[Show abstract][Hide abstract] ABSTRACT: Our objectives were to assess age differences in perceptual repetition priming and perceptual skill learning and to determine whether they are mediated by cognitive resources and regional cerebral volume differences. Fragmented picture identification paradigm allows the study of both priming and learning within the same task. The authors presented this task to 169 adults (ages 18-80), assessed working memory and fluid intelligence, and measured brain volumes of regions that were deemed relevant to those cognitive skills. The data were analyzed within a hierarchical path modeling framework. In addition to finding age-related decrease in both perceptual priming and learning, the authors observed several dissociations with regards to their neural and cognitive mediators. Larger visual cortex volume was associated with greater repetition priming, but not perceptual skill learning, and neither process depended upon hippocampal volume. In contrast, the volumes of the prefrontal gray and white matter were differentially related to both processes via direct and indirect effects of cognitive resources. The results indicate that age-related differences in perceptual priming and skill learning have dissociable cognitive and neural correlates.
[Show abstract][Hide abstract] ABSTRACT: Much of the response to an antidepressant is the result of placebo response. The placebo response embedded in drug response confounds studies seeking to identify brain mechanisms essential for pharmacologic response. Exclusion of patients who fail to meet entry criteria at the end of a placebo lead-in phase has been inadequate to reduce the effect of placebo during pharmacologic trials. This study focused on the placebo lead-in phase and examines whether change in severity of depression during placebo lead-in predicts change in depressive symptoms during antidepressant treatment.
The subjects were patients aged 60-85 years with nonpsychotic unipolar major depression not attributed to dementing disorders, medical illnesses, or drugs causing depression and had a 24-item Hamilton Depression Rating Scale score of 18 or greater. After a two-week placebo lead-in, subjects with Hamilton Depression Rating Scale score of 18 or greater received 10 mg escitalopram for 12 weeks.
Worsening or limited change in depression during placebo treatment predicted improvement in depressive symptoms during escitalopram treatment. Limited change in anxiety, melancholia, helplessness, and paranoia during placebo treatment were the strongest predictors of improvement in depression while on escitalopram.
These findings, if replicated, may be used to characterize depressed older patients likely to respond to the pharmacologic action of antidepressants rather than the placebo response embedded in drug trials and thus improve the methodology of biomarker studies of antidepressant response. On a clinical level, depressed older patients who improve during a prolonged evaluation may be candidates for nonpharmacologic treatments because their drug response may be limited.
American Journal of Geriatric Psychiatry 03/2007; 15(2):149-58. DOI:10.1097/01.JGP.0000232206.91841.d9 · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Executive dysfunction is common in geriatric depression and persists after improvement of depressive symptoms. This study examined the relationship of executive impairment to the course of depressive symptoms among elderly patients with major depression.
A total of 112 nondemented elderly patients with major depression participated in an 8-week citalopram trial at a target daily dose of 40 mg. Executive functions were assessed with the initiation/perseveration subscale of the Dementia Rating Scale and the Stroop Color-Word test. Medical burden was rated with the Cumulative Illness Rating Scale.
Both abnormal initiation/perseveration and abnormal Stroop Color-Word scores were associated with an unfavorable response of geriatric depression to citalopram. In particular, initiation/perseveration scores below the median (< or =35) and Stroop scores at the lowest quartile (< or =22) predicted limited change in depressive symptoms. Impairment in other Dementia Rating Scale cognitive domains did not significantly influence the outcome of depression.
Executive dysfunction increases the risk for poor response of geriatric depression to citalopram. Because executive functions require frontostriatal-limbic integrity, this observation provides the rationale for investigation of the role of specific frontostriatal-limbic pathways in perpetuating geriatric depression. Depressed elderly patients with executive dysfunction require vigilant clinical attention because they might be at risk to fail treatment with a selective serotonin reuptake inhibiting antidepressant.
[Show abstract][Hide abstract] ABSTRACT: We examined age-, sex-, and hemisphere-related differences in the cerebral cortex. Volumes of the cerebral hemispheres and 13 regions of interest (ROIs) were measured on magnetic resonance images of 200 healthy adults. The strength of association between age and volume differed across ROIs. The lateral prefrontal cortex exhibited the greatest age-related differences, whereas significantly weaker associations were observed in the prefrontal white matter, sensory-motor, and visual association regions. The hippocampal shrinkage was significant in people in their mid-fifties. The primary visual, anterior cingulate, the inferior parietal cortices, and the parietal white matter showed no age-related differences. The pattern of age-related regional differences replicated the findings previously obtained on an independent sample drawn from the same population. Men evidenced larger volumes in all ROIs except the inferior parietal lobule, even after sexual dimorphism in body size was statistically controlled. In some regions (hippocampus and fusiform gyrus) men exhibited steeper negative age-related trends than women. Although a typical pattern of global hemispheric asymmetry was observed, the direction and magnitude of regional volumetric asymmetry was as inconsistent as in the previous reports. Thus, a pattern of age-related shrinkage suggesting increased vulnerability of the lateral prefrontal cortex to aging appears stable and replicable, whereas little consistency exists in sex-related and hemispheric differences in regional cortical volumes.
Neurobiology of Aging 04/2004; 25(3):377-96. DOI:10.1016/S0197-4580(03)00118-0 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional neuroimaging studies have identified a role for the cerebellum in the neuropsychology of schizophrenia. Few studies, however, have examined the relationship between cerebellar size and neuropsychological functioning in schizophrenia. The authors' goal was to examine this relationship in patients and healthy comparison subjects.
Total cerebellar volume was computed from magnetic resonance images in 48 male and 33 female patients experiencing a first episode of schizophrenia and in 14 male and nine female healthy comparison subjects. Patients and comparison subjects completed a comprehensive neuropsychological assessment encompassing six domains of functioning: executive, motor, language, visuospatial, memory, and attention. A global domain of functioning was computed as the mean of these six domains.
Larger cerebellar volume correlated significantly with better global functioning in healthy subjects but not among patients with schizophrenia; this relationship was significantly stronger in healthy subjects than in patients. Additional analyses revealed significant associations between cerebellar volume and visuospatial, executive, and memory functions in healthy volunteers but not among patients.
The cerebellum plays a role in higher cognitive functions in healthy individuals, and normal associations between cerebellar size and function are absent in patients experiencing a first episode of schizophrenia. These findings are consistent with neurobiological models implicating the cerebellum in the pathogenesis of schizophrenia.
American Journal of Psychiatry 11/2003; 160(10):1884-7. DOI:10.1176/appi.ajp.160.10.1884 · 12.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Information about age-related changes in the striatum comes almost exclusively from cross-sectional studies. We examined age-related differences and longitudinal changes in the volume of the striatal nuclei, compared longitudinal measures of changes with their cross-sectional estimates, and addressed the question of differential aging of the basal ganglia.
We measured the volumes of the caudate nucleus (head), the putamen, and the globus pallidus on MR images of 53 healthy adults whose ages at baseline ranged between 20 and 77 years. The measurements were conducted twice, 5 years apart.
On both measurement occasions, the volume of the neostriatal nuclei (caudate and putamen) but not of the globus pallidus correlated negatively with age. However, longitudinal comparison revealed significant declines in the neostriatal volumes and smaller (but statistically significant) shrinkage of the paleostriatum. In 5 years, the striatal components (caudate, putamen, and globus pallidus) shrunk by 1.21, 0.85, and 0.55 standard deviation units, respectively. The average annual shrinkage rate was 0.83% in the caudate nucleus, 0.73% in the putamen, and 0.51% in the globus pallidus.
Although cross-sectional estimates suggested preservation of some striatal nuclei, longitudinal shrinkage of the whole striatum was evident even in a selected group of healthy adults. Moreover, the magnitude of observed longitudinal change was greater than predicted from cross-sectional studies.
American Journal of Neuroradiology 11/2003; 24(9):1849-56. · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abnormalities in cerebellar structure and function have been implicated in the pathophysiology of schizophrenia. In this study, we investigated whether patients experiencing first-episode schizophrenia differed from healthy comparison subjects in regional cerebellar volumes or cerebellar asymmetry.
Volumes of four cerebellar regions (right, left; anterior, posterior) were measured from contiguous coronal magnetic resonance (MR) images in 69 (37 men, 32 women) patients experiencing first-episode schizophrenia and in 49 (27 men, 22 women) healthy comparison subjects. Patients were rated on the Scale for the Assessment of Negative Symptoms and the Schedule for Affective Disorders and Schizophrenia-Psychosis/Disorganization before the initiation of antipsychotic medication and at the time of the MR imaging exam.
Patients and healthy comparison subjects did not differ in regional cerebellar volumes, but male patients demonstrated significantly reversed anterior and posterior asymmetry compared with healthy male subjects. Among male patients, greater reversals in a composite measure of cerebellar asymmetry (i.e., torque) correlated significantly with increased negative symptoms before the initiation of antipsychotic medication.
These findings implicate an aberrant neurodevelopmental process involving the metencephalon in the pathophysiology of schizophrenia and are consistent with prior studies implicating abnormal asymmetry in schizophrenia at the neocortical level.
[Show abstract][Hide abstract] ABSTRACT: Sex differences have been observed in neurobehavioral measures and in neuroanatomic studies. Men and women differ in emotion processing, including perception, experience and expression, most notably reflected in greater male aggression. We examine temporo-limbic and prefrontal structures volumetrically in a large well-characterized sample of healthy adults, applying morphometric methods across cerebral regions that regulate emotions. Quantitative magnetic resonance imaging (MRI) was performed in 116 healthy adults, 57 men and 59 women, age range 18-49 years. We used reliable methods of region of interest identification to examine sex differences in volume of temporo-limbic and frontal regions. An automated tissue segmentation procedure was used to obtain separate measurements for gray and white matter. After correcting for cranial volume, men and women had identical volumes of amygdala and hippocampus, as well as dorsal prefrontal cortex. However, women had larger orbital frontal cortices than men, resulting in highly significant difference in the ratio of orbital gray to amygdala volume (P = 0.002). The larger volume of cortex devoted to emotional modulation may relate to behavioral evidence for sex differences in emotion processing.
[Show abstract][Hide abstract] ABSTRACT: n-back letter and fractal tasks were administered to 11 participants during functional magnetic resonance imaging to test process specificity theories of prefrontal cortex (PFC) function and assess task validity. Tasks were matched on accuracy, but fractal n-back responses were slower and more conservative. Maintenance (1-back minus 0-back) activated inferior parietal and dorsolateral PFC, with additional activation in right ventrolateral PFC during letter n-back and left lingual gyrus during fractal n-back. Maintenance plus manipulation (2-back minus 0-back) activated inferior parietal, Broca's area, insula, and dorsolateral and ventral PFC, with greater right dorsolateral PFC activation for letter n-back. Manipulation only (2-back minus 1-back) produced additional and equivalent dorsolateral PFC and anterior cingulate activation in both tasks. Results support fractal n-back validity and indicate substantial overlap in working memory functions of dorsal and ventral PFC.
[Show abstract][Hide abstract] ABSTRACT: Pathology of the prefrontal cortices has been suggested to be a part of neural networks underlying deviant behavioral patterns. Recently, reduced overall prefrontal cortical volumes have been proposed in subjects with antisocial personality disorder (ASP). It is not known whether there are specific patterns of volume loss within the prefrontal regions. Nor is it known if there are correlations between the prefrontal volumes and degree of psychopathology. In this study, total prefrontal, prefrontal white, and cortical (dorsolateral, orbitofrontal, medial frontal) prefrontal volumes were measured from magnetic resonance images in 24 non-psychotic, violent male subjects who had a diagnosis of ASP in combination with type 2 alcoholism, and 33 age-matched control males. The degree of psychopathy in the ASP subjects was assessed using the Psychopathy Checklist-Revised (PCL-R). Compared with the controls, the ASP subjects had significantly smaller volumes of all three cortical regions on the left, but this significance disappeared after controlling for differences in education and duration of alcoholism. For the dorsolateral and orbitofrontal cortices, only duration of alcoholism was significantly associated with the observed volume deficit, and for the medial frontal cortex it was the difference in education. Thus, the observed volume deficits in this sample were related more to alcoholism or differences in education rather than to the diagnosis of ASP. Moreover, no significant correlations between any of the volumes and the degree of psychopathy were found.
Psychiatry Research 07/2002; 114(2):95-102. DOI:10.1016/S0925-4927(02)00005-7 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined the impact of age-related differences in regional cerebral volumes and cognitive resources on acquisition of a cognitive skill. Volumes of brain regions were measured on magnetic resonance images of healthy adults (aged 22-80). At the early stage of learning to solve the Tower of Hanoi puzzle, speed and efficiency were associated with age, prefrontal cortex volume, and working memory. A similar pattern of brain-behavior associations was observed with perseveration measured on the Wisconsin Card Sorting Test. None of the examined structural brain variables were important at the later stages of skill acquisition. When hypertensive participants were excluded, the effect of prefrontal shrinkage on executive aspects of performance was no longer significant, but the effect of working memory remained.
Psychology and Aging 04/2002; 17(1):72-84. DOI:10.1037/0882-79220.127.116.11 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The human brain exhibits a complex pattern of differential aging. The purpose of this study was to examine whether age differences in the volume of cerebellar regions and the ventral pons are differential or generalized, whether the age-related shrinkage is linear or exponential, and whether there are sex differences in the size of the cerebellum and pons.
The volumes of the cerebellar hemispheres (excluding the vermis and the peduncles), the vermis, and the ventral pons were estimated from the prospectively acquired MR scans of 190 healthy volunteers (aged 18-81 years). The relation between regional volumes, age, and sex was assessed while taking into account differences in body size (height).
We found a moderate age-related reduction in the volume of the cerebellar hemispheres and the cerebellar vermis. In contrast to previous findings that suggested differential vulnerability of the posterior vermis, the age-related shrinkage of the vermian lobules was uniform-about 2% per decade. In accord with all reports in the literature, the size of the ventral pons was unrelated to age. The volume of the cerebellar hemispheres, the vermis, and the ventral pons were larger in men, even after adjustment for height. The magnitude of the sex difference was the largest in the hemispheres and the anterior vermis, and the smallest in the lobules VI-VII (declive-folium-tuber).
Moderate age-related shrinkage of the cerebellum and lack of age-related differences in the ventral pons are robust phenomena. However, in all likelihood, the effects of age on the cerebellum are not differential but uniform. The cerebellum and the pons are larger in men than in women and the difference is especially pronounced in the cerebellar hemispheres and the anterior vermis.
American Journal of Neuroradiology 01/2001; 22(6):1161-7. · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to examine age differences in procedural learning and performance in conjunction with differential aging of central nervous system (CNS) structures. Sixty-eight healthy volunteers (age 22-80) performed a pursuit rotor task (four blocks of 20 15-second trials each). Volumes of the cerebellar hemispheres, neostriatum, prefrontal cortex, and hippocampus were measured from Magnetic Resonance (MR) images. Improvement in pursuit rotor performance was indexed by increase in time on target (TOT). A general improvement trend was evident across the blocks of trials. Overall, younger participants showed significantly longer TOT. The rate of improvement was age-invariant during the initial stages of skill acquisition but became greater in middle-aged participants as the practice progressed. When the influences of regional brain volumes were taken into account, the direct age effect on mean TOT measured during the first day of practice disappeared. Instead, reduced volumes of the cerebellar hemispheres and the putamen and poorer performance on nonverbal working memory tasks predicted shorter TOT. In contrast, neither the volume of the caudate and the hippocampus, nor verbal working memory showed association with motor performance. Pursuit rotor performance at the later stages of practice was unrelated to the reduction in putamen volume and was affected directly by age, cerebellar volume, and nonverbal working memory proficiency. We conclude that in a healthy population showing no clinical signs of extrapyramidal disease, age-related declines in procedural learning are associated with reduced volume of the cerebellar hemispheres and lower nonverbal working memory scores. During initial stages of skill acquisition, reduced volume of the putamen is also predictive of poorer performance.
Microscopy Research and Technique 10/2000; 51(1):85-93. DOI:10.1002/1097-0029(20001001)51:1<85::AID-JEMT9>3.0.CO;2-0 · 1.15 Impact Factor