Neuroimaging in psychiatry: an update

Journal of Psychosomatic Research 61 (2006) 289 – 293

Review article

Neuroimaging in psychiatry: an update Mohammed T. Abou-Saleh4 Division of Mental Health, St George’s Hospital Medical School, University of London, Cranmer Terrace, SW17 0RE London, United Kingdom Received 20 June 2006

Abstract The introduction of neuroimaging techniques in the 1960s has revolutionized the study of the biology of psychiatric disorders with implications for psychiatric practice. These comprise structural (computerized axial tomography, magnetic resonance imaging) and functional (including neurochemical/neuropharmacological techniques such as single-photon emission computerized tomography, positron emission tomography, functional magnetic resonance imaging, and magnetic resonance spectroscopy) techniques. As a result, we now have a better understanding of the morbid anatomy, pathophysiology, and chemical pathology of organic brain disease,

schizophrenia, addictions, and affective disorders. This selective review will focus on recent advances in the use and application of neuroimaging techniques in the study of addictions, schizophrenia, and depression. Reference will be made to studies conducted in the United Arab Emirates on Arab patients with depression, schizophrenia, and alcohol dependence. The refinement of these techniques and their application in the study of psychiatric disorders will redefine these disorders, promising their deconstruction and the development of novel and more specific treatments. D 2006 Elsevier Inc. All rights reserved.

Keywords: Arab; Addiction; Depression; Neuroimaging; Schizophrenia

Introduction The last two and half decades witnessed major advances in neuroscience, including the use and application of such advances in psychiatric practice. The 1990s were celebrated as the bDecade of the Brain,Q with unprecedented research funding and productivity that aim to reduce the burden of psychiatric and neurological diseases through translational and applied neuroscience research. However, the most significant advance was the introduction of neuroimaging techniques, complemented by the use of cognitive neuroscience, which has revolutionized the study of psychiatric disorders and their underpinning biological mechanisms. Importantly, emergent findings from neuroimaging studies promise to deconstruct present diagnostic entities into new functional entities with implications for their treatment. In this update, recent advances in the use of neuroimaging techniques and their applications in the study of major psychiatric disorders will be described. Reference is 4 Tel.: +44 2087250368; fax: +44 2087252914. E-mail address: [email protected]. 0022-3999/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2006.06.012

made to neuroimaging studies of schizophrenia, depression, and addictions, including studies involving Arab patients with these disorders. The implications of these advances for the diagnosis and treatment of such disorders will also be considered. Paradigm shifts and the introduction of new technologies have revolutionized psychiatric research, providing a useful framework for understanding rapid developments in the biology of psychiatric disorders [1]. The first paradigm shift is underpinned by the finding that clinical comorbidity is common and is the rule rather than the exception as shown in community and clinical population studies. There is evidence that comorbid disorders have shared biological substrate, including shared genes. This has implications in the classification of psychiatric disorders, which may become more etiology based rather than descriptive, on par with the classification of nonpsychiatric medical diseases [1]. It is therefore imperative to study clinical comorbidity in the context of the neuroimaging investigations. Secondly, it is increasingly recognized that the brain is a highly complex organ with marked structural and functional

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plasticity and capacity for repair and tissue remodeling. A new concept that may be essential in the field of psychiatry in the coming years is that of cumulative end-organ damage in different regions of the brain. Some concerted approaches for study, which integrate different methodologies concurrently (phenotypical assessment, pharmacological studies, animal models, molecular and cellular biology, genetics, and brain imaging), have been proposed [1]. For example, convergent functional genomics is an approach to integrate data from animal studies, human genetic studies, and brain imaging studies: to use data from brain imaging studies to select brain regions of interest in psychiatric disorders and analyze gene expression patterns in those regions in postmortem human brains [1]. Advances in neuroimaging technology, such as positron emission tomography (PET), single-photon emission computerized tomography (SPECT), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS), have provided powerful tools to investigate biological mechanisms underlying psychiatric disorders and their relationships with diagnostic and therapeutic measures.

Studies in addictions The introduction of neuroimaging techniques for the study of drug addiction has revolutionized the endeavor to elucidate its chemical pathology, offering new modalities of treatment including psychopharmacological ones. However, addiction is a complex set of disorders with underpinning biological, behavioral, and environmental mechanisms. Recent research has provided new knowledge on the effects of drugs of abuse on biological factors such as genes, protein expression, and neuronal circuits. Less is known about the interrelationships between these biological mechanisms and addictive behavior and about the effects of environmental factors on these biological mechanisms and related addictive behavior. Neuroimaging technological advances have provided powerful tools to investigate biological mechanisms underlying addictive behavior and its relationships with cognitive, behavioral, and environmental variables within addictions. The focus of PET and SPECT studies on drug addiction has been on the brain dopamine system, the pivotal neurotransmitter system through which drugs of abuse exert their reinforcing effects [2]. fMRI studies have identified brain regions and circuits involved in drug addiction (intoxication, withdrawal, and craving) and linked their activities to behavior [3]. Hamdi et al. [4], in a SPECT (TcHMPAO) study of Arab patients with alcohol dependence undergoing withdrawal treatment, reported diminished cerebral blood flow (CBF) in the anterior and middle frontal regions and increased perfusion in the posterior temporal regions. Frontal hypoperfusion was related to alcohol withdrawal and to cognitive impairment. However, temporal

hyperperfusion was more persistent, indicating long-term neuronal toxicity. Studies have shown that environmental factors such as social status can affect dopamine D2 receptor expression that, in turn, affects the propensity for cocaine selfadministration [5]. Recently, a model that conceptualizes addiction as a bstate initiated by the qualitatively different and larger reward value of the drug, which triggers a series of adaptations in the reward, motivation/drive, memory and control circuits of the brainQ has been recently proposed [6]. These changes result in an enhanced and permanent saliency value for the drug and in the loss of inhibitory control, favoring the emergence of compulsive drug administration. The model also highlights the need for therapeutic approaches that include pharmacological and behavioral interventions in the treatment of drug addiction. Further, there are new findings on biological vulnerability to drug addiction. It has been hypothesized that genetic factors make a major contribution to the individual innate vulnerability to addictive behavior. Individuals with low dopamine D2 receptor levels find methylphenidate pleasant, while higher D2 receptor level individuals find it unpleasant, supporting the breward deficiency hypothesisQ and the notion that individuals with low dopamine receptors may have an understimulated reward system and, as a result, experience pleasurable effects when subjected to druginduced elevation in dopamine [6]. It has been suggested that neuroimaging may provide the means to objectively link behavioral and neurochemical changes and to objectively evaluate treatment. With the identification of new genes related to addictive behavior, imaging promises to provide the necessary tool to directly translate this knowledge to human evaluation [6].

Studies in schizophrenia Structural MRI studies have conclusively shown reductions in prefrontal and medial temporal cortical regions in schizophrenia, including studies of first-episode schizophrenia. While there is a definite genetic causative factor for schizophrenia, there is controversy whether brain abnormalities are genetically determined with the evident environmental factors, as shown in studies of monozygotic twins discordant for the disorder. Studies have shown structural abnormalities in the cotwin with the disorder but not in the healthy cotwin [7]. These findings were confirmed using the related MRI technique of DTI that depicts the integrity of white matter tracts [8]. Studies using fMRI have also confirmed these findings, demonstrating reduced activation of the prefrontal cortex and medial temporal cortex in patients with schizophrenia. Moreover, the technique enabled the study of brain function in relation to the experience of auditory hallucinations in schizophrenic patients, reporting an association with reduced activation in the temporal region [9]. These abnormalities

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have also been detected using other functional neuroimaging techniques (e.g., PET and SPECT) to measure CBF, brain metabolism, and neurochemical mechanisms, indicating changes in frontal, temporal, cingulate, thalamic, and cerebellar regions in patients with schizophrenia [10]. Abou-Saleh et al. [11], in a SPECT study of Arab patients with schizophrenia, reported greater right CBF than normal controls in all cerebral regions except in the right and left anterior frontal regions. Patients showed a reversed left-toright laterality in the anterior frontal regions only. Several symptom scores were predicted by the CBF: delusions of control by greater left temporo-occipital CBF and longer duration of illness by greater left midfrontal, left temporal, right midfrontal, and right perisylvian CBF. These results suggested generalized cerebral activation in patients with schizophrenia. PET and SPECT techniques have been used to study neurotransmitter mechanisms; of particular importance are studies of dopamine D2 receptors using the amphetamineinduced reduction of raclopride binding, indicating increased dopamine release and confirming the dopamine hypothesis for schizophrenia [12]. Finally, MRS has also demonstrated in vivo neurochemical changes in patients with schizophrenia, most notably, a reduction in the concentration of N-acetyl aspartate in the frontal and temporal cortical regions, indicating neuronal loss and supporting findings obtained using structural MRI studies of reduced gray matter in patients with schizophrenia [13].

Studies in depression Neuroimaging studies of patients with mood disorders reported abnormalities of brain structure and function. A review of structural neuroimaging studies in mood disorders reported that the most replicated finding was an increased rate of white matter periventricular hyperintensities [14]. Moreover, unipolar depression was associated with smaller frontal lobe, cerebellum, caudate, and putamen, while bipolar disorder was associated with larger third ventricle and with smaller cerebellum and temporal lobe. The authors concluded that these abnormalities involve regions that may be critical in the pathogenesis of mood disorders and which may be related to age or vascular disease. Abou-Saleh et al. [15] showed that depressed Arab patients had greater CBF in the left and right posterior frontal and parietal cortical regions than normal controls. Moreover, the severity of depression was associated with increased CBF in the left frontal cortex, consistent with the results of studies of induced depressive affect and some studies of depression subsyndromes [16]. Drevets [17] reviewed the functional abnormalities in limbic and prefrontal cortical (PFC) regions in unipolar depression, some of which are mood-dependent abnormalities mediating emotional, behavioral, and cognitive changes, while other abnormalities persist after remission (orbital and medial PFC). The author speculated that

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bthese areas of ddeactivationT during the depressed state may reflect neurophysiological interactions between cognitive and emotional processing, and may relate to the subtle cognitive impairments associated with depressionQ [17]. An early study of elderly patients with depression showed a patchy pattern of blood perfusion defects using Tc-HMPAO SPECT [18]. Lesions, depicted by MRI in both white and gray matter, have been associated with old-age depression. Tupler et al. [19] reported that late onset depressed patients had more severe hyperintensity ratings in deep white matter, particularly left-sided lesions, than early onset depressed patients. Taylor et al. [20] showed greater MRI white and gray matter lesions in elderly depressed patients than in control subjects. These findings have established the clinical entity of subcortical ischemic depression characterized by older age, history of hypertension, and a negative family history of mental illness [21]. Seminowicz et al. [22] reported the results of an acrosssite meta-analysis of effective connectivity in major depression using PET data to create a formal model of depression to explicitly test current theories of limbic– cortical dysfunction in this disorder. A seven-region model consisting of lateral prefrontal cortex, anterior thalamus, anterior cingulate, subgenual cingulate, orbital frontal cortex, hippocampus, and medial frontal cortex was derived. Within this model, path differences among groups as a function of treatment response to pharmacotherapy and to cognitive behavioral therapy characteristics were identified. Another line of study was emotional processing in mood disorders. Philips et al. [23] have identified the neural substrate for emotional processing, which accounts for clinical features of prominent mood swings, emotional lability, and distractibility in bipolar disorder during depression and mania, as well as features of depressed mood and anhedonia in major depression. Using fMRI, Lawrence et al. [24] demonstrated that bipolar disorder patients had increased subcortical (ventral striatal, thalamic, and hippocampal) and ventral PFC responses, particularly to mild and intense fear, mild happy, and mild sad expressions, while those with non-bipolar depression showed diminished neural responses to all emotional expressions except to mild sadness. These findings, if confirmed, would introduce an important biological measure to distinguish between major depression and bipolar disorder and enable their correct diagnosis before the occurrence of a manic episode.

Neuroimaging and the mechanism of antipsychotic drugs An original study by Breier et al. [25] tested the dopamine hypothesis for schizophrenia using PET. They found that schizophrenic patients had greater reductions in amphetamine-related D2 [11C]raclopride striatal binding ratios than controls, which reflected larger increases in synaptic dopamine levels. Another line of study that used

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PET investigated 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia [26]. Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day, while its D2 occupancy increased with dose: patients taking 5–20 mg/day showed 43% to 80% D2 occupancy. The authors concluded that bolanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, doses of 30 mg/day and higher were associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.Q In patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%, and those with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects [27]. These findings confirmed that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. The application of these neuroimaging techniques for determining optimal dosages of pharmacological treatments is a major advance.

Diagnostic and prognostic applications While the debate on the validity of present-day diagnostic entities continues, major advances in the biology of these entities have not been considered as validating criteria. Yet, such advances cut through the heart of the matter and inform the face, concurrent, construct, and predictive validities and utility of these nosological binventionsQ and ultimately turn them into diagnostic bdiscoveries.Q The diagnostic application of neuroimaging techniques has been most promising in the diagnosis of dementia. Using SPECT Tc-HMPAO, studies have shown a symmetrical pattern of perfusion defects in Alzheimer’s disease (AD) [18,28], in contrast to the patchy pattern of these defects in vascular dementia (VD) and to the more specific pattern in dementia of Lewy body (DLB) involving the occipital lobe. Earlier studies of structural brain changes in AD showed that medial temporal lobe atrophy assessed by temporal-lobe-oriented computerized tomography (CT) gave 94% sensitivity and 93% specificity, while parietotemporal hypoperfusion on SPECT revealed 96% sensitivity and 89% specificity [29]. The combination of both changes yielded a sensitivity of 90% and a specificity of 97%— findings that clearly enhance diagnostic accuracy and can be readily applied in the clinical situation [29]. A further study using MRI and SPECT showed that combining information from both scans improved the proportion of correctly classified subjects in a discriminant function to 90% (sensitivity, 93%; specificity, 86%) [30]. A volumetric MRI study of the caudate nucleus in patients with DLB, AD, and VD showed that the left caudate volume was significantly reduced in AD and DLB compared with controls [31]. Roman et al. [32] advanced the Neuroepidemiology Branch of the National Institute of Neuro-

logical Disorders and Stroke diagnostic criteria for VD, which included the fact that the left caudate volume was significantly reduced in AD and DLB compared with controls. Fox et al. [33], using serial brain MRI to measure disease progression in AD, reported that the mean (S.D.) rate of brain atrophy for the patients with AD was 2.37% (1.11%) per year, while for the control group, it was 0.41% (0.47%) per year. They concluded that serial MRI volume images provide a powerful method of quantification of brain atrophy that can be used to monitor progression of AD in clinical trials.

Conclusions The introduction and the use of neuroimaging techniques have provided powerful tools for the study of the neurobiology of psychiatric disorders. Both structural (CT and MRI) and functional (fMRI, PET, and SPECT) techniques have been successfully employed to study the neural basis of addictions, schizophrenia, and mood disorders. In addictions, neuroimaging studies have identified the functional anatomy and biochemistry of addictive behavior: addictive behavior has been shown to be associated with abnormalities in structures that subserve reward, motivation/drive, learning/memory, and impulse control and has demonstrated the pivotal role of dopamine. In schizophrenia, studies have confirmed the long-suspected cognitive deficits, have proven the dopamine hypothesis for its pathogenesis, and have provided insights into its pharmacology. In mood disorders, studies have identified the dysfunctional circuitry, including the circuitry for emotional processing and the effects of treatment on the integrity of these pathways. These advances promise to contribute to the deconstruction of present diagnostic entities into their true genotype–phenotype entities and inform the development of designer medicines and the introduction of preventive interventions.

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