The resting and activation issue of hypofrontality: a single photon emission computed tomography study in neuroleptic-naive and neuroleptic-free schizophrenic female patients

BACKGROUND: Functional neuroimaging findings of "hypofrontality" in schizophrenic patients is still controversial, due to the heterogeneity of methods and patient samples. This study tries to prevent some of these concerns by studying neuroleptic-naive (NN) and neuroleptic-free (NF) young female patients both in resting conditions and during a frontal cognitive activation task. METHODS: Regional cerebral blood flow (rCBF) was studied at rest and during the Wisconsin Card Sorting Test (WCST) in 25 young acute unmedicated schizophrenic female patients (14 NN and 11 NF) and 15 female controls, using single photon emission computed tomography. RESULTS: The schizophrenic and control groups did not differ in rCBF during the baseline condition, but the schizophrenic group failed to activate the frontal lobe during the WCST condition. In addition, the left anterior temporal rCBF at rest correlated with the Scale for the Assessment of Positive Symptoms total score. CONCLUSIONS: The results suggest that hypofrontality in young acute unmedicated schizophrenic patients is a result of an inability to activate frontal regions during cognition, rather than a baseline decrease in frontal activity. Furthermore, positive symptoms seem to be associated with left temporal cortex activity.     

Effect of rebamipide, a novel antiulcer agent, on Helicobacter pylori adhesion to gastric epithelial cells

We examined regional cerebral blood flow (rCBF) during a long-term recognition memory task for words in schizophrenic patients and in healthy subjects using positron emission tomography (PET). The task was designed so that performance scores were similar in the patient and control subjects. This memory retrieval task did not increase rCBF in the patients' prefrontal cortex, precuneus and cerebellum as much as it did in the control group. These results point to a dysfunctional corticocerebellar circuit leading to poorly coordinated mental activity ('cognitive dysmetria'), which could explain the broad range of schizophrenic symptoms. In addition, other brain areas were more activated by the task in the patient group than in the control group and may form a compensatory network performing the memory retrieval task by assisting or replacing the dysfunctional cortico-cerebellar circuit.     

Age-related changes in regional cerebral blood flow during working memory for faces

Young and old adults underwent positron emission tomography during the performance of a working memory task for faces (delayed match-to-sample), in which the delay between the sample and choice faces was varied from 1 to 21 s. Reaction time was slower and accuracy lower in the old group, but not markedly so. Values of regional cerebral blood flow (rCBF) were analyzed for sustained activity across delay conditions, as well as for changes as delay increased. Many brain regions showed similar activity during these tasks in both young and old adults, including left anterior prefrontal cortex, which had increased rCBF with delay, and ventral extrastriate cortex, which showed decreased rCBF with delay. However, old adults had less activation overall and less modulation of rCBF across delay in right ventrolateral prefrontal cortex than did the young adults. Old adults also showed greater rCBF activation in left dorsolateral prefrontal cortex across all WM delays and increased rCBF at short delays in left occipitoparietal cortex compared to young adults. Activity in many of these regions was differentially related to performance in that it was associated with decreasing response times in the young group and increasing response times in the older individuals. Thus despite the finding that performance on these memory tasks and associated activity in a number of brain areas are relatively preserved in old adults, differences elsewhere in the brain suggest that different strategies or cognitive processes are used by the elderly to maintain memory representations over short periods of time.     

Neural activation of the brain with hemodynamic insufficiency

Little is known about how ischemia affects hemodynamic responses to neural activation in the brain. We compare the effects of a motor activation task and a cerebral vasodilating agent, acetazolamide (ACZ), on regional cerebral blood flow (rCBF) in primary sensorimotor cortex (PSM) in six patients with major cerebral artery steno-occlusive lesions without paresis of the upper extremities. Quantitative rCBF was measured in all patients using H2(15)O autoradiographic method and positron emission tomography. The CBF was determined at rest, during a bimanual motor activation task, and 10 minutes after ACZ administration. With bimanual motor activation, rCBF increased significantly in both PSM compared with at rest (P < 0.01 on lesion side, and P < 0.02 on contralateral side). However, rCBF did not increase after ACZ injection in the PSM on the lesion side, whereas rCBF increased significantly in the contralateral PSM after ACZ injection compared with the level at rest. This result suggests that despite a decreased hemodynamic reserve, there is a nearly normal flow response to neural activation, indicating that the mechanism of vasodilation responsible for perfusion change is different for acetazolamide and neural activation. The relations among neural activation, hemodynamic status, and cerebral metabolism in the ischemic stroke patients are discussed.     

Adult age differences in the functional neuroanatomy of verbal recognition memory

Adult age differences are frequently observed in the performance of memory tasks, but the changes in neural function mediating these differences are largely unknown. We used (H2)15O positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) during Encoding, Baseline, and Retrieval conditions of a recognition memory task. Twelve young adults (20-29 years) and 12 older adults (62-79 years) participated. During each task condition, participants made a two-choice manual response to each of 64 words. Analyses of the performance data yielded evidence of age-related slowing of encoding and retrieval processes, and an age-related decline in the accuracy of yes/no recognition (d'). The rCBF activation associated with both encoding and retrieval was greater for older adults than for young adults, but this pattern was more clearly evident for memory retrieval. For young adults, rCBF activation during retrieval occurred primarily in right prefrontal cortex, whereas older adults exhibited a more bilateral pattern of prefrontal activation. Regression analyses predicting reaction time in the memory task from regional PET counts confirmed that the neural system mediating memory retrieval is more widely distributed for older adults than for young adults. Both age groups exhibited some decrease in rCBF activation in the second half of the test session, relative to the first half. The practice-related decrease in rCBF activation was more prominent for young adults, suggesting that the older adults' recruitment of additional neural systems reflects a more continual allocation of attention to support task performance.     

Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia

OBJECTIVE: This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity. METHOD: Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined. RESULTS: The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with greater severity of both negative and positive symptoms. CONCLUSIONS: Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.     

Neurobiological findings in first admission patients with schizophrenia or schizophreniform disorder

Fifty patients with a DSM-III-R diagnose of schizophrenia or schizophreniform disorder were compared to 25 healthy volunteers on structural and functional brain measurements. The patients were studied during their first admission to psychiatric hospital. In the patient group correlations between structural and functional brain measurements and clinical symptoms were performed. Brain structure was studied by CT scans. The schizophrenic patients had significantly smaller brain volume and brain length and more sulcal, but not ventricular, CSF than the controls. These findings were not an effect of sex, abuse, educational status or neuroleptic treatment. Brain function was studied by rCBF measurement (at baseline conditions and during mental activation), neuropsychological tests and neurological examination. The patients had significantly lower rCBF in the prefrontal regions during baseline condition and this was more pronounced during mental activation when compared with the controls. In the striatal region the patients had higher rCBF than the controls during activation. In no other region did rCBF differ between the patients and the controls. This points to a dysfunction in schizophrenic patients somewhere in th fronto-striatal-thalamic circuit. The patients performed poorer than the controls on practically all the psychological tests. Especially poor performance was seen in the more complicated tests depending on ability of abstraction, planning and sequential organisation and on semantic memory. The patients had more neurological abnormalities than the controls. Correlations between brain structure and rCBF were few. The neurological impaired patient group had more signs of structural brain deficits than the neurological normal patient group. Poor performance on a variety of psychological tests was correlated to signs of structural cerebral deficits. The significant correlations between the neurobiological measurements and clinical symptoms in the patients were sparse. However there was a trend that more symptoms both positive, negative and thought disorder were correlated to higher rCBF values in frontal, temporal and striatal regions, and that absence of positive symptoms correlated to structural brain deficits. Thus both structural and functional brain deficits can be detected early in the disease of schizophrenia. The findings point to primary cortical deficits probably located in the frontal and temporo-limbic areas.     

The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study

We used H2 15O positron emission tomography (PET) to investigate the effect of ethyl alcohol on regional cerebral blood flow in 6 patients with alcohol-responsive essential tremor and 6 age-matched control subjects. The patients were scanned while at rest and during involuntary postural tremor of the extended right arm. Normal control subjects were scanned at rest and during passive wrist oscillation of the right arm at tremor frequency. Regional cerebral blood flow associated with these conditions was measured before and after oral administration of 2 to 3 units of alcohol. The mean blood alcohol level was 35.3 +/- 20.0 mg/dl in the patient group and caused marked suppression of tremor; it was 33.9 +/- 12.9 mg/dl in the control group. Similar to previous PET studies on essential tremor patients, tremor compared with rest was associated with bilateral cerebellar activation including the cerebellar vermis. This pattern of activation differed from passive wrist oscillation where ipsilateral cerebellar activation was observed. Ethanol ingestion led to bilateral decreases of cerebellar blood flow in both tremor patients and normal subjects, and this was associated with suppression of tremor in the patients. Alcohol-associated increases of regional cerebral blood flow were observed in the inferior olivary nuclei in the patients but not in the control subjects. We conclude that alcohol-induced suppression of essential tremor is mediated via a reduction of cerebellar synaptic overactivity resulting in increased afferent input to the inferior olivary nuclei.     

An association between increased serum-soluble interleukin-2 receptors and a disturbance in muscle force in schizophrenic patients

1. Serum-soluble interleukin-2 receptors (SIL-2Rs), a sign of immune activation, are increased in approximately 30% of schizophrenic subjects. 2. In a recent publication the authors found that SIL-2Rs were particularly elevated in schizophrenic subjects with tardive dyskinesia (TD). 3. This paper investigates the relationship between muscle force instability and SIL-2Rs in 32 schizophrenic patients, 10 of whom were neuroleptic-naive. 4. The authors hypothesized that there would be a positive correlation between increased levels of SIL-2Rs and muscle force instability. 5. Serum SIL-2Rs and muscle force instability were positively correlated (r = 0.54, p < .001) in the schizophrenic patients, and this correlation held even for the subset of neuroleptic-naive patients (r = .73, df 8, p = .016). 6. These findings suggest that there is an important correlation between immune activation and muscle force instability in schizophrenic patients.     

Neural activity during attention shifts between object features

To investigate the neural mechanisms involved in shifting attention we used positron emission tomography to examine regional cerebral blood flow (rCBF) during a task that demands shifting attention between color and shape. Significant activation was observed in the right dorsal prefrontal cortex and parieto-occipital cortex at all frequencies of attention shifts. The frequency of shifts between categories correlated significantly with rCBF in the rostral part of the supplementary motor area and the left precuneus, whereas the number of successive correct responses correlated with rCBF in the orbitofrontal cortex and the caudate nucleus. This study suggests that several prefrontal regions may participate in the processes of shifting attention in different ways.     

Abnormal saccadic distractibility in patients with schizophrenia: a 99mTc-HMPAO SPET study

Recent research has shown that some patients with schizophrenia have a severe impairment in the suppression of reflexive saccadic eye movements in the ANTI-saccade task. This saccadic distractibility has previously been found in patients with lesions of dorsolateral prefrontal cortex, implicating an abnormality of prefrontal cortex. The objective of the present study was to determine the contribution of these and other areas to the ANTI-saccadic abnormality in schizophrenia by functional neuroimaging. Using 99mtechnetium-HMPAO high resolution multidetector single-photon emission tomography, regional cerebral blood flow (rCBF) during performance of the ANTI-saccade eye-movement task was compared, by statistical parametric mapping, in ten male schizophrenic patients on stable antipsychotic medication who had a high distractibility error rate on the task, and eight similar patients who had normal distractibility error rates. Compared with the normal error group, the patients with high error rates showed significantly decreased rCBF bilaterally, in the anterior cingulate, insula, and in left striatum. These same patients also had increased perseverative errors on the Wisconsin Card Sort Test.     

PET study of human voluntary saccadic eye movements in darkness: effect of task repetition on the activation pattern

Using H2(15)O 3D Positron Emission Tomography (PET), regional cerebral blood flow (rCBF) was measured in six human subjects under two different conditions: at rest and while performing self-paced horizontal saccadic eye movements in darkness. These two conditions were repeated four times each. First, the comparison between the four saccadic and four resting conditions was investigated in a group and a single subject analysis. Saccades elicited bilateral rCBF increases in the medial part of the superior frontal gyrus (supplementary eye field), precentral gyrus (frontal eye field), superior parietal lobule, anterior medial part of the occipital lobe involving striate and extrastriate cortex (lingual gyrus and cuneus), and in the right inferior parietal lobule. At the subcortical level, activations were found in the left putamen. These results mainly replicate previous PET findings on saccadic control. Second, the interaction between the experimental conditions and their repetition was examined. When activations throughout repetition of the same saccadic task are compared, the supplementary eye fields show a progressive increase of activation. On the contrary, the activation in the cerebellum, left superior parietal lobule and left occipital cortex progressively decreases during the scanning session. Given the existence of such an interaction, the pattern of activations must be interpreted as a function of task repetition. This may be a factor explaining some apparent mismatch between different studies.     

The interaction between mood and cognitive function studied with PET

BACKGROUND: Experimentally induced depressed mood is a suggested model for retarded depression. We describe the neural response associated with induced mood and the locus of the interaction between systems mediating mood and cognitive function. METHODS: Normal subjects performed a verbal fluency task during induced elated and depressed mood states. Regional cerebral blood flow (rCBF) was measured as an index of neural activity using Positron Emission Tomography (PET). RESULTS: In both elated and depressed mood state rCBF was increased in lateral orbitofrontal cortex, rCBF was also increased in the midbrain in elated mood. In the depressed condition rCBF was decreased in rostral medial prefrontal cortex. Verbal fluency produced an expected increase of rCBF in left dorsolateral prefrontal, inferior frontal and premotor cortex, anterior cingulate and insula cortex bilaterally, the left supramarginal gyrus posteriorly and the thalamus. Activation in the verbal fluency task was attenuated throughout the left prefrontal, premotor and cingulate cortex and thalamus in both elated and depressed mood conditions. An attenuation of anterior cingulate activation was specific to depressed mood. CONCLUSIONS: Alteration of mood is associated with activation of orbitofrontal cortex which may be critical to the experience of emotion. The mood induced modulation of verbal fluency induced activations is consistent with resting state findings of decreased function in these regions in depressed patients. The present data suggest that resting state rCBF profile may represent the modulation of spontaneous activity in this network by a core system that is dysfunctional in depression.     

Adult age differences in regional cerebral blood flow during visual world identification: evidence from H215O PET

We used H215O PET to investigate adult age differences in regional cerebral blood flow (rCBF) during the performance of a visual word identification task. The study participants were 20 healthy, right-handed men: 10 young adults between 18 and 27 years of age, and 10 older adults between 63 and 75 years of age. The word identification task comprised six blocks of test trials representing four task conditions; subjects responded manually. The task conditions varied with regard to whether semantic retrieval was required (e.g., word/nonword discrimination vs simple response to each stimulus) and with regard to the difficulty of visual encoding (e.g., words presented normally vs words with asterisks inserted between adjacent letters). Each subject performed all six trial blocks, concurrently with each of six H215O PET scans. Analyses of quantitative CBF data obtained from the arterial time-activity curve demonstrated a significant age-related decline in global CBF rate. Analyses of the changes in rCBF between task conditions indicated that retrieval of semantic information sufficient to distinguish words from nonwords is mediated by a ventral occipitotemporal cortical pathway. Specific areas within this pathway were also associated with visual encoding processes. Several rCBF activations were significantly greater for young adults than for older adults, indicating an age-related decline in processing efficiency within this ventral occipitotemporal pathway. Although the performance data demonstrated a greater age-related slowing for visual encoding than for semantic retrieval, these age-related performance changes were not associated with corresponding changes in rCBF activation.     

Altered relationships between rCBF in different brain regions of never-treated schizophrenics

AIM: of this study was to investigate the relations between regional cerebral blood flow (rCBF) of different brain regions in acute schizophrenia and following neuroleptic treatment. METHODS: Twenty-two never-treated, acute schizophrenic patients were examined with HMPAO brain SPECT and assessed psychopathologically, and reexamined following neuroleptic treatment (over 96.8 days) and psychopathological remission, rCBF was determined by region/cerebellar count quotients obtained from 98 irregular regions of interest (ROIs), summed up to 11 ROIs on each hemisphere. In acute schizophrenics, interregional rCBF correlations of each ROI to every other ROI were compared to the interregional correlations following neuroleptic treatment and to those of controls. RESULTS: All significant correlations of rCBF ratios of different brain regions were exclusively positive in controls and patients. In controls, all ROIs of one hemisphere except the mesial temporal ROI correlated significantly to its contralateral ROI. Each hemisphere showed significant frontal-temporal correlations, as well as cortical-subcortical and some cortico-limbic. In contrast, in acute schizophrenics nearly every ROI correlated significantly with every other ROI, without a grouping or relation of the rCBF of certain ROIs as in controls. After neuroleptic treatment and clinical improvement, this diffuse pattern of correlations remained. CONCLUSIONS: These results indicate differences in the neuronal interplay between regions in schizophrenic and healthy subjects. In never-treated schizophrenics, diffuse interregional rCBF correlations can be seen as a sign of change and dysfunction of the systems regulating specificity and diversity of the neuronal functions. Neuroleptic therapy and psychopathologic remission showed no normalizing effect on interregional correlations.     

Cerebral blood flow in hypertensive patients: an initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks

We asked whether the altered cerebral vasculature associated with essential hypertension might dampen or redirect the regional cerebral blood flow (rCBF) response to cognitive work. Relative rCBF was assessed with [(15)O]water positron emission tomography during a working memory task, a memory span task, and two perceptual control tasks. Unmedicated hypertensive patients and control subjects differed in rCBF response during both memory tasks. Hypertensives showed relatively diminished rCBF responses in right hemisphere areas combined with compensatory activation of homologous areas in the left cerebral cortex. Essential hypertension appears to selectively influence the circulatory reserve of portions of cerebral cortex and secondarily induce recruitment of other cortical areas to process certain tasks.     

Correlation between regional cerebral blood flow and oxidative metabolism. In vivo studies in man

To test the hypothesis that regional cerebral blood flow (rCBF) is normally regulated by regional metabolic activity, rCBF and the regional cerebral metabolic rate for oxygen (rCMRO2) were compared in selected human subjects. In normal subjects and patients with chronic, stable diseases of brain, rCBF correlated well with rCMRO2. In one individual with mild dementia, rCBF and rCMRO2 were measured before and during exercise of the hand and forearm contralateral to the hemisphere studied. Appropriate parallel changes occurred in both rCBF and rCMRO2 during hand exercise. In patients with acute diseases affecting the hemisphere studied, however, the correlation between rCBF and rCMRO2 was unpredictable.     

Focal cognitively mediated blood-flow activation in Alzheimer's disease patients.

Measured regional cerebral blood flow (rCBF), estimated by the 133-Xe inhalation technique, in 7 Alzheimer's disease (AD) patients (mean age 65.6 yrs) and 7 normal elderly Ss (mean age 65.3 yrs) during the performance of a right–left discrimination task, a sensorimotor control task, and at normal rest. Significant focal task-related blood-flow activation, attributable primarily to the complex cognitive components of the cognitive task, was found in the normal and AD Ss. The determination of cognitively mediated activation was accomplished by using the blood-flow activation during sensorimotor task performance to account for most of the attentional and response requirements of the cognitive task. Although overall rCBFs were significantly higher for AD Ss, this did not result in a significant differential, cognitively mediated activation pattern. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging

BACKGROUND: Functional neuroimaging experiments have implicated prefrontal cortex (PFC) in memory processes. Several studies of schizophrenic patients have shown failure of activation in the dorsolateral region of PFC (DLPFC). We used a graded memory challenge to characterize functional neuroanatomical differences between schizophrenic and control subjects. The graded manipulation of task demands enabled us to assess group differences in the context of normal and abnormal psychological task performance. METHODS: Memory-related activity was assessed using positron emission tomography in schizophrenic patients and age-matched controls during performance of a graded memory task. Subjects underwent scanning while learning and recalling word lists of variable length. RESULTS: We used a model that assessed linear and nonlinear effects of memory load. Nonlinear group differences in DLPFC activation were observed. Controls showed a steepening slope of DLPFC increase as task demands increased. By contrast, schizophrenic subjects showed initial DLPFC increases that fell away with increasing memory load. The DLPFC response in schizophrenic subjects was closely related to measured task performance. In addition, schizophrenic subjects failed to show task-related decreases in activity in the left superior temporal and inferior parietal gyrus. CONCLUSIONS: Patients with schizophrenia showed a failure in DLPFC activation only in the face of diminished performance measures, suggesting that a full characterization of task-related changes in DLPFC activation must consider performance levels. However, striking failures of deactivation in superior temporal and inferior parietal regions were independent of task performance, possibly reflecting a core abnormality of the condition.     

Recognition and treatment of autonomic dysreflexia

We assessed functional relationships between hemispheres by calculating interhemispheric EEG coherence at rest and during photic stimulation in 18 never-medicated patients with paranoid schizophrenia and 30 control subjects. Although no significant group differences were found in the resting EEG, the schizophrenic patients had significantly higher coherence on EEGs recorded during photic stimulation, compared to the control subjects. In this study, we also examined the changes in interhemispheric coherence from rest to the stimulus condition (i.e., stimulation-related coherence reactivity); the patients were found to show significantly greater coherence reactivity to photic stimulation. These findings provide further evidence that schizophrenic patients have a higher degree of interhemispheric functional connectivity and thus have less lateralized cerebral organization than normal subjects. Our results also suggest that schizophrenic patients have excessive functional reorganization between hemispheres in association with photic stimulation.