For many years the cerebellum has been considered to serve as a coordinator of motor function. Likewise, for many years schizophrenia has been considered to be a disease that primarily affects the cerebrum. This review summarizes recent evidence that both these views must be revised in the light of emerging evidence about cerebellar function and the mechanisms of schizophrenia. Evidence indicating that the cerebellum plays a role in higher cortical functions is summarized. Evidence indicating that cerebellar abnormalities occur in schizophrenia is also reviewed. These suggest interesting directions for future research. Recent Evidence for the Role of the Cerebellum in CognitionThe tentorium was once the Maginot Line of the brain. Supratentorial regions governed "higher cortical functions," while the humble subtentorial cerebellum performed "lower" functions unrelated to cognition. Recent evidence has illustrated the possible falsity of this dichotomy and has led to a growing group of neuroscientists to reconceptualize the cerebellum as a key player in higher cognitive functions (2; 3; 7-15).One line of evidence for the importance of the cerebellum in cognition arises from evolutionary and developmental neurobiology. Two regions in the human brain are massively larger (by approximately 1/3) than in other higher primates who lack human capacities for complex language, high-level abstract concept formation, the creation of art in its many various forms, and social constructs such as government structure and economic principles. One region is obvious: the prefrontal cortex. The other would not be predicted by most: the cerebellum (16). Why did this convergent expansion occur? One likely explanation is that these two regions work together to perform the variety of "higher cognitive" tasks executed by the ingenious human brain.Anatomical support for the "cerebellar cognitive theory" has been provided by a group of careful tract-tracing studies (17-23). In particular, Strick's group has been applying retrograde and anterograde tract-mapping with herpes and rabies viruses for more than a © 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.Address correspondence to: Dr. Nancy C. Andreasen, The University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Room W278 GH, Iowa City, IA 52242-1057, Phone: 319-356-1553. Financial Disclosures: Dr. Andreasen is employed by The University of Iowa. This research was supported by NIH grants to her (5 R01 MH 04856 -20 and 5 R01 MH060990 -09). She has no other biomedical financial interests relevant to the subject matter of this review. Mr. Pierson is employed by the University of Iowa. His research contribution was also supported by NIH grants (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). He has no other biomedical financial interests relevant to the subject matter of this review.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are pro...

In addition to its well established role in balance, coordination, and other motor skills, the cerebellum is increasingly recognized as a prominent contributor to a wide array of cognitive and emotional functions. Many of these capacities undergo dramatic changes during childhood and adolescence. However, accurate characterization of co-occurring anatomical changes has been hindered by lack of longitudinal data and methodologic challenges in quantifying subdivisions of the cerebellum. In this study we apply an innovative image analysis technique to quantify total cerebellar volume and 11 subdivisions (i.e. anterior, superior posterior, and inferior posterior lobes, corpus medullare, and three vermal regions) from anatomic brain MRI scans from 25 healthy females and 25 healthy males aged 5-24 years, each of whom was scanned at least three times at approximately two year intervals. Total cerebellum volume followed an inverted U shaped developmental trajectory peaking at age 11.8 years in females and 15.6 years in males. Cerebellar volume was 10% to 13% larger in males depending on the age of comparison and the sexual dimorphism remained significant after covarying for total brain volume. Subdivisions of the cerebellum had distinctive developmental trajectories with more phylogenetically recent regions maturing particularly late. The cerebellum's unique protracted developmental trajectories, sexual dimorphism, preferential vulnerability to environmental influences, and frequent implication in childhood onset disorders such as autism and ADHD make it a prime target for pediatric neuroimaging investigations.

Context Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain. Objective To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change. Design Predictors of brain volume changes were assessed prospectively based on multiple informants. Setting Data from the Iowa Longitudinal Study. Patients Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years). Main Outcome Measure Brain volumes. Results During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted. Conclusions Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.

Background Schizophrenia has a characteristic onset during adolescence or young adulthood but also tends to persist throughout life. Structural magnetic resonance studies indicate that brain abnormalities are present at onset, but longitudinal studies to assess neuroprogression have been limited by small samples and short or infrequent follow-up intervals. Methods The Iowa Longitudinal Study is a prospective study of 542 first-episode patients who have been followed up to 18 years. In this report, we focus on those patients (n = 202) and control subjects (n = 125) for whom we have adequate structural magnetic resonance data (n = 952 scans) to provide a relatively definitive determination of whether progressive brain change occurs over a time interval of up to 15 years after intake. Results A repeated-measures analysis showed significant age-by-group interaction main effects that represent a significant decrease in multiple gray matter regions (total cerebral, frontal, thalamus), multiple white matter regions (total cerebral, frontal, temporal, parietal), and a corresponding increase in cerebrospinal fluid (lateral ventricles and frontal, temporal, and parietal sulci). These changes were most severe during the early years after onset. They occur at severe levels only in a subset of patients. They are correlated with cognitive impairment but only weakly with other clinical measures. Conclusions Progressive brain change occurs in schizophrenia, affects both gray matter and white matter, is most severe during the early stages of the illness, and occurs only in a subset of patients. Measuring severity of progressive brain change offers a promising new avenue for phenotype definition in genetic studies of schizophrenia.

Objective As therapeutics are being developed to target the underlying neuropathology of Huntington disease (HD), interest is increasing in methodologies for conducting clinical trials in the prodromal phase. This study was designed to examine the potential utility of structural MRI measures as outcome measures for such trials. Methods Data are presented from 211 prodromal individuals and 60 controls, scanned both at baseline and two-year follow-up. Prodromal participants were divided into groups based on proximity to estimated onset of diagnosable clinical disease: Far (>15 years from estimated onset); Mid (9–15 years); and Near (<9 years). Volumetric measurements of caudate, putamen, total striatum, globus pallidus, thalamus, total gray and white matter, and CSF were performed. Results All prodromal groups showed a faster rate of atrophy than Controls in striatum, total brain, and cerebral white matter (especially in the frontal lobe). Neither prodromal participants nor Controls showed significant longitudinal change in cortex (either total cortical gray or within individual lobes). When normal age-related atrophy (i.e., change observed in the Control group) was taken into account, there was more statistically significant disease-related atrophy in white matter than in striatum. Conclusion Measures of volume change in striatum and white matter volume, particularly in the frontal lobe, may serve as excellent outcome measures for future clinical trials in prodromal HD. Clinical trials using white matter or striatal volume change as an outcome measure will be most efficient if the sample is restricted to individuals who are within 15 years of estimated onset of diagnosable disease.

Previous MRI studies with participants prior to manifest Huntington disease have been conducted in small single-site samples. The current study reports data from a systematic multi-national study during the prodromal period of Huntington disease and examines whether various brain structures make unique predictions about the proximity to manifest disease. MRI scans were acquired from 657 participants enrolled at one of 32 PREDICT-HD research sites. Only prodromal Huntington disease participants (those not meeting motor criteria for diagnosis) were included and subgrouped by estimated diagnosis proximity (Near, Mid, and Far) based upon a formula incorporating age and CAG repeat length. Results show volumes of all three subgroups differed significantly from Controls for total brain tissue, cerebral spinal fluid, white matter, cortical gray matter, thalamus, caudate, and putamen. Total striatal volume demonstrated the largest differences between Controls and all three prodromal subgroups. Cerebral white matter offered additional independent power in the prediction of estimated proximity to diagnosis. In conclusion, this large cross-sectional study shows that changes in brain volume are detectable years to decades prior to estimated motor diagnosis of Huntington disease. This suggests that a clinical trial of a putative neuroprotective agent could begin as much as 15 years prior to estimated motor diagnosis in a cohort of persons at risk for but not meeting clinical motor diagnostic criteria for Huntington disease, and that neuroimaging (striatal and white matter volumes) may be among the best predictors of diagnosis proximity.

SummaryWhile the role of the cerebellum in motor coordination is widely accepted, the notion that it is involved in emotion has only recently gained popularity. To date, functional neuroimaging has not been used in combination with lesion studies to elucidate the role of the cerebellum in the processing of emotional material. We examined six participants with cerebellar stroke and nine age and education matched healthy volunteers. In addition to a complete neuropsychological, neurologic, and psychiatric examination, participants underwent [ 15 O]water positron emission tomography (PET) while responding to emotion-evoking visual stimuli. Cerebellar lesions were associated with reduced pleasant experience in response to happiness-evoking stimuli. Stroke patients reported an unpleasant experience to frightening stimuli similar to healthy controls, yet showed significantly lower activity in the right ventral lateral and left dorsolateral prefrontal cortex, amygdala, thalamus, and retrosplenial cingulate gyrus. Frightening stimuli led to increased activity in the ventral medial prefrontal, anterior cingulate, pulvinar, and insular cortex. This suggests that alternate neural circuitry became responsible for maintaining the evolutionarily critical fear response after cerebellar damage.

The large amount of imaging data collected in several ongoing multi-center studies requires automated methods to delineate brain structures of interest. We have previously reported on using artificial neural networks (ANN) to define subcortical brain structures. Here we present several automated segmentation methods using multidimensional registration. A direct comparison between template, probability, artificial neural network (ANN) and support vector machine (SVM)-based automated segmentation methods is presented. Three metrics for each segmentation method are reported in the delineation of subcortical and cerebellar brain regions. Results show that the machine learning methods outperform the template and probability-based methods. Utilization of these automated segmentation methods may be as reliable as manual raters and require no rater intervention.