Three-year longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder.

OBJECTIVE: The longitudinal course of neuropsychological functioning after the first manic episode in bipolar disorder is unknown. The present study evaluated cognitive change in bipolar disorder in the first 3 years after the initial manic episode. METHODS: Ninety-one newly diagnosed patients with bipolar disorder and 61 demographically similar healthy participants received a neuropsychological evaluation assessing multiple cognitive domains at baseline, 1-year, and 3-year time points. Patients also received clinical assessments including mood ratings at all time points. RESULTS: Patients showed deficits in all domains at baseline, but similar longitudinal trajectories across time relative to healthy participants in most cognitive domains. For processing speed, patients showed more gains than controls from baseline to 1 year, but these gains stabilized thereafter. Patients with alcohol/substance abuse showed an initial delay but subsequent recovery in executive functioning. Patients who discontinued antipsychotic treatment showed better cognitive outcomes in verbal memory. CONCLUSION: Appropriately treated patients with bipolar disorder showed favorable cognitive outcome in the first 3 years after experiencing an initial manic episode, arguing against cognitive neuroprogression at this stage of the illness. Discontinuation of antipsychotic treatment may be associated with better cognitive outcomes, but clarification of the role of antipsychotics on cognitive functioning requires further investigation.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Changes in brain-behavior relationships following a 3-month pilot cognitive intervention program for adults with traumatic brain injury.

Facilitating functional recovery following brain injury is a key goal of neurorehabilitation. Direct, objective measures of changes in the brain are critical to understanding how and when meaningful changes occur, however, assessing neuroplasticity using brain based results remains a significant challenge. Little is known about the underlying changes in functional brain networks that correlate with cognitive outcomes in traumatic brain injury (TBI). The purpose of this pilot study was to assess the feasibility of an intensive three month cognitive intervention program in individuals with chronic TBI and to evaluate the effects of this intervention on brain-behavioral relationships. We used tools from graph theory to evaluate changes in global and local brain network features prior to and following cognitive intervention. Network metrics were calculated from resting state electroencephalographic (EEG) recordings from 10 adult participants with mild to severe brain injury and 11 age and gender matched healthy controls. Local graph metrics showed hyper-connectivity in the right inferior frontal gyrus and hypo-connectivity in the left inferior frontal gyrus in the TBI group at baseline in comparison with the control group. Following the intervention, there was a statistically significant increase in the composite cognitive score in the TBI participants and a statistically significant decrease in functional connectivity in the right inferior frontal gyrus. In addition, there was evidence of changes in the brain-behavior relationships following intervention. The results from this pilot study provide preliminary evidence for functional network reorganization that parallels cognitive improvements after cognitive rehabilitation in individuals with chronic TBI.

Diagnosis and body mass index effects on hippocampal volumes and neurochemistry in bipolar disorder.

We previously reported that higher body mass index (BMI) was associated with greater hippocampal glutamate+glutamine in people with bipolar disorder (BD), but not in non-BD healthy comparator subjects (HSs). In the current report, we extend these findings by examining the impact of BD diagnosis and BMI on hippocampal volumes and the concentrations of several additional neurochemicals in 57 early-stage BD patients and 31 HSs. Using 3-T magnetic resonance imaging and magnetic resonance spectroscopy, we measured bilateral hippocampal volumes and the hippocampal concentrations of four neurochemicals relevant to BD: N-acetylaspartate+N-acteylaspartylglutamate (tNAA), creatine+phosphocreatine (Cre), myoinositol (Ins) and glycerophosphocholine+phosphatidylcholine (Cho). We used multivariate factorial analysis of covariance to investigate the impact of diagnosis (patient vs HS) and BMI category (normal weight vs overweight/obese) on these variables. We found a main effect of diagnosis on hippocampal volumes, with patients having smaller hippocampi than HSs. There was no association between BMI and hippocampal volumes. We found diagnosis and BMI effects on hippocampal neurochemistry, with patients having lower Cre, Ins and Cho, and overweight/obese subjects having higher levels of these chemicals. In patient-only models that controlled for clinical and treatment variables, we detected an additional association between higher BMI and lower tNAA that was absent in HSs. To our knowledge, this was the first study to investigate the relative contributions of BD diagnosis and BMI to hippocampal volumes, and only the second to investigate their contributions to hippocampal chemistry. It provides further evidence that diagnosis and elevated BMI both impact limbic brain areas relevant to BD.

Lower cognitive functioning as a predictor of weight gain in bipolar disorder: a 12-month study.

OBJECTIVE: In cross-sectional studies, elevated body mass index (BMI) is associated with cognitive impairment in bipolar disorder (BD). We investigated the direction of this association by prospectively examining changes in BMI and cognition. METHOD: We measured BMI and performance in six cognitive domains over 12 months in 80 adolescent and young adult BD patients and 46 healthy comparison subjects (HS). Ninety-three percent of patients received pharmacotherapy and 84% were euthymic. We used repeated-measures ancova and longitudinal mixed models to investigate whether (i) higher BMI and increasing BMI over time predicted lower subsequent cognitive functioning, and (ii) lower cognitive functioning and changes in cognition predicted increasing BMI. RESULTS: Neither baseline BMI nor BMI change predicted lower cognitive functioning. Lower baseline scores in attention, verbal memory, working memory, and a composite measure of global cognition predicted increasing BMI in patients and HS. In patients, lower cognitive functioning remained associated with increasing BMI when clinical and treatment variables were adjusted for. Improvement in working memory predicted a smaller subsequent BMI increase in patients. CONCLUSION: Lower cognitive functioning in specific domains predicts increasing BMI in patients with BD and healthy young adults. Targeting cognition may be important for minimizing weight gain in BD.

Childhood maltreatment and corpus callosum volume in recently diagnosed patients with bipolar I disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

Childhood trauma (CT) has been associated with abnormalities in the corpus callosum (CC). Decreased CC volumes have been reported in children and adolescents with trauma as well as adults with CT compared to healthy controls. CC morphology is potentially susceptible to the effects of Bipolar Disorder (BD) itself. Therefore, we evaluated the relationship between CT and CC morphology in BD. We using magnetic resonance imaging in 53 adults with BD recently recovered from their first manic episode, with (n = 23) and without (n = 30) CT, defined using the Childhood Trauma Questionnaire (CTQ) and 16 healthy controls without trauma. ANCOVA was performed with age, gender and intracranial volume as covariates in order to evaluate group differences in CC volume. The total CC volume was found to be smaller in BD patients with trauma compared to BD patients without trauma (p < .05). The differences were more pronounced in the anterior region of the CC. There was a significant negative correlation between CTQ scores and total CC volume in BD patients with trauma (p = .01). We did not find significant differences in the CC volume of patients with/without trauma compared to the healthy subjects. Our sample consists of patients recovered from a first episode of mania and are early in the course of illness and reductions in CC volume may occur late in the course of BD. It might mean there may be two sources of CC volume reduction in these patients: the reduction due to trauma, and the further reduction due to the illness.

The impact of childhood trauma on cognitive functioning in patients recently recovered from a first manic episode: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).

BACKGROUND: Both bipolar disorder (BD) and childhood trauma are associated with cognitive impairment. People with BD have high rates of childhood trauma, which confer greater overall disease severity, but, it is unknown if childhood trauma is associated with greater neurocognitive impairment in BD patients early in the course of their illnesses. In this study, we investigated the impact of childhood trauma on specific cognitive dysfunction in patients who recently recovered from their first episode of mania. METHODS: Data were available for 64 patients and 28 healthy subjects matched by age, gender and pre-morbid IQ, recruited from a large university medical center. History of childhood trauma was measured using the Childhood Trauma Questionnaire. Cognitive function was assessed through a comprehensive neuropsychological test battery. RESULTS: Trauma was associated with poorer cognitive performance in patients on cognitive measures of IQ, auditory attention and verbal and working memory, and a different pattern was observed in healthy subjects. LIMITATIONS: We had a modest sample size, particularly in the group of healthy subjects with trauma. CONCLUSIONS: Childhood trauma was associated with poorer cognition in BD patients who recently recovered from a first episode of mania compared to healthy subjects. The results require replication, but suggest that the co-occurrence of trauma and bipolar disorder can affect those cognitive areas that are already more susceptible in patients with BD.

Relationship between cognitive functioning and 6-month clinical and functional outcome in patients with first manic episode bipolar I disorder.

BACKGROUND: Although cognitive deficits in bipolar disorder have been associated with diminished functional outcome, this relationship has been studied primarily through cross-sectional designs, and has not been studied in patients early in the course of illness. The purpose of this study was to evaluate the impact of cognitive functioning on longitudinal 6-month functional and clinical outcome in recently diagnosed clinically stable patients with bipolar disorder. METHOD: A total of 53 recently diagnosed patients with DSM-IV bipolar disorder type I were assessed within 3 months of their first manic episode using a neuropsychological battery measuring verbal/pre-morbid intellectual functioning, learning/memory, spatial/non-verbal reasoning, attention/processing speed and executive function. Functional outcome was assessed at baseline and 6 months using the Multidimensional Scale of Independent Functioning (MSIF) and DSM-IV Global Assessment of Functioning Scale (GAF). Clinical outcome was assessed with symptom ratings and by monitoring onset of new mood episodes. RESULTS: Memory, particularly verbal learning/memory, was robustly associated with 6-month functional outcome on the MSIF, even after partialling out the influence of mood symptoms and substance abuse co-morbidity. Depression ratings at 6 months, but not cognitive variables, were associated with 6-month GAF scores. Cognitive functioning was not associated with 6-month clinical outcome. CONCLUSIONS: Memory was associated with 6-month longitudinal functional but not clinical outcome in recently diagnosed patients with bipolar disorder. These data further support the distinction between clinical and functional outcome, and emphasize the need for identification of, and development of treatments for, cognitive impairments early in the course of bipolar disorder.

Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis.

OBJECTIVE: Although cognitive deficits are prominent in symptomatic patients with bipolar disorder, the extent and pattern of cognitive impairment in euthymic patients remain uncertain. METHOD: Neuropsychological studies comparing euthymic bipolar patients and healthy controls were evaluated. Across studies, effect sizes reflecting patient-control differences in task performance were computed for the 15 most frequently studied cognitive measures in the literature. RESULTS: Across the broad cognitive domains of attention/processing speed, episodic memory, and executive functioning, medium-to-large performance effect size differences were consistently observed between patients and controls, favoring the latter. Deficits were not observed on measures of vocabulary and premorbid IQ. CONCLUSION: Meta-analytic findings provide evidence of a trait-related neuropsychological deficit in bipolar disorder involving attention/processing speed, memory, and executive function. Findings are discussed with regard to potential moderators, etiologic considerations, limitations, and future directions in neuropsychological research on bipolar disorder.

Reduced anterior hippocampal formation volume in hyponatremic schizophrenic patients.

Diminished hippocampal volume occurs in the anterior segment of some schizophrenic patients, and in the posterior segment in others. The significance of hippocampal pathology in general and these segmental differences in specific is not known. Several lines of evidence suggest anterior hippocampal pathology underlies the life-threatening hyponatremia seen in a subgroup of patients with schizophrenia; therefore our goal was to determine if this region was preferentially diminished in hyponatremic patients. We studied seven polydipsic hyponatremic, ten polydipsic normonatremic, and nine nonpolydipsic normonatremic schizophrenic inpatients, as well as 12 healthy controls. All underwent structural scanning on a high resolution (3.0 T) magnetic resonance imaging (MRI) scanner. Hippocampal formation, amygdala, and third ventricle volumes were manually traced in each subject. The hippocampus was divided at the posterior extent of the uncus, and all structural volumes were corrected for whole brain volume and other significant recognized factors (i.e., age, gender, height, parental education). Despite being overhydrated, anterior hippocampal formation volume was diminished in those with polydipsia and hyponatremia relative to each of the other three groups. Third ventricle volume was larger in this group than in healthy controls but similar to the two patient groups. Posterior hippocampal and amygdala volumes did not differ between groups. Other potential confounds (e.g., water imbalance) either had no effect or accentuated these differences. We conclude the anterior hippocampal formation is smaller in hyponatremic schizophrenic patients, thereby linking an important and objective clinical feature of schizophrenia to a neural pathway that can be investigated in animal models. The findings strengthen the hypothesis that anterior hippocampal formation pathology disrupts functional connectivity with other limbic structures in schizophrenia.

A longitudinal neuropsychological study of partial brain radiation in adults with brain tumors.

OBJECTIVE: To investigate longitudinal cognitive functioning in patients with brain tumor treated with modern highly conformal fractionated partial brain radiation therapy (RT). METHODS: Seventeen (of 22 initial consecutive patients) adults with primarily low-grade brain neoplasms who underwent either biopsy or tumor resection were tested at pre-RT baseline and at 3, 6, 12, and 24 months after baseline. Participants were classified as RT-treated nonprogressors (n = 12) or progressors (n = 3) based on serial follow-up structural imaging. Two patients received surgery only and served as controls to help minimize surgical, practice, test form, or other potential non-RT effects. Serial neuropsychological assessments were conducted using alternate forms of the Selective Reminding Test, 10/36 Spatial Recall Test, and Symbol Digit Modality Test (oral, written) as well as the Shipley Scale (baseline only), Wechsler Adult Intelligence Scale-Revised Digit Span, Trail Making Test, and the Symptom Checklist-90-Revised Global Severity Index scale. RESULTS: There was evidence of subtle attention and memory improvement in RT-treated nonprogressors throughout the 2-year period, with no evidence of cognitive decline. In contrast, patients with disease progression evidenced more substantial decline in memory and attention. CONCLUSIONS: Partial brain fractionated RT was not associated with adverse neuropsychological effects through the first 2 years following therapy.

Effects of retroactive and proactive interference on word list recall in schizophrenia.

Schizophrenia spectrum patients (N = 143) and healthy controls (N = 160) were administered the Rey Auditory Verbal Learning Test (RAVLT) and tests of executive functioning to directly investigate the effects of proactive interference (PI) and retroactive interference (RI) on word list recall. It was hypothesized that by virtue of the predicted preferential association between executive functioning and RI (relative to PI), patients would demonstrate increased susceptibility to RI in their ability to recall word lists. Results indicated that patients show increased susceptibility to RI relative to PI. Furthermore, this difference appeared to be related to the frontally-mediated central executive functions that were preferentially associated with RI but not PI susceptibility.

Auditory and visual attention assessed with PET.

Brain mechanisms involved in the maintenance of attention to auditory and visual stimuli at different spatial locations were assessed using positron emission tomography with [15O]water to measure regional cerebral blood flow (rCBF) changes in 13 normal volunteers. Simultaneous auditory [dichotically presented consonant-vowel-consonants (CVCs)] and visual stimuli (vertically oriented, CVCs presented to the left and right of fixation) were presented on every trial. In different conditions subjects attended for targets in a specified stimulus channel (left or right ears or left or right visual fields) while maintaining fixation on a central x. Attending left or right for auditory stimuli increased rCBF in primary auditory cortex in Heschl's gyrus and in temporal lobe auditory association cortices in both hemispheres. Attending left or right for visual stimuli did not change rCBF in primary visual cortex, and only attention to the right significantly increased rCBF in contralateral occipital cortex. Visual attention caused significant rCBF changes in a widespread network that included frontal, parietal, and temporal cortical regions as well as the cerebellum, whereas rCBF changes due to auditory attention were largely localized in the temporal lobes. The results suggest that spatially directed attention is mediated by different mechanisms in the auditory and visual modalities.

Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls.

The purpose of the present study was to investigate putative neural substrates of long-term (delayed) memory in schizophrenia and young healthy controls. Ten "low" and 10 "high" memory patients were selected from a large sample of DSM-III-R diagnosed schizophrenia spectrum patients, based on composite verbal and nonverbal delayed recall memory scores. Ten "low" and 9 "high" memory individuals were also selected from a larger sample of young healthy controls. Magnetic resonance imaging scans were acquired on a 1.5-T GE Signa scanner using a SPGR sequence (repetition time = 24 msec, echo time = 5 msec). Hippocampal volumes were computed from manual tracings (intraclass correlation = .96), and temporal lobe and whole brain tissue volumes were obtained using a semiautomated technique. In both the patient sample and controls, there was no significant relationship between delayed memory ability and hippocampal, temporal lobe, or whole brain volume. The integration of results from this study, and from studies on normal aging and Alzheimer's disease, supports a model suggesting that hippocampal size may be an indicator of long-term memory ability, but only when hippocampal measures reflect aging and degenerative hippocampal atrophy. If the hippocampal measures reflect individual differences in hippocampal size prior to the onset of hippocampal atrophy, then hippocampal size does not appear to predict long-term memory ability.

Age, gender, and hemispheric differences in human striatum: a quantitative review and new data from in vivo MRI morphometry.

We reviewed postmortem and neuroimaging studies of striatal neuroanatomy in humans. The quantitative review revealed evidence of moderate age-related shrinkage of the caudate nucleus and the putamen and consistent leftward asymmetry of the globus pallidus. The data on sex differences were very sparse. We examined neostriatal structures in two samples (healthy volunteers and patients with negative radiological findings) using in vivo magnetic resonance imaging. In both samples, bilateral age-related shrinkage of the caudate nucleus was found, although among the patients the effect was significant only for males. The putamen was measured only in the second sample, and age-related reduction in its volume was found also only among males. A trend for rightward asymmetry in the volume of caudate nucleus was observed in both samples, although it reached statistical significance only among the patients. Putative pathological and physiological mechanisms underlying the observed differences in teh neostriatum are discussed.

Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry.

We examined the pattern of neuroanatomic abnormalities in adults with Down's syndrome (DS) and the cognitive correlates of these abnormalities. Specifically, we compared this pattern with what would be predicted by the hypotheses attributing DS pathology to either premature aging or Alzheimer's disease. We measured a number of brain regions on MRIs of 25 subjects: 13 persons with the DS phenotype and 12 age- and sex-matched healthy volunteers. Study participants had no history of cardiovascular disease, diabetes, thyroid dysfunction, or seizure disorder. After statistical adjustment for differences in body size, we found that, in comparison with controls, DS subjects had substantially smaller cerebral and cerebellar hemispheres, ventral pons, mammillary bodies, and hippocampal formations. In the cerebellar vermis of DS subjects, we observed smaller lobules VI to VIII without appreciable differences in other regions. In addition, we noted trends for shrinkage of the dorsolateral prefrontal cortex, anterior cingulate gyrus, inferior temporal and parietal cortices, parietal white matter, and pericalcarine cortex in DS subjects compared with normal controls. The parahippocampal gyrus was larger in DS subjects. We found no significant group differences in the volumes of the prefrontal white matter, the orbitofrontal cortex, the pre- and postcentral gyri, or the basal ganglia. We conclude that the pattern of selective cerebral damage in DS does not clearly fit the predictions of the premature aging or Alzheimer's disease hypotheses. To examine the relationship between brain abnormalities and cognitive deficits observed in DS, we correlated the size of brain regions that were significantly reduced in DS with performance on tests of intelligence and language. The correlation analysis suggested age-related decline in the DS subjects in general intelligence and basic linguistic skills. General intelligence and mastery of linguistic concepts correlated negatively with the volume of the parahippocampal gyrus. There was no relationship between total brain size and the cognitive variables.

Toward the neural basis of verbal priming: a cognitive-neuropsychological synthesis.

Repetition priming is a mnemonic phenomenon that has attracted considerable attention from neuropsychologists and cognitive scientists. In an attempt at elucidating the putative mechanisms of priming, the present review draws on evidence from both domains. The review is restricted to verbal priming of visually presented stimuli--an area that accounts for the majority of empirical studies of priming. A number of theoretical accounts are presented. The interim conclusion is that neither multiple systems nor unitary system-multiple process theories can adequately explain the data on priming, although both contain many valid components. An integrative model is proposed to improve the explanation of the empirical evidence. The central assertion of the proposed model is that repetition priming depends on perceptual processes that can be mapped on specific neural systems. It is postulated that individual differences in perceptual processing ability predict variability in memory performance. It is proposed that data-driven priming of verbal stimuli critically depends on the activity of primary and secondary visual cortices in the right hemisphere, whereas conceptually-driven priming is hypothesized to rely on the activities of higher order tertiary association cortices in language areas and more anterior neocortical areas.

Age-related shrinkage of the mamillary bodies: in vivo MRI evidence.

Mamillary body (MB) is a diencephalic structure hypothesized to be involved in memory, a cognitive function that declines with age. In this study, age-related differences in the size of MB were examined in vivo using magnetic resonance (MR) imaging. The cross-sectional area of the MB was estimated from MR images of the brain in healthy volunteers and neurologically intact patients (age 18-78). The cross-sectional area of the tectum was used as a control region of interest. We found a significant age-related reduction in the area of the MB, but not of the tectum. No sex differences were observed in the size of either structure.

Age-related regional differences in cerebellar vermis observed in vivo.

We investigated age-related differences in the cerebellar vermis. The areas of five vermal regions of interest were estimated from digitized midsagittal magnetic resonance imaging scans of 29 healthy volunteers and 30 neurologically intact patients (aged 18 to 78 years) who were free of vestibular symptoms, seizures, psychosis, or alcoholism. The five regions of interest included the following: (1) lingula and centralis, (2) culmen, (3) declive, folium, and tuber, (4) pyramis, and (5) uvula and nodulus. The ventral pons was used as a control region. After covarying skull size, we found a significant age-related reduction in the total area of the cerebellar vermis. The area of the dorsal regions declined with age, whereas the ventral segments of the vermis--lingula-centralis and uvula-nodulus--showed no significant age-related shrinkage. Notably, the area of the most dorsomedial portion, the declive-folium-tuber, tended to be more strongly associated with age than other segments. The pontine area was unaffected by age. No sex differences were found in the area of the vermis or its subdivisions, but the ventral pontine area was larger in male subjects than in female subjects, even after adjustment for skull size. The mechanisms underlying the observed differences are unclear. It appears, however, that phylogenetically more recent vermal regions, which are late to mature and are endowed with more extensive cortical connections, are the most vulnerable to the effects of aging.