Progressive Brain Changes Research Articles

The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia.

Kraepelin originally defined dementia praecox as a progressive brain disease, although this concept has received various degrees of acceptance and rejection over the years since his famous published textbooks appeared. This article places an historical perspective on the current renewal of Kraepelin's concept in brain imaging literature that supports progressive brain change in schizophrenia from its earliest stages through its chronic course. It is concluded that a great deal of future research is needed focusing on the longitudinal course of change, the extent to the regions of change within each individual and the underlying mechanism and implications of brain change through functional and neurochemical imaging, combined with structural studies in the same individuals.

Imaging Mental Disorders in the 21st Century

Computer-based brain-imaging technologies were introduced into medicine beginning in the 1970s, with the introduction of computed axial tomography (CAT or CT) and, subsequently, magnetic resonance imaging (MRI), magnetic resonance spectroscopy, functional MRI, positron emission tomography (PET), and single photon emission computed tomography (SPECT). These technologies have revolutionized the practice of neurology but, to date, have had less impact on the practice of psychiatry. Nevertheless, brain imaging has become an increasingly important area of psychiatric research over the past 30 years and is beginning to influence how we understand psychiatric illness and how it should be treated. Brain imaging arrived on psychiatry's doorstep when explanatory models for psychiatric illness were in transition. The introduction of the first generation of psychotropic medications challenged the field to address biological determinants of mental illness, as did the emergence of new research establishing that many major mental illnesses have a high degree of heritability. CT and MRI captured the imagination of the field by their ability to visually present the 3-dimensional structure of the brain-as if this might settle once and for all whether illnesses such as schizophrenia are really brain diseases. The search for the structural basis of schizophrenia offers a useful example of how brain imaging informs our understanding of the illnesses we psychiatrists treat. That CT scanning revealed chronically ill patients with schizophrenia to have enlarged lateral ventricles1 brought to the fore the need to understand the disorder's underlying neurobiology. Subsequent studies have led us to understand that structural brain changes are anything but simple; they point to a model of dis ease that should cause us to challenge many of our assumptions about schizophrenia. Although the magnitude of the ventricular enlargement and subsequently described gray matter volume deficits in schizophrenia2 had a medium effect size, further studies revealed that these differences were greatest in patients who had been ill for longer periods and in those who were more severely affected.3 The extent to which illness duration, compared with illness severity, contributes to the magnitude of structural brain abnormalities observed remains an important topic of debate, as these factors are often confounded. Several longitudinal studies have provided evidence for progressive brain changes in patients with schizophrenia,4,5 reinforcing the Kraepelinian conceptualization of schizophrenia as a progressive, deteriorating illness. However, other studies have failed to find that brain abnormalities significantly progressed over time,6,7 which should cause us to ask in what ways schizophrenia should be understood as a progressive illness. Longitudinal studies of patients presenting with a first episode of schizophrenia provide clear support for ongoing clinical improvement over time, rather than worsening of symptoms, cognition, and community functioning.8,9 Relapses, which are all too frequent in schizophrenia, are more determined by medication nonadherence than by the natural history of the illness. The magnitude of structural brain abnormalities and the degree to which they change over time may to some degree reflect risk but are likely to be only minor determinants of the variance in outcome. That some of the brain differences observed might be related to medication exposure, nutrition, endocrine changes, or differences in activity levels cannot yet be excluded.10 Thus, although some might assume that identifying structural brain abnormalities in patients with schizophrenia could contribute to our pessimism about treatment outcomes, the very modest magnitude of these findings, the overwhelming degree of overlap with the normal population, and the questionable progression of these changes over time should cause us to question this interpretation. How structural brain abnormalities relate to the biology of other major mental disorders such as depression, bipolar disorder, posttraumatic stress disorder, and anorexia nervosa has also been a major focus of psychiatric research. …

Schizophrenia is a disorder of aberrant neurodevelopment: A synthesis of evidence from clinical and structural, functional and neurochemical brain imaging studies

Byline: Ganesan. Venkatasubramanian Schizophrenia as a Disorder of Aberrant Neurodevelopment Several reasons have been advanced to support the view that schizophrenia is a neurodevelopmental disorder.[sup] [1] The primary reason is that the onset of schizophrenia has a cumulative age incidence distribution or developmental function, that is nonlinear with a peak change in slope or acceleration that usually takes to occur during young adulthood. Given the plausibility of the existence of brain abnormalities in schizophrenia at the onset of the illness, it further seems reasonable to conceive the onset of schizophrenia as a neurodevelopmental disorder. Further support has been provided by epidemiological studies showing premorbid intellectual deficits dating back to the early development[sup] [2] and neuropathological studies showing altered cerebral cytoarchitecture indicative of a developmental rather that acquired encephalopathy.[sup] [3] The main neurodevelopmental hypotheses for schizophrenia set forth in the last 10 years are relatively restricted and share three assumptions:[sup] [4] *The primary pathogenetic defect is an early derangement of the orderly development of the central nervous system that occurs in the pre- or perinatal period; *The period of active operation of the causative agent is of short duration, meaning that it is essentially static; *The behavioral consequences of this static process remain relatively latent until long after the primary pathogenetic process has run its course. Furthermore, aspects of illness suggesting neurodevelopmental deviation may not apply to all individuals and some authors have argued for neurodevelopmental and non-neurodevelopmental subtypes of the disorder[sup] [5] and even neurodegenerative subtypes of the disorder.[sup] [6] However, neurodegenerative hypotheses of schizophrenia have been criticized mainly because of the following reason: gliosis, which is regarded as a necessary neuropathological hallmark of neuronal degeneration, has not been found in a number of carefully controlled postmortem studies in patients with schizophrenia. These neuropathological studies provide strong evidence against a classic neurodegenerative pathogenesis of schizophrenia.[sup] [1],[4] In addition, the failure of the first prospective CT studies of schizophrenia to show the same age-disproportionate progressive increase in ventricle-brain ratio after onset of illness that is seen in disorders such as Huntington's disease also rejects neurodegeneration.[sup] [4] Some researchers have proposed another alternative that schizophrenia is a progressive neurodevelopmental disorder. This postulates that developmental mechanisms, such as apoptosis and pruning, can continue to go awry over many years without resulting in excessive gliosis. This accounts for both the neuropathological findings implicating prenatal pathology and the imaging findings (especially the recent Magnetic Resonance Imaging studies that report evidence for progressive brain changes in schizophrenia).[sup] [4] Thus, although schizophrenia is argued by a few as a neurodegenerative disorder,[sup] [6],[7] majority of the existing evidence points towards a neurodevelopmental etiopathogenesis.[sup] [1],[4] Neurodevelopmental Hypothesis of Schizophrenia - Evidence Base The tenets of the neurodevelopmental hypothesis of schizophrenia derive from observations of epidemiological, clinical and brain imaging evidence for neurodevelopmental deviance.[sup] [8] These include studies on schizophrenia patients examining obstetrical complications, age-at-onset (AAO), sex differences, minor physical anomalies (MPAs), neurological soft signs (NSS) and structural brain abnormalities. Other stigmata include abnormal dermatoglyphics and childhood neuromotor precursors of adult schizophrenic illness. This research paper attempts at providing an overview of evidence for neurodevelopmental basis for schizophrenia with specific focus on highlighting relevant Indian studies supporting this concept. …

Could linear MRI measurements of hippocampus differentiate normal brain aging in elderly persons from Alzheimer disease?

Although mild progressive specific structural brain changes are commonly associated with normal human aging, it is unclear whether automatic or manual measurements of these structures can differentiate normal brain aging in elderly persons from patients suffering from cognitive impairment. The objective of this study was primarily to define, with a standard high resolution MRI, the range of normal linear age-specific values for the hippocampal formation (HF), and secondarily to differentiate hippocampal atrophy in normal aging from that occurring in Alzheimer disease (AD). Two MRI-based linear measurements of the hippocampal formation at the level of the head and of the tail, standardized by the cranial dimensions, were obtained from coronal and sagittal T1-weighted MR images in 25 normal elderly subjects, and 26 patients with AD. In this study, dimensions of the HF have been standardized and they revealed normal distributions for each side and each sex: the width of the hippocampal head at the level of the amygdala was 16.42 +/- 1.9 mm, and its height 7.93 +/- 1.4 mm; the width of the tail at the level of the cerebral aqueduct was 8.54 +/- 1.2 mm, and the height 5.74 +/- 0.4 mm. There were no significant differences in standardized dimensions of the HF between sides, sexes, or in comparison to head dimensions in the two groups. In addition, the median inter-observer agreement index was 93%. In contrast, the dimensions of the hippocampal formation decreased gradually with increasing age, owing to physiological atrophy, but this atrophy is more significant in the group of AD.

Neurogenesis in adolescent brain is potently inhibited by ethanol

Adolescence is a period of progressive changes in brain that likely contribute to the maturation of behavior. Human adolescents consume large amounts of ethanol. To investigate the effects of ethanol on adolescent neural progenitor cells, male rats (35–40 days old) were treated with an acute dose of ethanol (1.0, 2.5 or 5.0g/kg, i.g.) or vehicle that resulted in peak blood levels of 33, 72, and 131 mg/dl, respectively. Bromodeoxyuridine (300mg/kg i.p.) was administered to label dividing cells and rats were killed at 5 h to assess proliferation or at 28 days to assess cell survival and differentiation. After 5 h, bromodeoxyuridine-immunoreactivity was reduced by 63, 97 and 99% in the rostral migratory stream and 34, 71 and 99% in the subventricular zone by 1.0, 2.5 and 5.0g/kg of ethanol respectively. In the dentate gyrus, ethanol reduced bromodeoxyuridine-immunoreactivity by 29, 40, and 78% at the three doses respectively. The density of doublecortin immunoreactivity was decreased after 3 days and the number of bromodeoxyuridine+ cells remained decreased at 28 days when most hippocampal bromodeoxyuridine+ cells coexpressed neuronal nuclei, a neuronal marker. These studies indicate that the adolescent brain is very sensitive to acute ethanol inhibition of neurogenesis.

The neurodevelopmental model of schizophrenia: update 2005

Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.

S.26.04 Progressive brain changes in schizophrenia as an endophenotype

S.26.04 Progressive brain changes in schizophrenia as an endophenotype

S.3.2 Progressive brain changes in schizophrenia as an endophenotype

S.3.2 Progressive brain changes in schizophrenia as an endophenotype

Early and late neurodevelopmental disturbances in schizophrenia and their functional consequences.

The evidence from structural imaging studies supports the notion that schizophrenia arises from an early abnormality in brain development. In this paper we review the timing of structural changes in schizophrenia and argue that schizophrenia is a neuro-developmental disorder with limited progressive brain changes occurring during the evolution and early phase of psychosis. The available cross-sectional and longitudinal studies are reviewed, along with data from our own research. The current literature, including our own data, suggests that structural brain changes are apparent premorbidly, consistent with a neurodevelopmental lesion. These are prominent in frontal and cingulate regions, and appear related to premorbid neuropsychological deficits in executive function. However, there appear to be additional brain changes over the transition to illness and beyond. We propose first, that an early neurodevelopmental insult interacts with either normal or abnormal postpubertal brain maturation to produce further (late neurodevelopmental) brain structural and functional changes; and second, that the effect of such neurodevelopmental lesions will have different consequences for functions that normally develop early in life, such as memory, compared with functions developing later, such as executive functions. A model is presented suggesting that the structural and functional abnormalities in schizophrenia can be understood as a consequence of the neurodevelopmental stage at which brain changes occur.

Evidence for non-progressive changes in adolescent-onset schizophrenia: follow-up magnetic resonance imaging study.

It is not clear how far brain abnormalities in early-onset schizophrenia result from progressive neurodevelopmental or neurodegenerative processes. Aims To investigate the hypothesis that structural brain abnormalities in adolescent-onset schizophrenia are progressive in the early phase of the illness. A magnetic resonance imaging case-control study of 16 adolescents with schizophrenia (mean age 16.6 years, s.d.=1.9 years) with a mean time of 2.7 years (s.d.=1.7 years) between measurements and 16 matched controls (average age 16.0 years, s.d.=2.0 years) with a mean time of 1.7 years (s.d.=0.5 years) between measurements. There was no evidence of progressive structural brain changes during late adolescence. Significant ventricular enlargement (greater in males) and left-sided temporal lobe changes were evident from the outset of the illness. Neurodevelopmental brain abnormalities are non-progressive during late adolescence.

Longitudinal study of brain morphology in first episode schizophrenia

Background: Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up. Methods: To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up. Results: Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time. Conclusions: The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.

A review of MRI studies of progressive brain changes in schizophrenia.

In the early twentieth century, when Kraepelin first described ‘dementia praecox’ which eventually evolved into the concept of schizophrenia, he proposed that dementia praecox was probably an unknown organic brain disease. However, in contrast to the case of Alzheimer’s disease and Huntington’s disease, subsequent pathological studies of the brain failed to establish the neuropathology of schizophrenia. As a result, it had been generally accepted that schizophrenia would be a functional psychosis with neurochemical aberrations but without organic abnormalities. In 1976, Johnstone et al first reported the computerassisted tomography (CT) finding of lateral ventricular enlargement in patients with schizophrenia. This finding has been replicated in a number of CT studies and has been recognized as representing brain structural abnormalities in schizophrenia. Magnetic resonance imaging (MRI) enables more detailed and quantitative assessments of the fine brain structures, providing considerable evidence for the view that schizophrenia is a brain disorder with structural brain abnormalities.

Cognitive impairment in elderly patients with schizophrenia: age related changes.

Cognitive impairment in schizophrenia is a major feature of the illness. Like many of the other aspects of the illness, however, it has not been studied extensively in older patients. Several studies of older patients with a lifetime course of poor outcome and chronic institutional stay have indicated that some patients manifest evidence of profound cognitive impairments on a cross-sectional basis and cognitive and functional decline over longitudinal follow-ups of 30 months or longer. Risk factors for this decline include lower educational attainment and more severe positive symptoms, but do not include more severe symptoms of physical illness. These impairments have been shown to be discriminable from normal age-related changes and from the changes associated with Alzheimer's Disease. In contrast, studies of patients with no history of lifetime institutional stay find no such evidence of either age-related changes in cognitive functioning or longitudinal decline in cognitive or functional status. Since there is accumulating evidence of progressive brain changes over the lifespan in patients with schizophrenia, the course of cognitive deficits in later life will remain an important topic, both for understanding the lifetime course of schizophrenia and for developing interventions aimed at reduction of disability in the illness.

Serial magnetic resonance imaging of rat brain after induction of renal hypertension.

Hypertension is a major risk factor for ischemic and hemorrhagic stroke and may also cause more chronic and subtle brain injury. Progressive brain changes in a rat model of renal hypertension have been assessed to better understand the pathogenesis of hypertensive brain damage. Young adult rats were made hypertensive by partial occlusion of both renal arteries. MR images of brain were obtained weekly, and histopathological outcome was assessed. A separate group of rats was used to measure brain specific gravity and Evans blue dye content as an indicator of extravasation. Rats developed maximal mean systolic blood pressures of 173 to >300 mm Hg, reaching a plateau in 6 to 8 weeks. Rats whose mean systolic pressure never exceeded 210 mm Hg never had brain lesions, while rats whose mean systolic pressure exceeded 276 mm Hg consistently developed brain lesions. Brain T2 values increased with increasing blood pressure. Lesions seen on MRI corresponded to those seen histologically. MRI also demonstrated transient brain expansion, probably due to diffusely increased water content, and rarely demonstrated focal cortical edema, which had no histological correlate. These transient phenomena, as well as hemorrhagic and ischemic infarcts, occurred mainly during the phase of climbing blood pressure and early stages of stable hypertension. Serial MRI reveals aspects of hypertensive brain disease that cannot be studied by histological examination alone. The observed phenomena are likely related to loss of autoregulation and/or blood-brain barrier integrity. Breach of blood vessel integrity is less likely once the vessels become accustomed to high pressures.

Childhood-onset schizophrenia: progressive brain changes during adolescence

Background: Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus. Methods: Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences. Results: Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group. Conclusions: These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia.

Resident's Guide to Treatment of People With Chronic Mental Illness: Report 136

Resident's Guide to Treatment of People With Chronic Mental Illness: Report 136

Biochemical and histopathological changes in the brains of mice inoculated with scrapie by the intraperitoneal route

Groups of mice were inoculated by the intraperitoneal route with suspensions of scrapie or normal brain, respectively. A study was made throughout the incubation period of a number of abnormalities which are known to occur preclinically in mice inoculated by the intracerebral route. The titre of scrapie agent in brain increased progressively starting at 4 weeks after inoculation and clinical signs appeared at 19 weeks. There was no evidence that an increased number of glial cells which synthesise DNA occurred in the brains of mice inoculated intraperitoneally, a finding in marked contrast to previous results with intracerebrally-inoculated mice. The other abnormalities studied, namely, vacuolation, astrocyte hypertrophy, increased incorporation of [ 3H] thymidine into whole brain DNA and increased activities of acid deoxyribo-nuclease, β-glucuronidase and N-acetyl-β-D-glucosaminidase, all showed progressive changes in scrapie brain starting 12 to 14 weeks after inoculation. Quantitatvely, the changes seen after intraperitoneal inoculation were the same as those found previously after intracerebral inoculation but there were some definite differences in the distribution of lesions. A comparison of the present results with previously published data suggests that once the agent starts to accumulate in brain the development of lesions and of the clinical disease follows a similar pattern, irrespective of the route of inoculation. The increased length of the incubation period after intraperitoneal inoculation corresponds with the delay before the agent reaches the brain.