The functional neuroanatomy of symptom dimensions in schizophrenia: A qualitative and quantitative review of a persistent question

Abstract

One of the fundamental goals in understanding schizophrenia is linking the observable symptoms to the underlying unobservable pathophysiology. Given recent advances in medical imaging, researchers are increasingly investigating brain-behavior relationships to better understand the neural substrates of negative, positive, and disorganization symptoms in schizophrenia. This review focused on 25 task-related functional magnetic resonance imaging studies and found meaningful small to moderate associations between specific symptom dimensions and regional brain activity. Negative symptoms were related to the functioning of the ventrolateral prefrontal cortex and ventral striatum. Positive symptoms, particularly persecutory ideation, were related to functioning of the medial prefrontal cortex, amygdala, and hippocampus/parahippocampal region. Disorganization symptoms, although less frequently evaluated, were related to functioning of the dorsolateral prefrontal cortex. Surprisingly, no symptom domain had a consistent relationship with the middle or superior temporal regions. While a number of adaptations in experimental design and reporting standards can facilitate this work, current neuroimaging approaches appear to provide a number of consistent links between the manifest symptoms of schizophrenia and brain dysfunction.

Introduction

One prominent conceptualization of schizophrenia is as a neurodevelopmental disorder, where genes and environment interact over the course of development to determine abnormalities in neural systems that give rise to the disorder. Early in life pre-schizophrenia individuals demonstrate physical, motor, cognitive, and social impairments. As the brain matures through childhood the illness is further expressed, ultimately manifesting in late adolescence and adulthood as psychotic symptomatology (for review see Lewis and Levitt, 2002, Rapoport et al., 2005). With the onset of the full syndrome, schizophrenia is diagnosed by the presence of diverse symptoms including distorted perceptions of reality, disorganized behavior, avolition, and flat or inappropriate affect. As expressed by Kraepelin (1907), to fundamentally understand schizophrenia one must relate the observable symptoms of the disorder to the unobservable neural pathophysiology. With refinements in neuroimaging technology, researchers are increasingly able to investigate brain-behavior relationships that reflect the neural basis of psychiatric symptoms. This review will focus on how blood-oxygenation level dependent response (BOLD) as measured by functional magnetic resonance imaging (fMRI) has added to our knowledge of the associations between neural substrates and symptom dimensions in schizophrenia. Symptom dimensions may reveal patterns of association with brain functioning which are not apparent when patient data are averaged into a single group and symptom heterogeneity obscures differences with a comparison group. Our goals were to determine whether consistencies emerged across studies, identify common problems that might be addressed in future studies, and highlight promising avenues for future work.

In addition to the tremendous progress made in imaging technology, considerable progress has been made in understanding the phenomenology of schizophrenia. Current diagnostic classifications and identified symptom dimensions of the disorder build on a number of theoretical and empirical approaches that have been used in the past to reduce the heterogeneity. One prominent strategy developed by Kraepelin, Bleuler, and others was to group together patients with similar symptoms, symptom courses, or patterns of symptoms, presuming that patients with shared patterns also shared underlying pathology. Our current diagnostic criteria and subtypes of schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Disease very much reflect the influence of this approach in their attempts to identify common phenomenology across patients. However, these diagnostic subtypes have not been found to be particularly useful in differentiating neural pathology in patients, partly due to the instability of subtypes across the course of the disorder (Buchanan and Carpenter, 1994).

More recently, researchers have attempted to further explore and develop subtypes of schizophrenia, which are more conducive to research. Timothy Crow developed a two-syndrome theory of schizophrenia (revised version, 1985) to reconcile the paradox that some symptoms can remit and are responsive to anti-psychotic medications, whereas other symptoms are associated with poorer long-term outcome and less responsive to anti-psychotic medications. Type I syndrome was characterized by delusions and hallucinations (positive symptoms), a good response to neuroleptics, a lack of intellectual impairment, a lack of involuntary movements, and an increase in D2 dopamine receptors. Type I schizophrenia was seen as a potentially reversible condition. Type II syndrome was characterized by flattening of affect and poverty of speech (negative symptoms), a poor response to neuroleptics, significant intellectual impairment, abnormal involuntary movements, and cell loss in temporal lobe structures. The two syndromes were regarded as relatively independent, but could coexist in the same patient. A second subtyping scheme was developed which emphasized the fundamental nature of negative symptoms to schizophrenia (Carpenter et al., 1988). This scheme distinguished between primary and secondary negative symptoms. Primary symptoms were thought to be more persistent and idiopathic, and secondary symptoms were considered a consequence of phenomena such as medication, depressive symptoms, or an absence of social stimulation. For example, social withdrawal would not be considered a direct measure of a negative symptom because it may be due to a range of symptoms interacting with one's environment. Yet, loss of social drive would be considered a negative symptom, whereas social withdrawal due to paranoia would not. The term ‘deficit syndrome’ was developed to describe the presence of primary negative symptoms. Thus, patients would be categorized as having deficit or nondeficit schizophrenia, depending on the prevalence of primary negative symptoms. Both Crow's and Carpenter's subtypes have influenced the measurement and understanding of symptoms that characterize schizophrenia.

A recently favored approach to characterizing the symptoms of schizophrenia has been to use quantitative dimensions to investigate domains of symptomatology on which individuals with schizophrenia vary. Dimensional approaches tend to divide symptoms, rather than patients, into groups. In addition, since clinical presentation in schizophrenia is often complicated with numerous coexisting symptoms, dimensions can be used to describe the level of symptomatology across several domains rather than merely categorizing an individual into a subtype (Andreasen et al., 1994). The first two dimensions of schizophrenia were conceptualized as positive and negative symptoms which in part were derived from Crow's Type I and II subtyping of schizophrenia. Inventories such as the Scale for Assessment of Positive Symptoms (SAPS; Andreasen, 1983), Scale for Assessment for Negative Symptoms (SANS; Andreasen, 1981), and Positive and Negative Syndromes Scale (PANSS; Kay et al., 1987) were developed to rate symptoms in these dimensions. Nevertheless, factor analyses in schizophrenia have consistently demonstrated that the symptoms may be better accounted for by three dimensions: negative, positive, and disorganization (Grube et al., 1998). Disorganization can contains symptoms (e.g., formal thought disorder, bizarre behavior, inappropriate affect, and attention) that were previously divided into either the positive or negative dimension. However, the number of factors that result from these scales depends on the sample size, sample chronicity, and nature and number of items included in the analyses. Others have argued for as many as 11 or more factors and suggest that the three factors may reflect higher-order factors or derive from a less than complete inclusion of symptoms (Stuart et al., 1999). Researchers have proposed that if the full range of symptoms, including the more transient affective symptoms, are taken into account, a more complex picture emerges (Liddle, 1995). Factor analysis of the PANSS on 100 schizophrenia patients has revealed negative, positive, disorganized, excited, anxious, preoccupied, depressive, and somatization dimensions (Peralta and Cuesta, 1994).

A few particularly influential factor analytic studies of symptoms exist. Liddle (1987b) used select items from the SAPS and SANS and the Present Status Examination (PSE) to measure symptoms in 40 chronic schizophrenia patients. Factor analysis revealed three factors. The first factor termed psychomotor poverty consisted of poverty of speech, decreased spontaneous movement, and four items related to blunted affect, which were unchanging facial expression, paucity of expressive gesture, affective nonresponsivity, and lack of vocal inflection. The second factor termed disorganization consisted of inappropriate affect, poverty of speech content, and four items measuring disturbances in thought, comprising of tangentiality, derailment, pressure of speech, and distractibility. The third factor, termed reality distortion, consisted of voices speaking to the patient, delusions of persecution, and delusions of reference. A similar structure was found using the PSE. However, there was modest differentiation between the delusions and hallucinations of Schneider's first rank symptoms (disintegrative reality distortion) and other symptoms (integrative reality distortion). The two factors were correlated though, suggesting that they may share etiology.

Andreasen et al. (1995) completed a factor analysis of the SANS and SAPS on a sample of 243 patients. The first factor was negative symptoms and consisted of avolition, anhedonia, and affective flattening. The second factor was disorganization which consisted of inappropriate affect and positive formal thought disorder. Bizarre behavior loaded onto both the negative and disorganization factors, but more strongly on the disorganization factor. A third factor, psychosis, consisted of delusions and hallucinations. When alogia and attentional impairments were added as global ratings, the global ratings did not clearly load onto either the negative or the disorganization factors, though the global rating for alogia correlated more highly with the negative dimension. The different items making up the attention and alogia global scales loaded onto either the disorganization or the negative dimension. Poverty of speech and increased latency of response loaded onto the negative dimension, whereas poverty of content of speech, blocking, and perseveration loaded onto the disorganization factor. Social inattentiveness loaded more strongly onto the negative dimension and inattentiveness during mental testing loaded more strongly onto the disorganization factor. To further our understanding, Arndt et al. (1995) investigated the stability and course of these symptom dimensions in 65 primarily neuroleptic naïve, acutely ill patients. All three dimensions of negative, disorganization, and positive symptoms were found to be prominent at the initial evaluation. Negative symptoms tended to be more stable longitudinally, whereas positive and disorganization symptoms tended to be less pervasive over time. Symptoms within a factor tended to change together, but independently of the symptoms of the other factors.

Factor analyses of symptoms in schizophrenia are quite useful in determining which symptoms are likely to co-occur; however demonstrating that they co-occur does not necessarily prove that they have a common etiological or biological underpinning (Andreasen et al., 1994). Nonetheless, given that dimensions provide a quantitative summary of symptomatology experienced by schizophrenia patients, they provide useful tools for examining associations between symptoms and brain function. Indeed, to more closely tie symptoms to underlying pathophysiology, many investigators have examined associations between symptom dimensions and brain activity. In this review we attempt to determine whether the symptoms of schizophrenia are associated with specific brain regions. Although, schizophrenia is likely due to dysfunction of distributed neural systems, if specific brain regions are affected it is likely that the behavior of the distributed neural system will also be disrupted. In sum, the goal of this monograph was to investigate nodes within neural systems and their association with symptom dimensions; knowledge of how these individual nodes function provides useful information of the working of higher-level systems. Thus, we specifically examined whether fMRI brain activity associated with experimentally revealed cognitive or emotive processes in schizophrenia was related to specific aspects of naturally occurring symptomatology.