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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Nivedita Agarwal, MD John D. Port, MD, PhD Massimo Bazzocchi, MD Perry F. Renshaw, MD, PhD, MBA Update on the Use of MR for Assessment and Diagnosis of Psychiatric Diseases 1 The lack of quantitative objective measures of psychiatric diseases such as anxiety and depression is one reason that the causative factors of psychiatric diseases remain obscure. The fact that human behavior is complex and cannot be easily tested in laboratories or reproduced in animal models further complicates our understanding of psychiatric diseases. During the past 3 decades, several magnetic resonance (MR)-based tools such as MR morphometry, diffusion-tensor imaging, functional MR imaging, and MR spectroscopy have yielded findings that provide tangible evidence of the neurobiologic manifestations of psychiatric diseases. In this article, we summarize major MR findings of schizophrenia, bipolar disorder, anxiety disorders, and attention deficit hyperactivity disorder as examples to illustrate the promise that MR techniques hold for not only revealing the neurobiological underpinnings of psychiatric disorders but also enhancing our understanding of healthy human behavior. However, many radiologists remain skeptical about the diagnostic value of MR in psychiatric disease. Many inconsistent, noncomparable reports in the literature contribute to this skepticism. The aims of this article are to (a) illustrate the most reported MR findings of major psychiatric disorders such as schizophrenia, mood disorders, anxiety disorders, and attention deficit hyperactivity disorder; (b) inform radiologists of the potential roles of MR imaging in psychiatric imaging research; and (c) discuss several confounding factors in the design and interpretation of MR imaging findings in psychiatry. REVIEWS AND COMMENTARY n REVIEW q RSNA, From the Neuroimaging Center, McLean Hospital/Harvard Medical School, Boston, Mass (N.A., P.F.R.); Institute of Radiology, Department of Medical and Morphological Sciences, University of Udine, Udine, Italy (N.A., M.B.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.D.P.); and The Brain Institute and Department of Psychiatry, University of Utah, 383 Colorow Dr, Salt Lake City, UT (N.A., P.F.R.). Received February 24, 2009; revision requested April 21; revision received June 10; accepted June 23; fi nal version accepted July 2. Address correspondence to N.A. ( niv_aga@yahoo.co.uk ). q RSNA, 2010 Radiology: Volume 255: Number 1 April 2010 n radiology.rsna.org 23

2 Psychiatric illnesses are perceived as fundamentally different from common medical disorders. This view likely arises from the classical mindbody problem, namely, despite millenia of debate, no one to date has been able to explain how the physiological substrate of the human brain generates the mind. In the past few decades, the rapid growth of magnetic resonance (MR) imaging research of psychiatric disorders has reflected the aspirations of many psychiatrists to link the signs and symptoms of psychiatric disease to specific brain structures or functional abnormalities. Note that this implies the existence of structural, biochemical, and/or functional brain abnormalities that underlie psychiatric disease. Furthermore, assuming that these abnormalities exist, this also implies that MR imaging is able to depict them. The recent upsurge of MR imaging research in psychiatry has been challenging for radiologists. In the past, when MR imaging of a psychiatric patient was ordered, the radiologist simply reviewed the examination findings to exclude any structural abnormality that might explain the subject s symptoms. In younger patients, this typically involved looking for temporal lobe abnormalities that Essentials n Advanced MR techniques such as diffusion-tensor imaging, functional MR imaging, MR spectroscopy, and T2 relaxometry have greatly enhanced our knowledge about the structural, functional, and chemical correlates of psychiatric disorders. n MR imaging is a promising tool for monitoring the effects of drugs on the structure, function, and chemical features of the brain, potentially enabling novel drug development. n While there are substantial dis- parities regarding the individual MR findings of various psychiatric diseases, some global patterns of MR findings that may soon serve as MR signatures of psychiatric disease are emerging. might induce psychogenic seizures; white matter abnormalities, such as metachromatic leukodystrophy, that are known to create psychiatric symptoms; or treatable toxic/metabolic disorders or infectious diseases. Most of the time, such images were interpreted as normal, adding little perceived value to the work-up of psychiatric diseases. As such, many radiologists have developed a quiet cynicism about performing such imaging examinations, wondering, what in the world are we looking for in this patient? It is important for radiologists to fully comprehend the usefulness of MR imaging methods for psychiatric research and to offer appropriate methods that enhance the general understanding of the pathophysiologic features of psychiatric disorders. Attempting to understand the highly sophisticated and complex neural networks that underlie cognition and human behavior will require the latest cutting-edge MR imaging modalities. Herein, we discuss the psychiatric findings seen with MR modalities such as MR-based morphometry, diffusion- tensor imaging, functional MR imaging, and MR spectroscopy. The technical details of these techniques will not be discussed in this article; we assume the readers have some familiarity with such techniques. Several nonimaging methods have been used successfully to study psychiatric diseases. For example, postmortem examinations have been instrumental in revealing the underlying abnormality of various diseases. The findings of these studies provide objective evidence of gross anatomic-pathologic alterations such as glial or neuronal density, cell size and shape, synaptic density, state of dendritic arborization, white matter distribution and connectivity, myelin structure and staining, and abnormal deposition of proteins such as amyloid proteins. Postmortem studies help to understand the end stages of a disease process, but they cannot resolve controversy over the progression of disease. Other tools such as electroencephalography, magnetoencephalography, evoked potentials, and transcranial magnetic stimulation are used to assay or exploit the electric activity of neurons, but these lack the spatial and/or temporal resolution of MR imaging. Clearly, there is a need to study the brain of individuals with psychiatric disorders by using a safe, noninvasive, and easily repeated method such as MR imaging. The current lack of strong biologic markers for psychiatric diseases makes MR imaging research in psychiatry all the more important. A negative MR image does not necessarily mean that our psychiatric patient has a normal brain; rather, it means that we need to improve our imaging tools to detect abnormalities within the brain. In this article we summarize the major MR imaging findings of schizophrenia, mood disorders, anxiety disorders, and attention deficit hyperactivity disorder. These disorders constitute the majority of the psychiatric burden of disease and represent the prototypic models used to comprehend major effective and cognitive brain circuits. This article is not intended as a review of all MR imaging findings in clinical psychiatry; rather, our aim is to assist radiologists in (a) understanding the potential of MR imaging in psychiatric research, (b) attaining a basic understanding of the brain regions thought to be involved in various psychiatric diseases, and (c) speculating about the future of MR imaging as a tool for the diagnosis and treatment of psychiatric disease. Schizophrenia Schizophrenia is a serious genetic illness with a lifetime incidence of 1% in the general population during adolescence and early adulthood (1). It is characterized by a diversity of complex symptoms that range from positive symptoms such as delusions and auditory hallucinations Published online /radiol Radiology 2010; 255:23 41 Abbreviations: Cr = combined creatine and phosphocreatine FA = fractional anisotropy Glx = combined glutamate and glutamine NAA = N-acetylaspartate Authors stated no fi nancial relationship to disclose. 24 radiology.rsna.org n Radiology: Volume 255: Number 1 April 2010

3 to negative symptoms such as apathy, anhedonia, blunted affect, poverty of speech, and broad cognitive deficits in domains such as attention, memory, and language. Structural MR neuroimaging has played a pivotal role in providing evidence of brain abnormalities in schizophrenia. Pooled analysis of 15 voxelbased morphometric studies revealed the left superior temporal gyrus and the left medial temporal lobe as key regions of structural difference between individuals with schizophrenia and healthy subjects ( 2 ). An increased ventricle-tocaudate ratio computed by using voxelbased morphometric analysis was suggested as a possible early biomarker of schizophrenia ( 3 ). In another metaanalysis, brain volumes were reduced by 2.7% in first-schizophrenic-episode medication-naïve subjects compared with the brain volumes of healthy control subjects ( 4 ). Patients with recurrent episodes of illness show extended alterations in the aforementioned brain areas in addition to bilateral gray matter loss in the prefrontal cortex, hippocampus, amygdala, and basal ganglia, suggesting that brain abnormalities are not static but progress over time ( Fig 1 ) ( 6 ). Figure 1 Those who later develop schizophrenia have a smaller intracranial size at birth, suggesting a neurodevelopmental etiology ( 7,8 ). Diffusion-tensor examinations have revealed profound white matter disruptions in the temporolimbic region, including the cingulum, and in the frontotemporal (uncinate fasciculus), parietotemporal (arcuate fasciculus), and corpus callosum regions ( 9 ) ( Fig 2 ). Greater coherence, in terms of higher FA of white matter bundles in the corpus callosum, hippocampus, and parahippocampus, correlated well with higher cognitive functioning ( 11 ). Low anisotropy in the prefrontal cortex has been associated with high degrees of impulsiveness and aggressiveness in male patients with schizophrenia and with increased negative symptoms such as blunted affect and anhedonia ( 8,12,13 ) ( Fig 3 ). One of the major theories regarding the cognitive dysfunction in schizophrenia has been the presence of hypofrontality that is, underactivation of the prefrontal cortex. Functional MR imaging examinations, however, have revealed both hypoactivation and hyperactivation of the prefrontal cortex. Figure 1: Three-dimensional color-coded statistical difference maps demonstrating early and late gray matter loss between patients and healthy subjects at baseline (top) and subsequently at 5 years (bottom). Greater loss of gray matter thickness is seen over the parietal, motor, and frontal cortices in patients. Continued gray matter loss over time is seen in superior temporal gyrus (STG) and dorsolateral prefrontal cortex (DLFPC) later in early adolescence in schizophrenia. (Reprinted, with permission, from reference 5.) The discrepancies in findings are due to a number of factors. Many studies have small patient numbers. The recruited patients may have different severities of symptoms and thus may be taking different medications. Postprocessing in functional MR imaging analysis including the threshold values and statistical methods used varies across examinations; this largely leads to inconclusive results. It is interesting that the results of a critical review of functional MR imaging findings suggest that the level of prefrontal cortex activation depends on the patient s baseline efficiency and the memory task load ( 15 ) ( Fig 4 ). Reduced activation of subregions of the prefrontal cortex and parietal cortex has been reported in the first-degree nonaffected siblings of patients with schizophrenia and in discordant twins, leading to the proposal that an aberrant prefrontal cortex could be an early biomarker of schizophrenia ( 17,18 ). Antipsychotic drugs namely, central dopamine D2 receptor antagonists are the first-line treatment for psychosis. In one study, basal ganglia volumes increased in first-episode drug-naïve patients after 12 weeks of typical antipsychotic treatment ( 19 ). Cortical glutamatergic neurons modulate dopamine release directly or indirectly through g -aminobutyric acid inhibitory neurons ( 20 ). An increase in the combined glutamate and glutamine (Glx) level specifically, a Glx peak has been found to correlate well with the cognitive dysfunction in schizophrenia ( 21,22 ). It is interesting that adolescents and unaffected twins at genetically high risk for schizophrenia also have increased levels of glutamate. On the other hand, chronically medicated patients, as compared with first-episode patients, have lower Glx levels in specific brain areas, suggesting either a progressive neurodegenerative disease or a positive medication effect ( 23,24 ). These findings have fueled the development of drugs for schizophrenia, such as N -methyl D -aspartate receptor agonists and metabotropic glutamate type II and type III agonists ( 25 ). While these findings emphasize the potential usefulness of MR spectroscopy for drug development, it Radiology: Volume 255: Number 1 April 2010 n radiology.rsna.org 25

4 Figure 2 Figure 2: In this whole-brain diffusion-tensor imaging analysis, fractional anisotropy (FA) maps from 76 patients and 76 controls were overlaid on single whole-brain template. Blue = regions of reduced FA in patients with schizophrenia compared with healthy controls. Left side of brain is on right side of figure. (Reprinted, with permission, from reference 10.) is important to realize that the spatial resolution of this modality is currently too low for localization of findings at the cellular level (eg, in neurons, glia, or synapses). Also, neurotransmitters such as glutamate are tightly coupled species, and the methods used to identify these molecules vary across studies and thus often contribute to discordant findings (Fig 5). NAA is reportedly reduced in both first-episode subjects and individuals with chronic schizophrenia (26). NAA is increased in patients taking medication, suggesting that antipsy26 chotic agents have a positive influence on neuronal health (27,28). Pathologic pruning of dendritic arborization, fewer dendrite spines, and reduced perikaryal size of pyramidal neurons probably reflect a reduced NAA level (7). This is in keeping with the cytoarchitectural findings of postmortem examinations, which are inevitably limited to only advanced phases of the disease. Proton MR spectroscopic findings, such as reduced NAA levels in first-episode patients, suggest that cytologic abnormalities might be present early during the course of the disease. Phosphorus 31 (31P) MR spectroscopic examinations performed in both first-episode individuals and patients with chronic schizophrenia have revealed an increase in membrane phospholipid breakdown in the anterior cingulate cortex, right prefrontal cortex, right thalamus, hippocampus, and cerebellum. Also, elevated levels of high-energy phosphates in the anterior cingulate of first-episode medicated patients suggest increased metabolism and membrane turnover (29,30) (Fig 6). radiology.rsna.org n Radiology: Volume 255: Number 1 April 2010

5 Figure 3 Figure 3: Diffusion-tensor images obtained in subjects with schizophrenia show color-coded significant correlations (P,.05) with (a) positive (purple), (b) negative (yellow), and (c) general (blue) symptoms. Overlaid on tracts are voxels with P <.05, represented according to color grades on color bar. CST(L) = left corticospinal tract, IFOF(L) = left inferior fronto-occipital fasciculus, ILF(L) = left inferior longitudinal fasciculus, SLF(L) = left superior longitudinal fasciculus SLF(R) = right superior longitudinal fasciculus. (Reprinted, with permission, from reference 14.) Figure 4 Mood Disorders Mood disorders can be classified as primary (functional) or secondary (ie, presumed to be directly caused by a cerebral or other physical disorder) (31). Primary mood disorders can be unipolar or bipolar. Bipolar disorder is a clinically heterogeneous disorder characterized by alternating periods of depression and mania interspersed with periods of euthymia. It is the sixth leading cause of disability in the world. Abnormally elevated moods are accompanied by a sense of grandiosity, impulsivity, and disinhibition. Several cognitive deficits such as impaired sustained attention and impaired working memory are common. The main subtype of unipolar mood disorder is major depressive disorder. Major depressive disorder is the leading cause of disease burden in the United States and the fourth cause of disease burden worldwide (32,33). It is characterized by one or more episodes of anhedonia, a sense of guilt, impaired concentration, fatigue, loss of sleep, and suicidal thoughts. Bipolar Disorder The most reproducible and robust structural brain abnormalities found in a pooled analysis of 141 MR imaging studies were increased volumes of the lateral ventricles (17% increase) and Radiology: Volume 255: Number 1 April 2010 n Figure 4: Activated maximum voxels in functional MR imaging during high- and low-load working memory tasks are represented for healthy subject and schizophrenic subject. Dorsolateral prefrontal cortex activation was dependent on level of task demand. Red = greater activation on color scale. (Reprinted, with permission, from reference 16.) the third ventricle, a decreased crosssectional area of the corpus callosum, and increased high-signal-intensity regions in the white matter. High signal radiology.rsna.org intensity in cortical (frequently in the frontal lobes) and subcortical regions but not periventricular white matter regions is most consistently reported in 27

6 Figure 5 Figure 5: Example of short-echo-time point-resolved spatially localized spectroscopy proton spectrum generated on a clinical 3-T scanner fi tted by using LCModel. Cho = combined choline, phosphocholine, and glycerophosphocholine; Cr = combined creatine and phosphocreatine; GABA = g -aminobutyric acid, GSH = glutathione; mi = myo-inositol; NAA = N -acetylaspartate. (Image courtesy of Andrew P. Prescot, PhD, The Brain Institute, University of Utah.) association with bipolar disorder ( 34 ). However, high-signal-intensity white matter regions are nonspecific and reflect cerebrovascular damage, astrocytic gliosis, dilated perivascular spaces, and demyelination ( 35 ). Yet both adults and children with bipolar disorder are 2.5 times more likely than healthy control subjects to have high-signal-intensity white matter regions ( 36 ). However, not all bipolar patients have high-signal-intensity white matter regions. The use of thinner image sections and fluid-attenuated inversion-recovery sequences has been advocated to improve sensitivity in the detection of these findings ( 37 ). Volumetric studies have largely revealed abnormal regional differences in prefrontal cortex, medial-temporal, and limbic structures. The prefrontal cortex can be subdivided into multiple histologically and functionally distinct regions. It subserves several higherorder cognitive functions such as rewardguided behavior, attention, short-term memory, strategy development, and cognitive flexibility. However, because it is not possible to delineate these subregions with use of the current MR spatial resolution of 1 mm 3, structural MR imaging cannot be used to distinguish these regions and findings in the prefrontal cortex may overlap across the disorders. In fact, in patients with bipolar disorder, as compared with patients who have schizophrenia, the orbitofrontal cortex rather than the dorsolateral prefrontal cortex might be altered ( 38 ). Voxel-based morphometric study results show cortical thinning of the prefrontal cortex across all age spectrums and in first-episode bipolar subjects ( 39,40 ). A common and important brain area in bipolar disorder is the anterior cingulate cortex. Histologic studies have revealed reductions in the density and number of glial cells in the subgenual cingulate cortex (ventral to the genu of the corpus callosum) without changes in the numbers of neurons in bipolar patients compared with these findings in mentally healthy control subjects. However, patients with schizophrenia have shown changes in neuronal size without glial cell changes. These findings suggest that a glial rather than neuronal abnormality underlies mood disorders ( 41 ). The subgenual anterior cingulate cortex volume is reduced by 39% in bipolar depressed subjects. Lithium, a mainstay drug for acute mania, augments the gray matter volume in subjects with bipolar disorder ( Fig 7 ) ( 42 ). Medial-temporal structures such as the amygdala, hippocampus, basal ganglia, and striatum in particular are extensively connected to the prefrontal cortex. An enlarged amygdala and striatum and normal hippocampal volumes have been reported with bipolar disorder, but these are not universal findings ( 43,44 ). In contrast, with schizophrenia, hippocampal volumes are reduced and amygdala volumes are normal ( 45 ). Striatal enlargement is found in bipolar adolescents and in first- and multiple-episode patients, and it might represent a heritable vulnerability factor in bipolar disorder ( 46 ). The two major symptom domains in bipolar disorder are mood instability and poor cognitive control over executive functions ( 47 ). Initially proposed as early as 1937 by Papez, regulation of emotion is made possible through rich reciprocal connections between parts of the prefrontal cortex and the amygdala, anterior temporal regions, subgenual anterior cingulate cortex, striatum, and thalamus. Working memory deficit and executive dysfunction have been mapped to alterations in subregions of the prefrontal cortex, anterior cingulate cortex, and hippocampus. To this effect, diffusion-tensor imaging based FA and apparent diffusion coefficient (ADC) or trace measures provide invaluable evidence of white matter disruption in various parts of the prefrontal cortex and the 28 radiology.rsna.org n Radiology: Volume 255: Number 1 April 2010

7 Figure 6 Figure 6: Typical phosphorus spectrum generated on high-fi eld-strength (3-T) spectroscopy scanner. DN = dinuleotide; γ-ntp, α-ntp, and β-ntp = gamma, alpha, and beta nucleotide triphosphates, respectively; PCr = phosphocreatine; PDE = phosphodiesters (glycerophosphocholine, glycerophosphoethanolamine); Pi = inorganic phosphate; PME = phosphomonoesters (phosphocholine, phosphoethanolamine, phosphoserine). (Image courtesy of John E. Jensen, PhD, McLean Hospital, Neuroimaging Center, Boston, Mass.) internal capsule, suggesting an anatomic dysconnectivity in the frontal-subcortical circuits ( ). However, the FA and ADC indexes in diffusion-tensor imaging alone may be misleading. While low ADC and FA generally signify a loss of white matter microstructure, normal ADC or high FA does not necessarily indicate normal findings ( 51 ). Structurally abnormal brain areas may not necessarily explain altered behavior, and normal brain structure does not guarantee normal function. In this context, functional MR imaging is helpful. However, especially in the setting of psychiatric disease, functional MR imaging findings depend on the baseline psychologic state underlying the personality of the individual. For instance, it is known that normal variations in emotional memory occur in healthy individuals. Variability in these neural systems is related to vulnerability in emotional memory formation and response to environmental stimuli in nonpsychiatrically ill individuals ( 52 ). Salient functional MR imaging findings observed in bi- polar patients are (a) abnormally increased activity in the amygdala that causes mood instability and (b) abnormally decreased activity in the subregions of the prefrontal cortex that are responsible for cognitive deficits. Mood instability is tested by using functional paradigms (scenes, words, or facial expression) that evoke emotion. Increased amygdalar activation in response to fearful facial affect and accompanied by reduced activation of the anterior cingulate cortex and the dorsolateral prefrontal cortex has been reported ( 53,54 ). Decreased activation of the ventrolateral prefrontal cortex and increased activation of the amygdala in manic patients indicate that underactivation of the ventrolateral prefrontal cortex is responsible for exaggerated emotional response (lack of inhibition) to emotional paradigms ( 55 ). Antiepileptic drugs such as lamotrigine substantially reduce activation of the amygdala bilaterally in bipolar adolescents and ameliorates prefrontal cortex function in stable bipolar patients ( ). A reduced NAA level in the prefrontal cortex and hippocampi of bipolar adults, adolescents, and at-risk subjects has been reported ( ). Proton MR spectroscopy findings have been inconsistent with regard to choline levels ( 60 ). There is some evidence that increased choline levels are found in the striatum and anterior cingulate cortex and that choline levels can be normalized or reduced with use of antidepressants and lithium ( 63 ). Abnormal myo-inositol level has received particular attention in the setting of bipolar disorder because lithium, an antimanic drug, reduces myo-inositol levels. Lithium inhibits inositol-monophosphatase via the phosphoinositol cycle, causing a decrease in the myo-inositol level ( 64 ). Increased myo-inositol levels are reported the most in individuals with mania and euthymia, and reduced myo-inositol levels are reported the most in bipolar depressed individuals. Reduced myo-inositol/cr levels are correlated to improved manic rating scores ( 65 ). Alterations in myo-inositol/ Cr levels might reflect both abnormal membrane metabolism and intracellular signaling mechanisms ( 66,67 ). Proton MR spectroscopy based evidence of increased glutamate and Glx in the dorsolateral prefrontal cortex, frontal lobes, basal ganglia, and gray matter of nonmedicated bipolar subjects and subjects with acute mania has been reported ( 62 ). An attempt to summarize these findings is as follows: Reduced NAA and abnormal choline, myo-inositol, and Glx levels, accompanied by altered phospholipid metabolism (at 31 P MR spectroscopy) point strongly toward a shift from oxidative phosphorylation to glycolysis owing to the mitochondrial dysfunction with bipolar disorder ( 68 ). Major Depressive Disorder Broadly speaking, major depressive disorder can be seen as an affective illness without manic episodes. Limbic structures and the prefrontal cortex have been implicated in the exaggerated response to negative emotions, with a sense of hopelessness, guilt, and despair, while alterations in the hypothalamus and in parts of the brain stem (locus coeruleus, periacqueductal Radiology: Volume 255: Number 1 April 2010 n radiology.rsna.org 29

8 Figure 7 Figure 7: Three-dimensional color-coded maps show cortical gray matter density (GMD) as a function of lithium use. A, Statistically significant maps of GMD in bipolar patients treated with lithium (Li+), as compared with control subjects are represented. Widespread areas of greater gray matter concentration are seen in diffuse cortical areas, in particular left cingulate cortex, paralimbic association cortices, and bilateral visual association cortex seen on sagittal planes, in Li+ patients with respect to controls. B, Maps of GMD obtained in bipolar patients who were not taking lithium (Li ), however, show that the GMD in these patients did not differ significantly from that in the control subjects in any cortical region. BA = Brodmann area. (Reprinted, with permission, from reference 42.) gray matter) are responsible for the neurovegetative symptoms (eg, loss of sleep and appetite, fatigue) and neuroendocrine alterations. Most MR findings overlap between those of major depression and those of bipolar disease because these two conditions share common depressive episodes. Many researchers tend to study mood disorders and affective illnesses, which include 30 major depression and bipolar disease. However, this leads to overlapping findings and some difficulty interpreting them. The prefrontal cortex and the anterior limbic structures are key players in the altered emotional processing and cognitive disturbances in major depression, as in bipolar disorder. The majority of volumetric MR studies have revealed gray matter loss and volume reductions in subregions of the prefrontal cortex, medial temporal lobe, amygdala, and hippocampus across all age ranges (69,70). Volumes of tissue in the hippocampus, amygdala, and orbital-frontal cortex are reduced in nonmedicated patients, pediatric patients, and at-risk subjects, making these brain areas stable correlates of major depression. Midline brain structures such as the basal ganglia and the thalamus are smaller in individuals who have major depression; however, this is not consistently reported. In contrast, with bipolar disorder, subcortical structures such as the striatum are frequently enlarged (71). As with bipolar disorder, with major depression, alterations in the limbic-cortical-striatal-pallidal-thalamic circuits are the mechanisms that underlie depression (72). Diffusion-tensor imaging studies have revealed altered FA in the prefrontal cortex of subjects with early onset of symptoms (73). Hippocampal volume loss in major depression is likely due to a hyperfunctioning hypothalamic, pituitary, and/or renal gland, which leads to increased levels of circulating glucocorticoids. Increased glutamatergic neuronal apoptosis induced by hypercortisolemia is one of the suggested mechanisms for hippocampal atrophy in major depression. (74). Life stressors such as job loss and marital conflict are acquired risk factors that contribute to depression by means of chronic stimulation of the hypothalamus-pituitaryadrenal axis. Hypercortisolemia induced in experimental rodents by means of repeated stress caused dendritic atrophy in brain areas that was homologous to gray matter loss (eg, in the hippocampus and prefrontal cortex) in depressed humans, as revealed at voxel-based morphometric analysis. However, hippocampal volume with depression has been found to be increased, decreased, or normal, and several factors such as medication status, illness duration, MR technique used, and postprocessing methods used contribute to these inconsistent findings. Abnormal Glx concentrations and g-aminobutyric acid peaks have been found in several proton MR spectroscopic studies. In a meta-analysis of proton MR spectroscopic studies of major radiology.rsna.org n Radiology: Volume 255: Number 1 April 2010

9 depressive disorder, decreased rather than increased (as in bipolar disorder) glutamate levels were found in depressed individuals ( 75 ). Low levels of Glx and g -aminobutyric acid have been found variably in the prefrontal cortex, anterior cingulate cortex, and posterior occipital cortex of depressed subjects ( 76 ). Use of the currently available antidepressants that target monaminergic (serotonin, noradrenaline) systems contribute to 30% of the remission rate, and newer treatment strategies are needed. Lithium, electroconvulsive therapy, and transcranial magnetic stimulation modulate glutamatergic and g -aminobutyric acid mediated transmission, with an associated antidepressant effect ( ). Anxiety Disorders Nearly one in every four adults in the United States experiences at least one anxiety disorder in his or her lifetime ( 80 ). These disorders are associated with high rates of comorbidity, serious disability, and chronic medical conditions. Exaggerated fear in response to relatively harmless situations is characteristic of these disorders. The National Institute of Mental Health classifies anxiety disorders into five main subgroups: (a) generalized anxiety disorder, characterized by uncontrollable anxiety and worrying; (b) panic disorder, characterized by spontaneous short episodes of escalating anxiety accompanied by palpitations, sweating, and rapid breathing; (c) phobia exaggerated fear in response to usually innocuous stimuli such as animals, objects, and persons, which includes social anxiety disorder; (d) posttraumatic stress disorder, in which a past severe traumatic or life-threatening event (eg, war or fire) causes an exaggerated response (ie, avoidance, high arousal) to events or thoughts with similar cues; and (e) obsessive-compulsive disorder, characterized by unwanted intrusive thoughts (obsessions) that drive repetitive and ritualistic behaviors (compulsions). A neurobiologic substrate for anxiety disorders has been defined largely through initial work with animal models of stress. Animal models are created by using a Pavlovian type of fear condi- tioning, which requires exposure to a repeated conditioned stimulus followed by an unconditioned stimuli such as electric shock. Even without the electric shock, these conditioned stimuli elicit fear responses, such as startle reflexes, freezing, analgesia, and autonomic changes, in animals. However, animal models of stress cannot entirely explain human behavior. First, these models fail to mimic human response to fear. Humans worry about the future, while animals do not. The complex process of elaboration of life events unique in humans is also the seat for anxiety and pathologic fear response. Second, animal models require conditioning or prior exposure to an aversive event, which, for instance in posttraumatic stress disorder, is not always present in humans. Animal literature suggests that the amygdala is a crucial structure in the acquisition, expression, and consolidation of conditioned fear. In humans, volumetric MR imaging examinations have revealed decreased volumes of the anterior cingulate cortex, insula, amygdala, and hippocampus in patients with anxiety disorders. However, the diversity of the causative factors, the presence of comorbidities, and the chronicity of anxiety disorders confound the findings and make generalization impossible. There is some MR evidence that paroxetine, a serotonin-selective re-uptake inhibitor, can increase hippocampal volume. In addition, alterations in the brain structures of the cortical- thalamic -striatal-cortical circuitry in patients with obsessive-compulsive disorders have been reported. Ultrafast sequences and cardiac gating give functional MR imaging an advantage over other functional neuroimaging techniques in patients with anxiety. Results of a meta-analysis of functional MR imaging studies of posttraumatic stress disorder, social anxiety disorder, and specific phobias showed hyperactivation of the amygdala, which suggests the recruitment of a common fear network in these disorders ( 81 ). Sensory information reaches the amygdala through the thalamus. The thalamus prompts the amygdala to activate autonomic and various behavioral responses via heavy reciprocal projections to the brain stem, hypothalamus, and other limbic structures. This activation causes the release of serotonin and noradrenaline, which is responsible for increases in heart rate, blood pressure, and respiratory rate, in addition to initiating a variety of defensive behaviors, startle reflexes, and postural responses. These processes make antiserotoninergic and antinoradrenergic drugs the first-line anxiolytic agents. Anxiety symptoms are due in part to suboptimal recruitment of the prefrontal cortex ( 82 ). The amygdalar response to sensory stimuli is regulated by the medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex through a top-down regulation that allows context and memory representations, attention capability, and the self conscious to modulate responses to threatening stimuli ( 81 ). In disorders characterized by intense fear and panic namely, panic disorder, social anxiety disorder, and posttraumatic stress disorder underactivation of the prefrontal cortex and anterior cingulate cortex and hyperactivation of the amygdala are consistent findings. On the other hand, the anxiety disorders characterized by worry and ruminations, such as obsessive-compulsive disorder and generalized anxiety disorder, frequently manifest as hyperactivation of the prefrontal cortex and amygdala. Hyperactivation of the prefrontal cortex is related to intrusive thoughts. With obsessive-compulsive disorder, hyperactivation of the caudate nuclei and inferior orbitofrontal cortex has been observed, providing obsessive-compulsive disorder with a neuroimaging signature ( 83 ). Diffusion-tensor imaging studies have revealed abnormal anisotropy and apparent diffusion coefficient values in parts of the cortical-striatal-thalamic-cortical circuitry in subjects with obsessivecompulsive disorder ( 84 ). An emerging area of study is the insula, which is involved in introspection or realization of an internal body state and is activated during the processing of a variety of negative emotions ( 85 ). The insula is well connected with the amygdala, hypothalamus, and periacqueductal gray Radiology: Volume 255: Number 1 April 2010 n radiology.rsna.org 31

10 matter. Hyperactivation of the insula has been found in association with social anxiety disorder, specific phobias, and posttraumatic stress disorder. There is a relative paucity of MR spectroscopic studies of anxiety disorders. Reduced NAA levels have been reported in the striatum and anterior cingulate cortex in individuals with obsessive-compulsive disorder, posttraumatic stress disorder, or generalized anxiety disorder. Reduced NAA levels in the right hippocampus might be a predictor of developing posttraumatic stress disorder after trauma ( 86 ). Abnormally high levels of Glx and low levels of g -aminobutyric acid in the thalamus of patients with social affective disorder and a subsequent reduction in the Glx level after levetiracetam therapy raise hope for the development of newer drugs for anxiety disorders, for which there is still a high remission failure rate (. 40%) with traditional anxiolytic agents ( 87 ). Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder was first described about 100 years ago as a childhood disorder seen mainly in boys and is initially characterized by hyperactivity ( 88 ). Attention deficit hyperactivity disorder is defined on the basis of developmentally inappropriate symptoms such as lack of attention, motor restlessness, and impulsivity. It is heavily genetic, affects 3% 5% of school-aged children, and accounts for 30% 50% of mental health referrals for children. Attention deficit hyperactivity disorder also occurs frequently in adults. The most frequent alteration seen in children with attention deficit hyperactivity disorder is a 3% 4% reduction in total cerebral and cerebellar volumes. There is also a substantial decrease in the white matter of nonmedicated children that is inversely related to age, suggesting early damage ( 89,90 ). On the basis of the framework provided by neuropsychological tests, structural and functional MR imaging research has been largely focused on putative brain regions of interest such as the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, and striatum. The frontostriatal circuitry is key in understanding the pathogenesis of this disorder. These systems regulate attention shifting, planning, executive function, working memory, response inhibition, and reward motivation ( 91 ). Cortical thinning in the medial prefrontal cortex was found to be a predictor of poorer clinical outcome at 5 years ( 92 ) ( Fig 8 ). The dorsal anterior cingulate cortex plays an important role in adaptive functioning, which requires capability for prompt inhibitory control over a preplanned response and interruption of responses that have been started, as well as the ability to reduce interference ( 94 ). Dorsal anterior cingulate cortex volume is reduced in both adults and children with attention deficit hyperactivity disorder. The striatum lies in an arterial watershed zone of the terminal lenticulostriate branches of the middle cerebral artery and is therefore particularly vulnerable to hypoxic damage ( 95 ). Higher rates of attention deficit hyperactivity disorder exist among children who had perinatal hypoxia. Morphometric MR imaging has depicted smaller volumes and abnormal shapes of the caudate nucleus, putamen, and globus pallidus ( 96 ). Caudate nucleus volumes tend to normalize by adolescence ( 90 ). Children with attention deficit hyperactivity disorder who have smaller left caudate volumes are more impulsive. Lack of attentiveness is related to alterations in the caudate nucleus bilaterally ( 97 ). Patients with small symmetric caudate nuclei are considered good responders to stimulant medication ( 98 ). Cerebellar parceling enables precise delineation of the lobules of the cerebellum. Cerebellar connections to the cerebral cortex through subcortical nuclei are the current focus of study ( 99 ). In a longitudinal study, the superior vermis showed nonprogressive volume loss over time, while inferoposterior cerebellar volumes reduced progressively over time in only those children with a worse outcome ( 100 ). A dysfunctional prefrontal cortex might result from an interruption of cerebellar input; this suggests that a primary lesion in the cerebellum can mimic prefrontal cortex lesions ( 101 ). In fact, the prefrontal cortex was found to be inconsistently dysfunctional, and functional MR imaging studies have revealed hypoactivation of the cerebellum and only a trend toward hypoactivation of the prefrontal cortex when the working memory of children and adults with attention deficit hyperactivity disorder was tested ( 102,103 ). In diffusion-tensor studies, aberrant anatomic connectivity has been detected in not only the frontostriatal regions but also the parietal and occipital regions in these subjects. Many of these regions are connected to the cerebellum ( 104 ). Reduced FA in the prefrontal-striatal fiber tracts of both children with attention deficit hyperactivity disorder and their parents correlated positively with the go no go task (attention), demonstrating the heritability of aberrant frontostriatal systems ( 105 ). A dysfunctional basal ganglia and hypoactivation of the frontostriatal systems substantiate the reported structural abnormalities in the same regions ( 106,107 ). Intuitively enough, the two main brain regions that are currently being investigated spectroscopically are the frontal region and the basal ganglia ( 108 ). An increased choline/cr ratio in the anterior cingulate cortex in medication-naïve adults with attention deficit hyperactivity disorder and in the basal ganglia of medication-naive children with attention deficit hyperactivity disorder suggests subtle structural membrane alterations ( 109 ). Increased choline levels have correlated directly with performance on the context-processing test, which is a measure of attention ( 109 ). Reductions, elevations, and no change in NAA/Cr ratios have been reported in the prefrontal cortex, striatum, and semiovale of individuals with attention deficit hyperactivity disorder ( 109,110 ). Methylphenidate is the first-line stimulant treatment for attention deficit hyperactivity disorder. It causes an increase in dopamine levels and is effective in 70% of cases. Prefrontal glutamate neurotransmission modulates the release of dopamine and serotonin in several 32 radiology.rsna.org n Radiology: Volume 255: Number 1 April 2010

11 Figure 8 Figure 8: High-spatial-resolution structural MR images transformed by using sophisticated tools to extract information regarding cortical gray matter thickness in the (a) right and (b) left hemispheres and on the lateral (A, C) and medial (B, D) surfaces. In this study, 24 adults with attention defi cit hyperactivity disorder were compared with healthy control subjects. Red and yellow areas represent brain areas of signifi cant cortical thinning in the patients ( P,.05) compared with the cortical thickness in the healthy control subjects ( P,.001). In C and D, superimpositon of standard Montreal Neurologic Institute brain templates enable the identifi cation of signifi cantly different brain areas. In this case, the dorsolateral prefrontal cortex and the inferior parietal areas are the most signifi cantly altered in the patients. BA = Brodmann area, FI = superior frontal gyrus, F2 = middle frontal gyrus. (Reprinted, with permission, from reference 93.) The burgeoning literature on major psychiatric disorders has provided us with exciting knowledge about the structures and functions of the brain that underlie human cognition (ie, attention, memory, language) and emotion. MR imaging research in psychiatry has provided objecbrain areas ( 111 ). Genetic studies have revealed alterations in the glutamate receptors with this disorder ( 112 ). The glutamate/cr ratio is reduced in the right anterior cingulate cortex in children and adults with attention deficit hyperactivity disorder; however, in another study ( 113 ), increased glutamate resonance in both the frontal and striatal regions in pediatric patients with attention deficit hyperactivity disorder was reported ( ). Such discrepancies are thought to result from methodologic differences and patient population heterogeneity. A treatment-related decrease in the striatal glutamate/cr ratio has been reported and is suggestive of a normalization of glutamatergic neurotransmission ( 116 ). Increased Glx/myo-inositol ratio in the anterior cingulate cortex of individuals with attention deficit hyperactivity disorder and decreased Glx/myo-inositol ratio in individuals with comorbid bipolar disorder are probably due to a differential increase in myo-inositol levels with bipolar disorder and to an increase in Glx levels with attention deficit hyperactivity disorder ( 117 ). Preliminary findings indicate that there is a 56% decrease in the striatal glutamate/cr ratio in children with attention deficit hyperactivity disorder who take atomoxetine (a noradrenaline transporter antagonist) compared with children who take methylphenidate, suggesting possible drug alternatives to methylphenidate ( 118 ). There is growing interest in the use of both morphometric and functional MR imaging in brain regions such as the hippocampus, thalamus, and amygdala in individuals with attention deficit hyperactivity disorder, although findings to date remain inconsistent. These applications are not reviewed here. Discussion tive evidence that psychiatric diseases have a definite neuropathologic basis ( Table 1 ). However, the imaging-based differential diagnosis of psychiatric disorders is not yet possible. In this review, we attempted to coalesce some global MR patterns that might be emerging in psychiatric disorders ( Fig 9 ). For example, in a clinical context, psychosis would be more likely to be accompanied by a reduction in the total brain volume and ventriculomegaly, whereas high-signal-intensity regions in the cortical white matter and reduced subgenual anterior cingulate cortex volume are more related to mood disorders. A dysfunctional prefrontal-striatal-thalamic-cerebellar circuit points more toward schizophrenia-like symptoms, whereas dysfunctional frontolimbic structures are more likely to be related to mood disorders (Table 2). Moving forward, a logical extension of the work performed to date would be to relate imaging findings to specific symptom patterns, such as psychosis, depression, mania, panic attacks, and attention deficits. Radiology: Volume 255: Number 1 April 2010 n radiology.rsna.org 33

12 Table 1 Most Reported MR Findings of Major Psychiatric Disorders Disorder Structural MR Imaging Findings Diffusion-Tensor Imaging (FA) Findings Functional (Activity) MR Imaging Findings Proton MR Spectroscopy Findings* Schizophrenia Bipolar disorder Major depressive disorder Decreased frontal lobe, temporal lobe, cerebellum, and total brain volumes Increased lateral ventricular volume Unchanged or decreased prefrontal cortex, striatum, and thalamus volumes Cortical gray matter thinning Increased T2-weighted hyperintensity in WM Increased lateral ventricular and third ventricular volumes Decreased subgenual anterior cingulate cortex and prefrontal cortex volumes Increased amygdala and striatum volumes Cortical gray matter thinning Increased high-signal-intensity WM regions Decreased prefrontal cortex, subgenual anterior cingulate cortex, medial temporal lobe, amygdala, hippocampus, striatum, and basal ganglia volumes Anxiety disorders Decreased hippocampus and medial prefrontal cortex volumes in patients with PTSD and those with GAD Decreased medial temporal lobe volume in patients with PD Decreased prefrontal cortex, cingulum bundle, uncinate fasciculus, and corpus callosum Decreased prefrontal cortex, corpus callosum, and internal capsule Decreased prefrontal cortex Decreased cortico-striato-thalamostriato-cortical circuitry in patients with OCD Decreased prefrontal cortex, cerebellum, and frontalstriatal-thalamic circuit Decreased prefrontal cortex and anterior cingulate cortex in depressed patients Increased prefrontal cortex, anterior cingulate cortex, basal ganglia, and striatum in manic patients Increased amygdala and prefrontal cortex in patients with euthymia Decreased dorsal anterior cingulate cortex, prefrontal cortex, amygdala, and striatum Decreased prefrontal cortex and hippocampus in patients with PTSD Increased amygdala and hippocampus in patients with SAD and those with PD Increased insula in patients with PD Increased orbitofrontal cortex, anterior cingulate cortex, and striatum in patients with OCD Decreased NAA in prefrontal cortex and anterior cingulate cortex Increased Cho in prefrontal cortex and anterior cingulate cortex Increased Glu in prefrontal cortex and hippocampus in fi rst-episode and/or at-risk patients Decreased Glu in prefrontal cortex in patients with chronic schizophrenia Decreased NAA in prefrontal cortex Unchanged or increased Cho Increased mi in patients with mania and those with euthymia Decreased mi in depressed patients Increased Gln/Glu Decreased NAA in prefrontal cortex and hippocampus Decreased Glu in anterior cingulate cortex, posterior occipital cortex, and hippocampus Increased Glu in prefrontal cortex Decreased GABA in prefrontal cortex and posterior occipital cortex Decreased NAA in striatum and anterior cingulate cortex in patients with OCD Decreased NAA Increased Glu in patients with SAD and those with OCD Decreased GABA in anterior cingulate cortex and posterior occipital cortex in patients with GAD (Table 1 continues) 34 radiology.rsna.org n Radiology: Volume 255: Number 1 April 2010

13 Table 1 (continued) Most Reported MR Findings of Major Psychiatric Disorders Disorder ADHD Structural MR Imaging Findings Decreased anterior cingulate cortex, prefrontal cortex, striatum, and cerebellum volumes Cortical gray matter thinning Diffusion-Tensor Imaging (FA) Findings Decreased frontostriatal circuitry Functional (Activity) MR Imaging Findings Decreased prefrontal cortex and cerebellum Proton MR Spectroscopy Findings* Unchanged or decreased NAA and Cho in prefrontal cortex and striatum Increased Glu in prefrontal cortex and striatum Note. ADHD = attention defi cit hyperactivity disorder, Cho = choline, Cr = creatine, GABA = g -aminobutyric acid, GAD = generalized anxiety disorder, Gln = glutamine, Glu = glutamate, mi = myoinositol. OCD = obsessive-compulsive disorder, PD = panic disorder, PTSD = posttraumatic stress disorder, SAD = social anxiety disorder, WM = white matter. *All metabolites are ratios to Cr. Figure 9 Figure 9: Summary of most reported fi ndings on axial (top row), sagittal (middle row), and coronal (bottom row) MR image sections. (a c) Findings of schizophrenia: The prefrontal cortex (turquoise), striatum (caudate: dark green, putamen: olive), thalamus (light blue), medial temporal lobe (light green), cerebellum (orange), and corpus callosum (yellow) are key areas of functional, structural, and neurochemical alterations. (d f) Findings of bipolar disorder: The prefrontal cortex, anterior cingulate cortex (dark pink), striatum, corpus callosum, and limbic structures such as the hippocampus (dark blue) and amygdala (purple) are frequently reported as altered on MR images. (g i ) Findings of major depressive disorder: The prefrontal cortex, anterior cingulate cortex, striatum, basal ganglia (light pink), and limbic structures such as the amygdala and hippocampus are the most reported areas of abnormal structure, function, and neurochemical features. (j l ) Findings of anxiety disorders: The prefrontal cortex, anterior cingulate cortex, caudate, insula (dull orange in j ), amygdale, and hippocampus are major sites of abnormality. (m o) Findings of attention defi cit hyperactivity disorder: The prefrontal cortex, anterior cingulate cortex, cerebellum, striatum, amygdala, and hippocampus are the most reported areas of alteration. Ideally, we would like to find specific MR markers for each psychiatric disease. For example, a biomarker is defined as an indicator of disease activity ( 119 ). Ideally, a neuroimaging biomarker would (a) be a measure of the disease or the disease symptom, (b) be used to monitor drug response, (c) assist in the identification of responders to treatment, and (d) correlate with treatment-induced changes. In contrast, endophenotypes are internal phenotypes that lie between the genes and the disease. As opposed to biomarkers, endophenotypes reflect the genetic underpinnings of a disease ( 120 ). Endophenotypes must be heritable, associated with illness, present regardless of whether the illness manifests, and detected at a higher rate in nonaffected family members than in the general Radiology: Volume 255: Number 1 April 2010 n radiology.rsna.org 35