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Book Title: Treating and Preventing Adolescent Mental Health Disorders
> pp. [85]-[89]
UNDEFINED: AUTHORS
Treating and Preventing Adolescent Mental Health Disorders
Print ISBN 9780195173642, 2005
pp. [85]-[89]
cents at risk can predict the onset and course of illness. The executive functions impaired in adults with schizophrenia are the very abilities that are essential for an adolescent to make the transition to young adulthood, when navigation through an increasing complexity of alternatives becomes the issue. In addition to the cognitive impairment, emotion-processing deficits in identification, discrimination, and recognition of facial expressions have been observed in schizophrenia (Kohler et al., 2003; Kring, Barrett, & Gard, 2003). Such deficits may contribute to the poor social adjustment already salient before disease onset. Emotional impairment in schizophrenia is clinically well established, manifesting in flat, blunted, inappropriate affect and in depression. These affect-related symptoms are notable in adolescents during the prodromal phase of illness preceding the positive symptoms. While these may represent a component of the generalized cognitive impairment, they relate to symptoms and neurobiological measures that deserve further research. Several brain systems are implicated by these deficits. The attention-processing circuitry includes brainstem-thalamo-striato-accumbens-temporal-hippocampal-prefrontal-parietal regions. Deficits in working memory implicate the dorsolateral prefrontal cortex, and the ventromedial temporal lobe is implicated by deficits in episodic memory. A dorsolateral-medial-orbital prefrontal cortical circuit mediates executive functions. Animal and human investigations have implicated the limbic system, primarily the amygdala, hypothalamus, mesocorticolimbic dopaminergic systems, and cortical regions including orbitofrontal, dorsolateral prefrontal, temporal, and parts of parietal cortex. These are obviously complex systems and impairment in one may interact with dysfunction in others. Studies with large samples are needed to test models of underlying pathophysiology. The link between neurobehavioral deficits and brain dysfunction can be examined both by correlating individual differences in performance with measures of brain anatomy and through the application of neurobehavioral probes in functional imaging studies. With these paradigms, we can investigate the topography of
brain activity in response to engagement in tasks in which deficits have been noted in patients. Thus, there is “online” correlation between brain activity and performance in a way that permits direct examination of brain–behavior relations (Gur et al., 1997).
The availability of methods for quantitative structural neuroimaging has enabled examination of neuroanatomic abnormalities in schizophrenia. Because the onset of schizophrenia takes place during a phase of neurodevelopment characterized by dynamic and extensive changes in brain anatomy, establishment of the growth chart is necessary to interpret findings. Two complementary lines of investigation have proved helpful. By examining the neuroanatomical differences between healthy people and individuals with childhood-onset and first-episode schizophrenia, as well as individuals at risk, regional abnormalities early in the course of illness may be identified. Complementary efforts are needed to examine changes associated with illness progression. An understanding of the neuroanatomic changes in the context of the dynamic transitions of the developing brain during adolescence, however, requires careful longitudinal studies during this critical period. A brief introduction to the methodology of quantitative MRI and its application to examine neurodevelopment is needed to appreciate findings in schizophrenia. Several approaches have been developed in the early 1990s, and these have now become standard and have been shown to produce reliable results (e.g., Filipek, Richelme, Kennedy, & Caviness, 1994; Kohn et al., 1991). These methods have provided data on the intracranial composition of the three main brain compartments related to cytoarchitecture and connectivity: gray matter (GM), the somatodendritic tissue of neurons (cortical and deep); white matter (WM), the axonal compartment of myelinated connecting fibers; and cerebrospinal fluid (CSF). In one of the first studies examining segmented MRI in children and adults, Jernigan and Tallal ( 1990) documented the “pruning” process
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proposed by Huttenlocher's ( 1984) work. They found that children had higher GM volumes than adults, a finding indicating loss of GM during adolescence. This group has more recently replicated these results by use of advanced methods for image analysis (Sowell, Thompson, Holmes, Jernigan, & Toga, 1999). Their new study also demonstrated that the pruning is most “aggressive” in prefrontal and temporoparietal cortical brain regions. As a result of this work, we now recognize that both myelination and pruning are important aspects of brain development. In a landmark paper published in 1996, a National Institutes of Health (NIH) group reported results of a brain volumetric MRI study on 104 healthy children ranging in age from 4 to 18 (Giedd et al., 1996). Although this group did not segment the MRI data into compartments, they did observe developmental changes that clearly indicated prolonged maturation beyond age 17. In a later report on this sample, in which segmentation algorithms were applied, the investigators were able to pinpoint the greatest delay in myelination, defined as WM volume, for frontotemporal pathways (Paus et al., 1999). This finding is very consistent with the Yakovlev and Lecours ( 1967) projections. The NIH group went on to exploit the ability of MRI to obtain repeated measures on the same individuals. Using these longitudinal data, they were able to better pinpoint the timing of preadolescent increase in GM that precipitates the pruning process of adolescence. Of importance to the question of maturation as defined by myelogenesis are results indicating that the volume of WM continued to show increases up to age 22 years (Giedd et al., 1999). A Harvard group developed a sophisticated procedure for MRI analysis (Filipek et al., 1994) which they applied to a sample of children with the age range of 7 to 11 years and used to compare results with those of adults (Caviness, Kennedy, Richelme, Rademacher, & Filipek, 1996). They found sex differences suggesting earlier maturation of females, and generally supported the role of WM as an index of maturation. Their results also indicated that WM shows a delay in reaching its peak volume until early adulthood. Another landmark study, published by a Stanford group, examined segmented MRI on a “retrospective” sample of 88 participants ranging in age from 3 months to 30 years and a “prospective” sample of 73 healthy men aged 21 to 70 years (Pfefferbaum et al., 1994). Scans for the retrospective sample were available from the clinical caseload, although images were carefully selected to include only those with a negative clinical reading; the prospective sample was recruited specifically for research and was medically screened to be healthy. The results demonstrated a clear neurodevelopmental course for GM and WM, the former showing a steady decline during adolescence whereas the latter showed increased volume until about age 20 to 22 years. A Johns Hopkins group used a similar approach in a sample of 85 healthy children and adolescents ranging in age from 5 to 17 years (Reiss, Abrams, Singer, Ross, & Denckla, 1996). Consistent with postmortem and the other volumetric MRI studies, these investigators reported a steady increase in WM volume with age that did not seem to peak by age 17. Unfortunately, they did not have data on older individuals. Their results are consistent with those of Blatter et al. ( 1995) from Utah, although the extensive Utah database combines ages 16 to 25 and therefore does not permit evaluation of changes during late adolescence and early adulthood. In the only study to date that has examined segmented MRI volumes from a prospective sample of 28 healthy children aged 1 month to 10 years and a small adult sample, Matsuzawa et al. ( 2001) applied the segmentation procedures developed by the Penn group. Matsuzawa et al. demonstrated increased volume of both GM and WM in the first postnatal months, but whereas GM volume peaked at about 2 years of age, the volume of WM, which indicates brain maturation, continued to increase into adulthood (Figure 5.2). Furthermore, consistent with the postmortem and other MRI studies that have examined this issue, the frontal lobe showed the greatest maturational lag, and its myelination is unlikely completed before young adulthood. Magnetic resonance imaging studies in first-episode patients have indicated smaller brain
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volume and an increase in CSF relative to that in healthy people (e.g., Gur et al. 1998a; Ho et al., 2003). The increase is more pronounced in ventricular than in sulcal CSF. Brain and CSF volumes have been related to phenomenological and other clinical variables such as premorbid functioning, symptom severity, and outcome. Abnormalities in these measures are likely to be more pronounced in patients with poorer premorbid functioning, more severe symptoms, and worse outcome. The concept of brain reserve or resilience may apply to schizophrenia as well, with normal brain and CSF volumes as preliminary indicators of protective capacity. As our understanding of how brain systems regulate behavior in health and disease improves, we can take advantage of neuroimaging to examine specific brain regions implicated in the pathophysiology of schizophrenia. Gray and white matter tissue segmentation can help determine whether tissue loss and disorganization in schizophrenia are primarily the result of a GM deficit or whether abnormalities in WM are also involved. Several studies using segmentation methods have indicated that GM volume reduction characterizes individuals with schizophrenia, whereas the volume of WM is
normal. The reduction in GM is apparent in first-episode, never-treated patients and supports the growing body of work that schizophrenia is a neurodevelopmental disorder (e.g., Gur et al., 1999). In evaluating specific regions, the most consistent findings are of reduced volumes of prefrontal cortex and temporal lobe structures. Other brain regions also noted to have reduced volumes include the parietal lobe, thalamus, basal ganglia, cerebellar vermis, and olfactory bulbs. Relatively few studies have related sublobar volumes to clinical or neurocognitive measures. Available studies, however, support the hypothesis that increased volume is associated with lower severity of negative symptoms and better cognitive performance (e.g., Gur et al., 2000 a, b; Ho et al., 2003). The question of progression of tissue loss has been addressed in relatively few studies and in small samples, reflecting the difficulty of recruiting for study patients in the early stages of illness. Longitudinal studies applying MRI have examined first-episode patients. One group of investigators found no ventricular changes in a follow-up study, conducted 1 to 2 years after the initial study, of 13 patients and 8 controls (De
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greef et al., 1992). Another study evaluated 16 patients and 5 controls, studied 2 years after a first psychotic episode (DeLisi et al., 1991). Patients showed no consistent change in ventricular size with time, although there were individual increases or decreases. With a slightly larger group of 24 patients and 6 controls, no significant changes were observed in ventricular or temporal lobe volume at follow-up (DeLisi et al., 1992). Subsequently, 20 of these patients and 5 controls were rescanned over 4 years, and greater decreases in whole-brain volume and enlargement in left ventricular volume were observed in patients. The authors concluded that subtle cortical changes may occur after the onset of illness, suggesting progression in some cases (DeLisi et al., 1995). In a longitudinal study with a larger sample, 40 patients (20 first-episode, 20 previously treated) and 17 healthy participants were rescanned an average of 2.5 years later. Volumes of whole brain, CSF, and frontal and temporal lobes were measured (Gur, Cowell, et al., 1998). First-episode and previously treated patients had smaller whole-brain, frontal, and temporal lobe volumes than controls at intake. Longitudinally, a reduction in frontal lobe volume was found only in patients, and was most pronounced at the early stages of illness, whereas temporal lobe reduction was seen also in controls. In both first-episode and previously treated patients, volume reduction was associated with decline in some neurobehavioral functions. The question of specificity of neuroanatomic findings to schizophrenia was addressed in a recent study that evaluated 13 patients with first-episode schizophrenia, 15 patients with first-episode affective psychosis (mainly manic), and 14 healthy comparison subjects longitudinally, with scans separated by 1.5 years (Kasai et. al., 2003a). The investigators reported that patients with schizophrenia had progressive decreases in GM volume over time in the left superior temporal gyrus, compared with that in both of the other groups. The existence of neuroanatomical abnormalities in first-episode patients indicates that brain dysfunction occurs before clinical presentation. However, the longitudinal studies suggest evidence of progression, in which anatomic changes may impact some clinical and
neurobehavioral features of the illness in some patients. There is also evidence that progression is significantly greater in early-onset patients during adolescence than it is for adult subjects (Gogate, Giedd, Janson, & Rapoport, 2001). Findings from MRI have been most consistent for GM volume reduction, but more recently, WM changes have also been reported. In the coming years the availability of diffusion tensor imaging will enhance the efforts to examine compartmental abnormalities. The growing understanding of brain development and MRI data obtained from children suggest that the neuroanatomic neuroimaging literature in schizophrenia is consistent with diffuse disruption of normal maturation. Thus, there is clear evidence for structural abnormalities in schizophrenia that are associated with reduced cognitive capacity and less clearly with symptoms. Future work, perhaps with more advanced computerized parcellation methods, is needed to better chart the brain pathways most severely affected.
The electroencephalogram (EEG) measures the electrical activity of the brain; it originates from the summated electrical potentials generated by inhibitory and excitatory inputs onto neurons. The main source of the scalp-recorded EEG is in the cortex of the brain, which contains the large and parallel dendritic trees of pyramidal neurons whose regular ordering facilitates summation. One of the important advances in EEG-based research was the development of a technique to isolate the brain activity related to specific events from the background EEG; this activity related to specific events is termed event-related potentials, or ERPs. Using averaging techniques, it is possible to visualize events related to one of the many different brain operations reflected in the EEG. Typically, these ERPs are related to the specific processing of certain sensory stimuli. In recent years, many new means of measuring brain structure and function have been developed, each with its advantages in study of the brain. Electroencephalographic and ERP measures are unsurpassed in providing real-time,
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millisecond resolution of normal and pathological brain processing, literally at the speed of thought, whereas functional magnetic resonance imaging (fMRI) and PET have temporal resolutions some thousand-fold less. Moreover, fMRI and PET only indirectly track neural activity through its effects on blood flow or metabolism. However, the ability of EEG and ERP techniques to localize sources of activity is much less than that of fMRI and PET, and these methods, together with structural MRI, are needed to supplement EEG and ERP information.
Current Event-Related Potential Research in Schizophrenia
Space limitations preclude discussion of all ERPs. We provide here a sample of current work designed to illuminate a fundamental question in schizophrenia research—namely, how the brains of patients suffering from this disorder differ from those of healthy subjects. Event-related potentials provide a functional window on many aspects of brain processing. These include the most elementary ones, likely involving cellular circuitry (gamma band activity), early, simple signal detection and gating (P50), and automatic detection of changes in the environment (mismatch negativity activity), and more complex activity such as conscious updating of expectations in view of unusual events (P300). In this section we will first briefly review studies of ERP processes in adults with schizophrenia that illustrate the potential of these measures to provide clues about the cellular circuitry that may be impaired in schizophrenia. The auditory modality plays a special role because it is severely affected in schizophrenia, as evinced in the primacy of auditory hallucinations and speech and language pathology. The data presented here support the hypothesis that schizophrenia involves abnormalities in brain processing from the most simple to the most complex level, and that the anatomical substrates of auditory processing in the neocortical temporal lobe, most carefully investigated in the superior temporal gyrus, themselves evince reduction in GM volume. Next, we briefly summarize a series of studies of adolescents with schizophrenia in which ERPS are recorded while the youngsters perform
poorly on cognitive tasks that make extensive demands on processing resources. These studies use ERPs in an attempt to identify the earliest stage of cognitive processing at which deficits emerge in adolescents with schizophrenia.
Gamma-band activity and neural circuit abnormalities at the cellular level.
The first ERP we will consider is the steady-state gamma-band response. Gamma band refers to a brain oscillation at and near the frequency of 40 Hertz (Hz) or 40 times per second; steady-state refers to its being elicited by a stimulus of the same frequency. At the cellular level, gamma-band activity is an endogenous brain oscillation thought to reflect the synchronizing of activity in several columns of cortical neurons, or between cortex and thalamus, with this synchronization facilitating communication. At the cognitive level, work in humans suggests that gamma activity reflects the convergence of multiple processing streams in cortex, giving rise to a unified percept. A simple example is a “fire truck”; a particular combination of form perception, motion perception, and auditory perception are melded to form this percept. Gamma activity at its simplest, however, involves basic neural circuitry composed of projection neurons, usually using excitatory amino acid (EAA) neurotransmission, linked with inhibitory gamma-aminobutyric acid (GABA)ergic interneurons. Studies of gamma activity in schizophrenia aim to determine if there is a basic circuit abnormality present, such as might arise from a deficiency in recurrent inhibition, postulated by a number of workers (see review in McCarley, Hsiao, Freedman, Pfefferbaum, & Donchin, 1996). Gamma-band studies themselves, however, cannot reveal any specific details of neural circuitry abnormality. Kwon and colleagues ( 1999) began the study of gamma in schizophrenia using an exogenous input of 40-Hz auditory clicks, leading to a steady-state gamma response. The magnitude of the brain response was measured by power, the amount of EEG energy at a specific frequency, with the degree of capability of gamma driving being reflected in the power at and near 40 Hz. Compared with healthy controls, schizophrenia patients had a markedly reduced power at 40-Hz input, although they showed normal driving at slower frequencies, which indicated that this
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doi:10.1093/9780195173642.003.0006
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![Figure 5.2 Compartmental volumes of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) from birth [from Matsuzawa. J., Matsui, M., Konishi, T., Noguci, K., Gur, R.C., Bilker, W., & Miyawaki, T. (2001). Age-related volumetric changes of brain gray and white matter in healthy infants and children. Cerebral Coretex, 11, 335–342, used with permission].](/anbrg/public/mentalhealth/9780195173642/figures/graphic008.gif)
