third ventricles. Again the WMHI appeared to be the most robust finding. The Dupont et a1 s t u d p also failed to find any increased ventricular volume or ventricular size. These white-matter abnormalities are expected to be stable over however, the exact cause has not been clearly defined. Aylward et a17 also studied a large sample of bipolar-disordered patients. They were looking for changes in ventricular size and basal ganglia volumes that had been predicted from previous research. With the exception of male bipolar patients, who had larger caudate volumes than comparison subjects, no other basal ganglia changes were noted. Again, WMHI was found primarily in the frontal lobe and more consistently in older patients. Attempts to separate the cardiovascular risk factors from these findings are difficult. Some have found bipolar patients to have greater risk for cardiovascular disease. The interaction of brain lesions with major depressive disorder is not well known. In the landmark study of the biologic roots of mental illness in identical twins, Torrey126studied small groups of twins who were discordant for schizophrenia and for bipolar disorder. They noted the conflicting evidence regarding ventricular size. In their small number of subjects, they found outliers among the well twins, which reduced the power of the statistical comparisons. They could therefore conclude a trend toward ventricular dilation of the affected twin, similar to that seen in schizophrenia. These findings had to be viewed as tentative. Changes in the hippocampus amygdala were not shown as significantly different. They also found no significant difference in the basal ganglia for their seven pairs of twins. WMHI were apparently not measured or reported in this sample. Functional studies of rCBF have not contributed significantly to our understanding. In a study of 20 mood-disordered patients, mostly bipolar, PET scans with deoxyglucose tracers showed relatively hypofrontality with significantly lower metabolic rates in the basal ganglia when compared with control subjects.28 This would support some CT and MRI studies that found decreased frontal-lobe volume, although some of the most recent and best-controlled studies have not confirmed this finding. Some studies have also shown reduced frontal metabolism in unipolar mood disorders'O, 99 with diminished metabolism in the basal ganglia and the temporal 10bes.3~Neuroscanning the findings did not seem to differentiate unipolar from bipolar effectively in any of these studies. Findings on SPECT have clearly not been consistent. In a large study comparing several psychiatric diagnoses?l depressive patients were found to have decreased cortical and subcortical rCBF. Confirmation of other studies is difficult since Ebert et a P reports that using some metasensory stimulation results in similar findings that are common to all psychiatric patients. This tends to be increased rCBF to the subcortical regions contralateral to the somatosensory stimulation in the thalamus and the basal ganglia and ipsilateral to the cerebellum. They again reported hypofrontal blood flow in schizophrenicand depressed patients but primarily in the right inferior frontal lobe of those who have mood

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disorder. The affective psychosis showed a relative increase in activity in the inferior parietal lobe. Their principal conclusion was that "depressed patients with schizophrenia were different from depressed patients with major depression in showing decreased activity in interrelating brain regions participating in an attentional network" (p. 250). In summary it appears that few findings are reliable other than a preponderance of WMHI that are not clearly localized but do differentiate mood disorder from normal subjects, particularly those who have bipolar disorders. A neurologic substrate for this group of disorders is clearly evident as there are multiple findings of hypofrontality, diminished overall white-matter volume, increased ventricular size, and changes in volume and in function of the basal ganglia. This is true in many studies but not all. In the most recent and best-controlled studies, these latter findings of volumetric change are not confirmed. Although new scanning measures such as fMRI offer more accessible and useful diagnostic procedures, currently the use of neuroscanning is not providing significant help in making the day-to-day diagnoses that face clinicians. The need for ruling out other neurologic states is still imperative, particularly in latedeveloping depressions for which there is no history of major depressive disorder, dysthymic states, and other such factors. SCHIZOPHRENIA

As previously noted, the very nature of schizophrenia with its pervasive and life-altering symptoms has led researchers in so many theoretic directions that the disorder gives the impression of a pervasive syndromal pattern. The research history is immense and the variety of inconsistent findings seems illustrative of the apparent complexity of the disorder. Its clinical presentation with positive symptoms of thought disorganization, delusional thinking, and auditory and visual hallucination have always demanded attention from practicing clinicians. The so-called negative symptoms described as social withdrawal and deterioration, poverty of thought, apathy and a lack of initiative, and diminished attention to self-care are in many cases more debilitating than the positive symptoms. The fact that the symptoms present even inconsistent and alternating histories has further contributed to the diagnostic and research dilemma. As early as 1798, from observations made as a result of autopsy, John Haslam reported apparent structural changes in schizophrenic brains.130With the discovery of imaging technologies, his early observations have finally been confirmed and the genetic and the biologic substrate of schizophrenia seems generally unquestioned now. Although many current theories still point to apparent functional qualities of the disorder, neuroimaging findings of structural change along with dopenergic theories are most compelling. Owing to its earlier development, CT studies led the way in the early investigations. Since the resolution of these images was very inferior to the more recent MRIs, only the most apparent structures could be studied. The most reliable and compelling finding in both CT and MRI studies is that of enlarged ventricles when compared with normal control subjects. In over 80 CT studies this finding is evident4 (Fig. 9). In 1990, Raz and Raz1O2summarized much of the neuroimaging literature (1993 studies) with a metanalysis. These were primarily CT studies with very few MRI results. They clearly found increased lateral ventricular volume with an effect size of .70. This corresponds to a 43% nonoverlap between the distribu-

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Figure 9. MR imaging done in schizophrenia. Top, Axial views of T,-weighted MR scans showing ventricular dilation and prominent cortical CSF with distinct enlargement in sucal width. Bottom, Coronal section depicting cortical atrophy and ventricular dilation. This is in a 24-year-old male patient with longstanding history of paranoid schizophrenia. (Compare with Figs. 7 and 8.)

tions of schizophrenics and controls. Findings also suggested that differences in the third ventricle had a similar effect size (d = .66). This effect was even greater when more reliable measurement methods were used. These effect sizes would be classified as medium, when Cohen's criteria%was used. They further found that males were at greater risk for abnormalities, and "the average cumulative length of hospitalization, adjusted for patient's age and duration of illness,

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predicted ventriculomegaly in schizophrenia” (p. 93). They were also unable to differentiate schizophrenia and mood disorder based on cortical atrophy or ventricular enlargement. The effect size for mood disorder was smaller (d = 0.49), although not significantly different from schizophrenia. In 1991 Hyde et a P reported more than 100 controlled studies for which both CT and MRI were used and that showed mild to moderate dilation of the lateral and third ventricles. From review of these studies it was concluded that dilation was not the result of medication taken by patients, since several of these studies control for premorbid brain volumes. It was further asserted from the studies that the ventricular dilation appeared to be static and not progressive in its deterioration. These findings appear relevant to theories of schizophrenia since the diagnostic criteria lead us to at least three different assumptions: (1) schizophrenia must have an origin with a discreet or identifiable pathognomic lesion; (2) because the disorder results in disturbances of reason and higher cortical activity, the cortex must be implicated; and (3) schizophrenia characteristically starts in late adolescence and early adulthood, results in social and economic deterioration and, therefore, is presumably a neurodegenerative illness.5O The preponderance of studies to now seems to provide broad confirmation of numbers one and two while number three remains questionable. If gliosis is the most expected finding in active neurodegeneration, then recent studies are unconvincing.68,Io5 These assumptions have led to structural studies of the frontal and the temporal lobes as well as the limbic system, since all seem theoretically important. Further elaboration of the enlarged ventricular findings have been recently reported in a well-controlled twin study by Torrey.lZ6In monozygotic twins who are discordant for schizophrenia, the ventricular enlargement is virtually always found in the schizophrenic twin but not in the genetically identical well twin. This strongly argues for an environmental insult or an undetermined slow-developing pathognomic process. In at least one other publication%a comprehensive study of MlU scans were searched for signs of early developmental anomaly, and the scans did not differ from normal in this regard. MRI has also been used extensively to replicate the finding of ventricular enlargement in both acutew,41 as well as chronic schizophrenic^.^, 71 MRI has made it possible to obtain volumetric measures of lobular differences and look at more specific temporal and limbic structures. In a comprehensive review, Hyde et a P pointed to an established finding of reduced size of the hippocampus and amygdala. These are known to be critical components of the limbic system. Several different research labs were reported to have found changes in both neuropathology and neurochemistry related to the hippocampus and the amygdala both through MRIs and autopsy studies. Studies of dopenergic effects within these systems have also been found although this is beyond the scope of this paper. Recent well-controlled representative studies of these findings illustrate structural changes. Turetsky et allz7obtained quantitative MRI studies to examine specifically the left-frontal and the temporal-lobe CSF volumes in 71 schizophrenic patients and 77 control subjects. The patients were subtyped regarding negative and positive symptom presentation. Abnormal brain asymmetry was reported with reduced volume in both left and right frontal lobes. In those subjects who showed greater left parenchymal volume reduction with attendant CSF volume increase, an increased number of negative symptoms were reported. This led to conclusions that there are selected structural deficits in schizophrenia rather than the diffusely undifferentiated CNS abnormalities that are inferred by a preponderance of studies that did not specifically look for volumes. This

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also suggests that the negative symptoms are more associated with temporallobe rather than frontal-lobe abnormality. This was reported as "consistent with suggestions of temporolimbic prefrontal network abnormality in schizophrenia" (p. 1061). Another studylls had shown a reduction in the volume of gray matter in the left anterior hippocampus amygdala. This represented an average 19%reduction from normal subjects. The left parahippocampal gyrus was also reduced by 13%. However, in this study, they did not find the overall volume of the temporal lobe to be reduced. They still concluded that the left temporal lobe is clearly implicated by localized reduction of gray matter. The subcortical structures can be implicated because of many related pathways, including subcortical damage, neurotransmitter abnormalities, or the massive reciproconnections between the thalamus and most brain structure^.^^ In a recent and well-controlled studyz7researchers obtained both PET and MRI studies of the thalamus in never-medicated schizophrenic patients (see Color Plate: Fig. 6). It is well known that the extensive connections between the nuclei of the thalamus and the prefrontal cortex modulate sensory input. This disorder has often been viewed as a defect in sensory filtering. In spite of its weaknesses in focusing on function in specific structures, earlier PET scans have shown metabolism in the thalamus of schizophrenics to be increased,Io3 reduced,133lower in patients who have negative symptoms onlyiz4 or unchanged.l17 It is unclear whether this is a result of medication effects, other control problems, or the difficulty in applying PET to localized structures. In the reported study:7 volumetric studies of subcortical structures found the thalamus of the patients to be significantly smaller than that of the volunteers. This appeared to be the greatest in the left anterior region. They concluded from their PET findings that "differences were greater for metabolism in the weighted thalamic area (rate X area) than for rate per area, a finding consistent with reported greater decreases in total neuron number than in neuron density in the thalami of schizophrenic patients" (p. 191).In another finding?O the limbic, prefrontal cortex and the caudate structures were specifically evaluated with MRI. Breier et alZoreport that schizophrenic patients had significantly reduced volume in both the right and the left amygdala-hippocampal complex. They also found smaller right and left prefrontal volumes and larger left caudate size. Reductions in the right and the left amygdala and the left hippocampus were also reported. An incidental finding was that "the right white matter volume in schizophrenic patients was significantly related to right amgdala/hippocampal volumes (X = .39), data that provide preliminary support for the hypothesis of abnormal limbic-cortical connection in schizophrenia" (p. 921). Although some studiesz5illustrate changes in some structures that are related directly to symptom constellations (negative symptoms seen in enlarged right caudate, but not in the hippocampus and the amygdala), other research fails to include the existence of specific clinical subgroups or point to brain structural changes that are inherently symptomatic of the schizophrenia disease process.37A continuum hypothesis that would account for the diversity of findings may be more justified. The studies showing differences related to specific structures have not been particularly robust and again points to the research dilemma of using behavioral diagnostic criteria to predict brain morphology, and so forth. In the important study conducted by TorreyIz6reported in the book Schizophrenia and Manic Depressive Disorder: the biological roots of mental illness as revealed by the landmark study of identical twins, structural changes in the brain were observed in identical twins who were discordant for the disorder. When a

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neuroradiologist was asked to blindly pick the twin that was schizophrenic on visual inspection of twelve pairs, he was able to do so in most cases. Two of the pairs had MRIs that appeared to be virtually identical and one showed the greatest pathology to be in the unaffected twin. This illustrates the difficulty for the clinician who has hoped to use neuroscanning to enhance diagnostic efficiency. In most cases the affected twin was selected because of ventricular and sulcal enlargement. This was possible because comparison could be made with the other identical twin. If the scan of the schizophrenic twin was viewed alone, in most cases it could not be differentiated from normal patients. The actual structural differences noted were "the twins with schizophrenia had larger left ventricles (14 of 15 pairs), larger right ventricles (13 of 15 pairs), larger third ventricles (13 of 15 pairs), smaller left anterior hippocampi (14 of 15 pairs), smaller right anterior hippocampi (13 of 15 pairs), and reduced left temporal lobe gray matter (14 of 15 pairs)" (p. 108). These findings suggested that the pathology was on a continuum rather than being dichotomous. They also found no significant anatomic differences related to the age of onset, duration, or the length of time using antipsychotic medications in these schizophrenic twins. This again illustrates the problems inherent in making diagnosis from structural changes. The changes are subtle in many people affected with this illness and the structural changes are statistically significant for groups but not predictive of individuals. Andreason et a1.5 broadly summarized the findings of SPECT, evaluating frontal metabolism in schizophrenia. They used a variety of verbal, visual, and spatial tasks and their studies ranged broadly over many resting and activation studies. The variability of frontal metabolism is marked in the differences in test conditions, medication status, metabolic tracers, and other such factors, and therefore make it very difficult to derive conclusions. In this study three patient groups were evaluated, including neuroleptic-naive schizophrenic patients, nonnaive schizophrenic patients who were described as chronically ill but medication-free over a 3-week period and healthy, normal control subjects. Xenon 133was used as a tracer. They used the Tower of London task as a way to stimulate the left medial frontal cortex. They found that both the neuroleptic-naive and the nonnaive patients showed reduced activation in this area. They also found that an area in the right parietal cortex, expected to be activated by the Tower of London, was decreased. Most compelling was the finding that only patients who had high scores on negative symptoms showed this pattern of hypofrontality (see Color Plate: Fig. 7). The findings of this study may be the result of the nature of the task; however, this appeared to be appropriate for illiciting problem solving, attention, and planning. These are functions that have consistently been an area of concern in schizophrenic patients. OConnell et aP1 compared schizophrenic, manic, and normal subjects on CBF in prefrontal, temporal, and basal ganglia. Relative levels of activation can in which fMRI was used be seen in Figure 10. In one of the very few with schizophrenics, "schizophrenic subjects demonstrated sigruficantly less left frontal activation and greater left temporal activation than in comparison subjects during a word fluency t a s k (p. 200). The finding was quite robust in spite of having only 12 schizophrenic subjects. The patterns of activation in the left frontal and the temporal regions were very different from normal, and this difference did not appear to be the result of generally impaired performance in schizophrenics. This research protocol allows multiple 30-second images and therefore has significant advantage over PET and SPECT scanning for such studies. Of more compelling interest to the clinician is: What activation patterns

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Figure 10. SPECT study of regional cerebral blood flow in (A) control subjects; (B) schizophrenics; and (C) manic patients. (From O’Connell RA, Cueva JE, Van Heertum RL, et al: Single-photon emission computed tomography of the brain in acute mania and schizophrenia. Journal of Neuroimaging 5 103, 1994; with permission.)

may be observed during hallucinatory or delusional thinking compared with normal thought? Neuroimaging studies in individuals who develop schizophrenic or affective symptoms in late life produce further complication. Here coexisting dementia states, WMHI, or normal brain atrophy make it even more difficult to differentiate these conditions diagnostically. For an excellent review of this area see

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Neuroimaging and the Psychiatry of Late Life. edited by Ames and Chiu2In another one of the newest forms of scanning technology, MRS, schizophrenics have also been evaluated. This technology has distinct limitations since it requires extended periods of time in the MRI machine and it is hard to measure the specific effects of a task performance. In one study, Pettigrew et a198found reduced phosphomonoesters and increased phosphodiesters in the dorsal-prefrontal cortex when compared with normal control subjects. In another studyz9a ratio of phosphocreatinine/inorganic phosphate (PCr/B-Am) was found that was higher in the right temporal lobe than in the left in schizophrenics. This seems to bring additional support to relatively greater left temporal underactivity. The most defensible observations appear to be the following: (1) there are structural changes in the brains of schizophrenics that appear to affect frontal and temporal lobes more than posterior brain, and the left is generally more implicated than the right. These changes in volume are generally illustrated by increased lateral ventricular size as well as the third ventricle. Inconsistent changes in the size of hippocampi are also commonly observed. (2) Consistent with observed frontal structural changes, which appears to be more white matter than gray, hypofrontality is observed when the patient is required to perform a task that might require activation of frontal-lobe-linked neuronehvorks. (3) One of the more consistent findings is a disruption of the limbic system and complex circuitry involving thalamocortical projections that affects patients filtering, organizing, and formulating concepts. It appears to involve subcortical systems and not discreet lesions or related anomolies. (4)The abnormalities in the neurologic substrate cannot be accounted for by medication effect or developmental history, and there is no evidence of neurodegenerative effects. CONCLUSION AND FUTURE DIRECTION

In a recent editorial in the American Journal Psychiatry, the hopes and frustrations of neuroimaging for the clinical psychiatrist were illustrated. Although we continue to see great advances in technology and MRI shows the greatest promise, the hope that imaging techniques can clearly differentiate depression, dementias, schizophrenia, and other psychopathologic states has not been met. Brodie= reminds us that In part, this might be because of the circularity of using behavioral descriptors to define the experimental populations for essentially biological studies, but it may also be because of the failure to integrate the results of most imaging studies with the ongoing process of theory construction. Thus many isolative but seemingly attractive findings have resulted in speculative musings, rather than the construction of a significant, testable hypothesis in validation with an independent sample (p. 145). Techniques such as PET and SPECT, which rely on a complex technology in which statistical techniques are used to arrive at an image, may be inherently visually compelling but are very blurry when it comes to identifying specific structure. As pointed out by Brodie,Z3if a map, constructed to show our planet, was arbitrarily based on some cutoff, topographic features that are at least 20,000 feet above sea level, the map would look quite flat with few or no mountain tops. While it would be accurate to say that these mountain tops vary from sea level by an amount greater than can be ascribed by chance,

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the contribution to the threshold (everything under 20,000 feet) features to the overall gestalt are not visible. Hence, even as we struggle to identify some features we must be mindful of the information we are choosing to ignore. Not only can images distort the quality of the underlying data, but, under the guise of making it easier for the reader to understand, they give the impression that the distinction of the underlying element is fact. It is difficult to escape this problem (p. 146). We may still rely more on actual observable brain features on MRI even though our evaluation of a dynamic process pushes us toward these functional techniques with their attendant error. Conditions such as traumatic brain injury, vascular disorders, Parkinson’s, and dementias continue to have the most valid application of scanning techniques. Although not yet fulfilling all of its hopes, brain-mapping techniques continue to make a contribution to theory and substantiate the underlying neuropathology in many of these disorders. Other areas of research (not referenced in this paper) are leading to discovery of drug selection and dosing with its attendant effects on functional imaging. The hope for fMRI is still on the horizon since changes in protocol and in the engineering of scanners will make it possible to image more of the thinking behaviors most important to clinicians. As the scanning procedures become more economically feasible, this imaging technology will also give greater access to clinicians dealing with more traditional psychopathology as well as the more established neuropathologic states. In summary, it is first apparent that the findings are difficult to summarize in this area. Some continuum of neurologic changes in structure and function seems most evident. This certainly has something to do with the fact that the psychiatric description of the disorder has had syndromal qualities and has been hard to describe specifically. As Freeman and Karson50 noted, the early studies started by looking for discreet areas of cortical pathology in the brains of schizophrenic patients. ”After nearly a half century of study, little evidence emerged from a great body of data suggesting any consistent, discreet neuropathological finding associated with this illness” (p. 290). This has obviously led to frustration on the part of researchers and clinicians. CT, MRI, fMRI, PET, and SPECT are providing more data and better confirmation of theory but are not yet providing the clinician with identifiable structural patterns that would differentiate these disorders from many other conditions. References 1. Alexander MP, Warren RL: Localization of callosal auditory pathways: A CT case study. Neurology 38802404, 1988 2. Ames D, Chiu E: Neuroimaging and the psychiatry of late life. Cambridge, England, Cambridge University Press, 1997 3. Anderson JC, et a1 DSM-I11 disorders in preadolescent children: prevalence in a large sample from the general population. Arch Gen Psychiatry 4469-76, 1987 4. Andreasen NC: Brain imaging: Applications in psychiatry. Science 239:1381-1388,1988 5. Andreasen NC, et al: Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Arch Gen Psychiatry 49:943-958, 1992 6. Awad IA, et al: Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. I. Correlation with age and cerebrovascular risk factors. Stroke 1431084-1089, 1986 7. Aylward EH, et al: Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry 151:687-693, 1994

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