Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response.

BACKGROUND: Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS: Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS: Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS: Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.

Do specific neurocognitive deficits predict specific domains of community function in schizophrenia?

We examined whether specific neurocognitive deficits predicted specific domains of community outcome in 40 schizophrenic patients. Neuropsychological assessments were conducted before hospital discharge, and measures of functional outcome were obtained 1 to 3.5 years later. A priori hypotheses were generated based upon a recent review by Green (Green MF [1996] What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry, 153(3):321-330). As hypothesized, verbal memory predicted all measures of community outcome, vigilance predicted social outcomes, and executive functioning predicted work and activities of daily living (ADLs). However, in addition to the predicted relationships, many other associations were found between neuropsychological test scores and adaptive function. Furthermore, both cognitive and functional measures were intercorrelated. If deficits in adaptive functioning are neurocognitively multi-determined, utilizing compensatory strategies to bypass multiple areas of cognitive impairment may be more efficient than cognitive remediation in improving community outcomes.

Equivalence of the Color Trails Test and Trail Making Test in nonnative English-speakers.

The Color Trails Test (CTT) has been described as a culture-fair test of visual attention, graphomotor sequencing, and effortful executive processing abilities relative to the Trail Making Test (TMT). In this study, the equivalence of the TMT and the CTT among a group of 64 bilingual Turkish university students was examined. No difference in performance on the CTT-1 and TMT Part A was found, suggesting functionally equivalent performance across both tasks. In contrast, the statistically significant differences in performance on CTT-2 and TMT Part B, as well as the interference indices for both tests, were interpreted as providing evidence for task nonequivalence of the CTT-2 and TMT Part B. Results have implications for both psychometric test development and clinical cultural neuropsychology.

Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness.

OBJECTIVE: Theories of human behavior from Plato to Freud have repeatedly emphasized links between emotion and reason, a relationship now commonly attributed to pathways connecting phylogenetically "old" and "new" brain regions. Expanding on this theory, this study examined functional interactions between specific limbic and neocortical regions accompanying normal and disease-associated shifts in negative mood state. METHOD: Regions of concordant functional change accompanying provocation of transient sadness in healthy volunteers and resolution of chronic dysphoric symptoms in depressed patients were examined with two positron emission tomography techniques: [15O]water and [18F]fluorodeoxyglucose, respectively. RESULTS: With sadness, increases in limbic-paralimbic blood flow (subgenual cingulate, anterior insula) and decreases in neocortical regions (right dorsolateral prefrontal, inferior parietal) were identified. With recovery from depression, the reverse pattern, involving the same regions, was seen--limbic metabolic decreases and neocortical increases. A significant inverse correlation between subgenual cingulate and right dorsolateral prefrontal activity was also demonstrated in both conditions. CONCLUSIONS: Reciprocal changes involving subgenual cingulate and right prefrontal cortex occur with both transient and chronic changes in negative mood. The presence and maintenance of functional reciprocity between these regions with shifts in mood in either direction suggests that these regional interactions are obligatory and probably mediate the well-recognized relationships between mood and attention seen in both normal and pathological conditions. The bidirectional nature of this limbic-cortical reciprocity provides additional evidence of potential mechanisms mediating cognitive ("top-down"), pharmacological (mixed), and surgical ("bottom-up") treatments of mood disorders such as depression.

WAIS-III Matrix Reasoning test performance in a mixed clinical sample.

This study examined the relationship between the Matrix Reasoning subtest (MRT) of the WAIS-III and a selected number of neuropsychological tests in a heterogeneous clinical sample of English-speaking American (n = 41), and non-English-speaking immigrant (n = 14) adults. A moderate association between the Halstead Category Test and the MRT (-.58) was found in the English-speaking sample. Multiple regression analysis revealed a significant association between measures of verbal abstract reasoning and verbal fluency, and performance on the MRT. Among the immigrant sample, the MRT was also found to be significantly associated with verbal fluency task performance, as well as with the Comprehensive Test of Nonverbal Intelligence. Correlational analyses therefore suggest a strong verbal mediation element in the MRT, and that labeling it a nonverbal task may be misleading.

Behavioral effects of low-level exposure to Hg0 among dental professionals: a cross-study evaluation of psychomotor effects.

A Across-study design was used to evaluate the sensitivities of five psychomotor tasks previously used to assess preclinical effects of low-level Hg0 (urinary < or =55 microg/l). Pooling dental professional subject populations from six studies conducted over the last 6 years, a larger study population was obtained with a high degree of uniformity (N = 230). The five psychomotor tests were: Intentional Hand Steadiness Test (IHST); Finger Tapping: The One-Hole Test: NES Simple Reaction Time (SRT); and Hand Tremor. Multivariate analyses were conducted following the hierarchical analysis of multiple responses (HAMR) approach. First, multiple scores of each test were combined into a single-factor (or related summary) variable and its reliability was estimated. Second. multiple regression analyses were conducted including log-transformed [Hg0]U levels, age, gender, and alcohol consumption in each model. Computed were both B and bu, the magnitudes of the log-Hg0 standardized coefficient. respectively uncorrected and corrected for dependent variable attenuation due to unreliability. Results indicated remarkable differences in the effects of relative level of Hg0 on psychomotor performance. Significant associations were found for the IHST factor (B = 0.415, p < 10(-6)), followed by finger tapping, which was relatively meager and insignificant (B 0.141, p = 0.17). The IHST results hold the greatest occupational relevance for dental professionals who rely on manual dexterity in restorative dentistry. Further, this statistical approach is recommended in future studies for condensation of multiple scores into summary scores with enhanced reliabilities useful in correcting for attenuation relationships (B(u)s) with exposure levels.

Executive-frontal lobe cognitive dysfunction in schizophrenia: a symptom subtype analysis.

Impairment of executive-frontal lobe functioning, affecting the planning, initiation and regulation of goal-directed behavior, is a common cognitive deficit in schizophrenia. However, it is unclear if deficits in these frontal-lobe-mediated abilities are differentially expressed across clinical subgroups. We analyzed executive-frontal abilities in relation to symptom expression in 53 hospitalized schizophrenic patients. Patients were assigned to one of three subgroups based on rank order analysis of Brief Psychiatric Rating Scale factors: Withdrawal-Retardation, Reality Distortion and Conceptual Disorganization. Executive-frontal tests included Visual Search, Verbal Fluency, Verbal Series Attention, Trail Making - Part B, Symbol Digit, Hopkins Verbal Learning, Digit Span, Wisconsin Card Sorting, Stroop Color-Word and Attentional Capacity. The schizophrenia group showed significant deficits relative to healthy control subjects (n = 20) on all tests. Exploratory factor analysis of test scores revealed three factors: (i) Verbal Processing/Memory; (ii) Cognitive Flexibility/Attention; and (iii) Psychomotor Speed/Visual Scanning. The three symptom subgroups were differentially impaired on executive-frontal abilities: Withdrawal-Retardation on psychomotor speed, verbal fluency, working memory, visual search and cognitive flexibility; Conceptual Disorganization on attention; Reality Distortion on verbal memory. The results have implications for syndrome definition, pharmacological intervention and prediction of outcome in schizophrenia.

Neurobehavioral effects from exposure to dental amalgam Hg(o): new distinctions between recent exposure and Hg body burden.

Potential toxicity from exposure to mercury vapor (Hg(o)) from dental amalgam fillings is the subject of current public health debate in many countries. We evaluated potential central nervous system (CNS) toxicity associated with handling Hg-containing amalgam materials among dental personnel with very low levels of Hg(o) exposure (i.e., urinary Hg <4 microg/l), applying a neurobehavioral test battery to evaluate CNS functions in relation to both recent exposure and Hg body burden. New distinctions between subtle preclinical effects on symptoms, mood, motor function, and cognition were found associated with Hg body burden as compared with those associated with recent exposure. The pattern of results, comparable to findings previously reported among subjects with urinary Hg >50 microg/l, presents convincing new evidence of adverse behavioral effects associated with low Hg(o) exposures within the range of that received by the general population.

The functional significance of symptomatology and cognitive function in schizophrenia.

The relationships between positive and negative symptomatology, cognitive function, and the ability to perform basic activities of daily living in patients with schizophrenia were examined in two studies. In study 1, 112 medicated patients were assessed utilizing the Brief Psychiatric Rating Scale (positive symptoms), the Negative Symptom Assessment (negative symptoms and cognitive function), and the Functional Needs Assessment (activities of daily living). Study 2 (n = 41), utilized the same measures of symptomatology and added a comprehensive neuropsychological test battery. Regression analyses in both studies determined that symptomatology predicts a relatively small amount of the variance in the ability to perform basic activities of daily living. Cognitive function, whether assessed with the Cognition subscale of the Negative Symptom Assessment or a comprehensive neuropsychological test battery, predicted over 40% of the variance in scores on the Functional Needs Assessment. A path model in which cognition predicted both concurrent symptomatology and activities of daily living and where symptomatology had little direct impact upon activities of daily living fit the data. The importance of addressing cognitive deficits in psychosocial intervention programs is discussed.

Chronic neurologic effects of pesticide overexposure.

Pesticide exposure in humans can have persistent effects, even in the absence of acute symptoms of intoxication or after their resolution. Drs. Keifer and Mahurin describe some of the most important examples of established pesticide neurotoxicity.

Relationship between specific types of communication deviance and attentional performance in patients with schizophrenia.

Communication Deviance (CD) characterizes the speech of schizophrenic patients and their relatives. The relationship between specific types of CD as measured from verbatim transcripts of Thematic Apperception Test protocols and attentional performance was investigated in 27 patients with schizophrenia. Assessments were conducted just prior to hospital discharge. Results revealed that a continuous performance attentional test with visually presented stimuli was most highly related to the CD factor indicating that the respondent had misperceived elements of the card. A continuous performance attentional test with auditory stimuli was found to be associated with the factor reflecting odd language use in the speaker. A measure of selective attention/executive control, from the Stroop Color-Word test, was found to be most highly related to the CD factors which involve higher level functions such as abstraction and integration of various elements of the card into a coherent story. Results suggest that CD may be a behavioral consequence of deficits in attention and executive control, and add to the growing literature suggesting that specific types of neuropsychological deficits can be linked to specific overt behaviors.

Cingulate function in depression: a potential predictor of treatment response.

The relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.

Effects of captopril and propranolol on cognitive function and cerebral blood flow in aged hypertensive rats.

Chronic hypertension has been reported to produce adverse cognitive effects in elderly individuals, perhaps by altering central nervous system hemodynamics. The beneficial or adverse effects of antihypertensive drugs on these processes are not well understood. We examined the effects of captopril (90 mg/kg/day) and propranolol (80 mg/kg/day) on cognitive function and brain blood flow in hypertensive and normotensive rats. Cognitive function was assessed by the Morris water maze, and regional brain blood flow was measured by the [14C]iodoantipyrine method. Nineteen-month-old propranolol-treated hypertensive rats exhibited poorer performance (p < .05) than control rats and had lower brain blood flows, particularly in white matter regions (p < .01). Captopril-treated hypertensive rats did not differ significantly from control rats with regard to either cognitive performance or brain blood flow. In the normotensive rats, there were no effects of either drug on cognitive performance or brain blood flow. Thus, blood pressure reduction by propranolol but not captopril has an adverse effect on cognitive function and brain blood flow in hypertensive rats.

The relationship between parental communication deviance and relapse in schizophrenic patients in the 1-year period after hospital discharge. A pilot study.

The present pilot study examined the ability of parental communication deviance (CD) to predict relapse in schizophrenic patients in the 1-year period after hospital discharge. Measures of CD were obtained from verbatim transcripts of family problem-solving discussions for 20 schizophrenic patients and their parents at an initial assessment and before the patients' hospital discharge. Relapse was assessed using the Brief Psychiatric Rating Scale at 3-month intervals after discharge. Findings indicated that parental CD measured at an assessment immediately before the patient's release from the hospital was moderately correlated (r = .49, p < .05) with relapse in the 1-year follow-up period. Results are discussed with respect to the possible role of parental CD as an environmental stressor in the period after discharge. Potential contributors to parental CD, including genetically transmitted cognitive deficits and stress resulting from resuming the care-giver role, are also discussed.

Preliminary evaluation of cognitive adaptation training to compensate for cognitive deficits in schizophrenia.

Cognitive adaptation training is a treatment approach designed to alter the physical environment of patients with schizophrenia to compensate for cognitive deficits and improve adaptive function. A wide range of environmental manipulations such as labels, signs, schedules, and rearrangement of objects are employed. In a preliminary study at a state hospital, outcomes for cognitive adaptation training were compared with outcomes for standard psychosocial treatment for two groups of patients with schizophrenia, matched on levels of functional impairment and symptoms. Both groups showed improvement in symptoms and adaptive function, but patients receiving the specialized training showed greater improvement in adaptive function than did the standard-treatment group.

Effect of depression on dementia presentation: qualitative assessment with the Qualitative Evaluation of Dementia (QED).

Two novel, bedside, dementia assessment instruments, the Executive Interview (EXIT) and the Qualitative Evaluation of Dementia (QED) were used to examine the effects of DSM-III-R major depressive episodes on the clinical presentation of patients diagnosed with NINCDS "possible" AD. Intergroup comparisons were made of the various bedside cognitive measures given to 102 of 118 consecutive patients presenting to a university geriatric assessment clinic and consultation service. The assessment instruments used were: (1) the EXIT: a 15-minute, 25-item bedside interview for the assessment of executive control function (ECF); (2) the QED: a brief, clinically based checklist that operationalizes the approach of a geriatric psychiatrist to the qualitative assessment of dementing illnesses (when QED scores are mapped against EXIT scores, a qualitative picture of dementia typology emerges); and (3) the Mini-Mental State Exam (MMSE): a familiar bedside measure of cognitive function. Depressed and nondepressed patients differed significantly on the QED. There was no overlap in the QED scores of patients with probable AD versus those with depression. The QED discriminated between depressed and nondepressed patients with possible AD. Possible AD patients with depression could not be qualitatively distinguished from those with depression alone, although they could be discriminated by the EXIT. Only 44% of possible AD cases fall within the EXIT x QED 90% confidence limits for probable AD. No differences were found on either the QED or the MMSE between depressed non-AD patients and nondepressed patients exhibiting "dementia with no cortical features." The MMSE was insensitive to cognitive impairment in non-AD cases. NINCDS "possible" AD is a qualitatively heterogeneous group.(ABSTRACT TRUNCATED AT 250 WORDS)

Bedside assessment of frontal degeneration: distinguishing Alzheimer's disease from non-Alzheimer's cortical dementia.

Two instruments, the Executive Interview (EXIT) and the Qualitative Evaluation of Dementia (QED), that are useful in the evaluation of frontal system failure are discussed. The ability of these instruments to discriminate frontal-type dementia (FTD) from Alzheimer's disease (AD) and the dementia of major depression (DMD) was examined in 100 consecutive elderly dementia patients presenting to a multidisciplinary geriatric clinic. All groups showed executive impairment by the EXIT, and 46% of the FTD patients were found to be unimpaired by the Mini-Mental State Examination (MMSE). The AD and FTD groups differed significantly from the DMD group on the QED. The QED alone could not distinguish AD from FTD cases. However, mapping of EXIT scores against MMSE (errors) scores revealed that AD and FTD follow very different regression lines.

Executive impairment among the functionally dependent: comparisons between schizophrenic and elderly subjects.

OBJECTIVE: Executive deficits have traditionally been associated with frontal lobe brain damage. They are relevant to a variety of disabling mental conditions, including schizophrenia and Alzheimer's disease. To measure these deficits, the authors developed the Executive Interview, a 25-item, 15-minute interview. It has been validated among elderly subjects across a wide range of functional impairment. METHODS: Forty young, chronically ill schizophrenic residents of a state mental health facility and 104 elderly residents, representing three levels of care, of a comprehensive retirement community were tested with the Executive Interview and the Mini-Mental State. RESULTS: When age, gender, education, and number of prescribed medications were controlled, cognitive impairment on the Executive Interview and Mini-Mental State rose with level of care. The Executive Interview alone discriminated between subjects at each level of care, and it was more sensitive to cognitive impairment than the Mini-Mental State. Executive Interview scores correlated the strongest with level of care. Mini-Mental State scores, number of prescribed medications, and age also correlated significantly. Schizophrenic patients showed as much executive impairment on the Executive Interview as elderly subjects at the same level of care despite significant differences in age, sex, and neuroleptic use. Executive Interview and Mini-Mental State scores were highly correlated among the elderly but less so among the schizophrenic patients. Cross-group differences were also found in the pattern of failure on selected Executive Interview items despite similar total Executive Interview scores. CONCLUSIONS: Increasing executive dyscontrol is associated with the need for increasing levels of care and supervision. This finding is neither age nor disease specific. Cross-group differences on selected Executive Interview items suggest the existence of disease-specific patterns of failure. Their recognition could prove useful in the identification of anatomically or pathophysiologically distinct subgroups among patients with executive dyscontrol.

Application of Hick's law of response speed in Alzheimer and Parkinson diseases.

Reaction time in normal subjects is known to increase in a log-linear fashion relative to the number of alternative choices. However, this relationship (formalized as "Hick's law") has received limited investigation in populations with neurological cognitive impairment. The present study used timed sorting of standard playing cards to test Hick's law for 20 young control subjects, and 20 each of age-matched elderly subjects with Alzheimer disease, Parkinson disease, and no cognitive abnormalities. Although Parkinson patients were slowest in the simple tasks of dealing out the cards and sorting by color, Alzheimer patients showed the greatest slowing for the more cognitively complex conditions of sorting by suit and rank of the cards. The performance of all four groups followed Hick's law in displaying a significant linear relationship between response time and log2 of the number of choices. These findings suggest that, although limitations of information-processing speed in Alzheimer and Parkinson disease affected choice response time, there may be sparing of fundamental cognitive organization in these disorders.