Neuropsychological dysfunction in depression: the relationship to regional cerebral blood flow

The relationship between neuropsychological test performance and regional cerebral blood flow (rCBF) was examined in 29 patients meeting Research Diagnostic Criteria (RDC) for major depression. Following a comprehensive neuropsychological assessment two subsets of tests, comprising tests that discriminated between patients and controls or between patients with varying degrees of global cognitive impairment, were selected. These subtests were entered into a principal components analysis (PCA) which generated a two-factor solution, accounting for 50% of the overall variance in test scores. Individual patient loadings on each of these factors were subsequently correlated with regional cerebral blood flow (rCBF), as measured by positron emission tomography (PET). Both factors demonstrated significant correlations with rCBF in the medial prefrontal cortex and frontal polar cortex while for each factor there were also unique patterns of correlations with posterior brain regions. The findings provide additional evidence that neuropsychological deficits in depression are associated with abnormalities in regional brain function and in particular with the function of the medial prefrontal cortex.     

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.     

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.     

Interference and facilitation effects during selective attention: an H215O PET study of Stroop task performance

To investigate the functional anatomy of interference and facilitation during selective attention, we studied 15 normal subjects using the H215O positron emission tomography technique and a computer presented single-trial Stroop task for cognitive activation. Increases in regional cerebral blood flow (rCBF) were observed in a network of structures that have been previously associated with selective attention, including the anterior cingulate gyrus, the frontal polar cortex, the inferior parietal lobule, and the thalamus, as well as the lingual gyrus. Furthermore rCBF decreases (compared to control states) were observed in lateral extra-striate cortex. rCBF changes in prefrontal and extra-striate regions varied with differences in the need to modulate the influence of word and color information while subjects responded to either incongruent or congruent Stroop stimuli. These results indicate the utility of Stroop procedures for investigating the functional anatomy of selective attention. Given recent interest regarding the role of the anterior cingulate gyrus in the pathophysiology of neuropsychiatric disorders, our results also suggest that the Stroop task can serve as a reliable neurobehavioral probe for this region. The significance of these results for understanding processing mechanisms underlying selective attention is discussed within the framework of a parallel distributed processing model of Stroop task performance.     

Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: a resting and activation SPECT study

Regional cerebral blood flow (rCBF) was measured with single photon emission computed tomography (SPECT) in six neuroleptic-naive, young, acute schizophrenic patients and six normal control subjects. We evaluated rCBF changes in prefrontal areas at rest and during a prefrontal activation task, the Wisconsin Card Sorting Test (WCST). Schizophrenic patients had significantly higher prefrontal blood flow than did control subjects during the resting conditions. During activation, the control group showed significant increases in prefrontal blood flow, whereas the schizophrenic group did not. These results suggest that at rest there is no evidence of hypofrontality, whereas hyperfrontality seems to be the most frequent pattern in our selected sample of young acute neuroleptic-naive schizophrenic patients. Furthermore, schizophrenic patients seem to be unable to increase prefrontal blood flow under conditions that challenge the prefrontal cortex.     

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Previous functional imaging studies have demonstrated a number of discrete brain structures that increase activity with noxious stimulation. Of the commonly identified central structures, only the anterior cingulate cortex shows a consistent response during the experience of pain. The insula and thalamus demonstrate reasonable consistency while all other regions, including the lentiform nucleus, somatosensory cortex and prefrontal cortex, are active in no more than half the current studies. The reason for such discrepancy is likely to be due in part to methodological variability and in part to individual variability. One aspect of the methodology which is likely to contribute is the stimulus intensity. Studies vary considerably regarding the intensity of the noxious and non-noxious stimuli delivered. This is likely to produce varying activation of central structures coding for the intensity, affective and cognitive components of pain. Using twelve healthy volunteers and positron emission tomography (PET), the regional cerebral blood flow (rCBF) responses to four intensities of stimulation were recorded. The stimulation was delivered by a CO2 laser and was described subjectively as either warm (not painful), pain threshold just painful), mildly painful or moderately painful. The following group subtractions were made to examine the changing cerebral responses as the stimulus intensity increased: (1) just painful - warm; (2) mild pain - warm; and (3) moderate pain - warm. In addition, rCBF changes were correlated with the subjective stimulus ratings. The results for comparison '1' indicated activity in the contralateral prefrontal (area 10/46/44), bilateral inferior parietal (area 40) and ipsilateral premotor cortices (area 6), possibly reflecting initial orientation and plans for movement. The latter comparisons and correlation analysis indicated a wide range of active regions including bilateral prefrontal, inferior parietal and premotor cortices and thalamic responses, contralateral hippocampus, insula and primary somatosensory cortex and ipsilateral perigenual cingulate cortex (area 24) and medial frontal cortex (area 32). Decreased rCBF was observed in the amygdala region. These responses were interpreted with respect to their contribution to the multidimensional aspects of pain including fear avoidance, affect, sensation and motivation or motor initiation. It is suggested that future studies examine the precise roles of each particular region during the central processing of pain.     

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.     

Dissociable forms of inhibitory control within prefrontal cortex with an analog of the Wisconsin Card Sort Test: restriction to novel situations and independence from "on-line" processing

Attentional set-shifting and discrimination reversal are sensitive to prefrontal damage in the marmoset in a manner qualitatively similar to that seen in man and Old World monkeys, respectively (Dias et al., 1996b). Preliminary findings have demonstrated that although lateral but not orbital prefrontal cortex is the critical locus in shifting an attentional set between perceptual dimensions, orbital but not lateral prefrontal cortex is the critical locus in reversing a stimulus-reward association within a particular perceptual dimension (Dias et al., 1996a). The present study presents this analysis in full and extends the results in three main ways by demonstrating that (1) mechanisms of inhibitory control and "on-line" processing are independent within the prefrontal cortex, (2) impairments in inhibitory control induced by prefrontal damage are restricted to novel situations, and (3) those prefrontal areas involved in the suppression of previously established response sets are not involved in the acquisition of such response sets. These findings suggest that inhibitory control is a general process that operates across functionally distinct regions within the prefrontal cortex. Although damage to lateral prefrontal cortex causes a loss of inhibitory control in attentional selection, damage to orbitofrontal cortex causes a loss of inhibitory control in affective processing. These findings provide an explanation for the apparent discrepancy between human and nonhuman primate studies in which disinhibition as measured on the Wisconsin Card Sort Test is associated with dorsolateral prefrontal damage, whereas disinhibition as measured on discrimination reversal is associated with orbitofrontal damage.     

Frontotemporal cerebral blood flow change during executive and declarative memory tasks in schizophrenia: A positron emission tomography study.

Schizophrenia affects prefrontal and temporal-limbic networks. These regions were examined by contrasting regional cerebral blood flow (rCBF) during executive (Wisconsin Card Sorting Test [WCST]), and declarative memory tasks (Paired Associate Recognition Test [PART]). The tasks, and a resting baseline, were administered to 15 patients with schizophrenia and 15 healthy controls during 10 min positron emission tomography 1?O-water measures of rCBE Patients were worse on both tasks. Controls activated inferior frontal, occipitotemporal, and temporal pole regions for both tasks. Similar results were obtained for controls matched to level of patient performance. Patients showed no activation of hypothesized regions during the WCST and activated the dorsolateral prefrontal cortex during the PART. On the PART, occipitotemporal activation correlated with better performance for controls only. Better WCST performance correlated with CBF increase in prefrontal regions for controls and in the parahippocampal gyrus for patients. Results suggest that schizophrenia may involve a breakdown in the integration of a frontotemporal network that is responsive to executive and declarative memory demands in healthy individuals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regional cerebral blood flow during the Wisconsin Card Sorting Test in normal subjects studied by xenon-133 dynamic SPECT: comparison of absolute values, percent distribution values, and covariance analysis

We studied regional cerebral blood flow (rCBF) by xenon-133 dynamic single photon emission computed tomography (SPECT) in 17 normal volunteers who were performing the Wisconsin Card Sorting Test (WCST), a task that is particularly sensitive to disturbance of the prefrontal cortex, and a simple matching-to-sample task (BAR) as a sensorimotor control. Three methods for statistical analysis of regional "subtraction" data were used: absolute rCBF values, percent distribution values, and means adjusted for global CBF changes (covariance analysis). The absolute values had high variance, due to the combination of interindividual differences in global flow and intra-individual variation, and showed no statistically significant regional changes. This variation was greatly reduced by percent values and covariance analysis, which had quite similar outcomes. With both methods, significant increases of rCBF during the WCST as compared with the BAR were seen in the right anterior dorsolateral prefrontal and left occipital cortices, and reduction of rCBF in the left pararolandic region. Moreover, significant correlations with performance were found in the medial regions of the frontal lobes, with opposite trends for the right and left hemisphere. The posterior dorsolateral prefrontal region showed a negative correlation with sensory-motor frequency, an index related to the task's difficulty. These results are consistent with previous findings using other rCBF techniques and confirm the statistical advantage of normalization and covariance methods, which yield practically identical results, at least in this analysis based on regions of interest.     

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.     

Fear conditioning and brain activity: A positron emission tomography study in humans.

Regional cerebral blood flow (rCBF) was measured with H? 1?O positron emission tomography in 8 healthy women before and after fear conditioning (i.e., paired shocks) and unpaired shocks to videotape cues. Conditioning was supported by enhanced peripheral nervous system recordings and subjective ratings. Fear conditioning increased rCBF in the central gray of the midbrain; bilaterally in the hypothalamus, the thalamus, and the left striatum; and in the right and left anterior cingulate and right prefrontal cortices. Regional CBF was attenuated bilaterally in the right and left prefrontal, temporal (including the amygdala), parietal, and occipital cortices, and in the left orbitofrontal cortex. When compared with unpaired shock presentations, fear conditioning resulted in elevated rCBF in the left cerebellum. Hence, in the present paradigm, only neural activity in the left cerebellum solely reflected processes associated with true Pavlovian conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural evidence linking visual object enumeration and attention

Visual object enumeration is rapid and accurate for four or fewer items but slow and error-prone for over four items. This dichotomy has recently been linked to visual attentional phenomena by findings suggesting that 'subitizing' of small sets of objects is preattentive whereas 'counting' of over four items demands spatial shifts of attention. We evaluated this link at a neural level, using H2 15-O positron emission tomography to measure changes in regional cerebral blood flow while subjects enumerated the number of target vertical bars that 'popped out' of a 16-bar visual display consisting of both horizontal and vertical bars. Relative to a condition with a single target, subitizing (one to four targets) activated foci in the occipital extrastriate cortex, consistent with involvement of early, preattentive visual processes. Relative to subitizing, counting (five to eight targets) activated a widespread network of brain regions, including multiple foci implicated in shifting visual attention-large regions of the superior parietal cortex bilaterally and a focus in the right inferior frontal cortex. These results offer the first direct neural support for mapping the subitizing-counting dichotomy onto separable processes mediating preattentive vision and shifts of visual attention.     

Neuropsychological correlates of early symptoms of autism

Both the medial temporal lobe and dorsolateral prefrontal cortex have been implicated in autism. In the present study, performance on two neuropsychological tasks--one tapping the medial temporal lobe and related limbic structures, and another tapping the dorsolateral prefrontal cortex--was examined in relation to performance on tasks assessing autistic symptoms in young children with autism, and developmentally matched groups of children with Down syndrome or typical development. Autistic symptoms included orienting to social stimuli, immediate and deferred motor imitation, shared attention, responses to emotional stimuli, and symbolic play. Compared with children with Down syndrome and typically developing children, children with autism performed significantly worse on both the medial temporal lobe and dorsolateral prefrontal tasks, and on tasks assessing symptoms domains. For children with autism, the severity of autistic symptoms was strongly and consistently correlated with performance on the medial temporal lobe task, but not the dorsolateral prefrontal task. The hypothesis that autism is related to dysfunction of the medial temporal lobe and related limbic structures, such as the orbital prefrontal cortex, is discussed.     

Impairment of executive function induced by hypertension in the Rhesus monkey (Macaca mulatta).

The effects of chronic, untreated hypertension on executive function were investigated in a nonhuman primate model of hypertensive cerebrovascular disease. Executive function was assessed with the Conceptual Set-Shifting Task (CSST), a task adapted from the human Wisconsin Card Sorting Test (WCST). Like the WCST, the CSST requires abstraction of a stimulus set, followed by a series of set shifts. Performance on the CSST by 7 young adult monkeys (Macaca mulatta) with surgically induced hypertension was compared with that of 6 normotensive monkeys. The hypertensive group was significantly impaired relative to the normotensive group in abstraction and set shifting. Although the neural basis of this impairment is unclear, evidence from studies with humans and monkeys suggests that the prefrontal cortex may be the locus for this effect of hypertension. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Production and characterization of profilin monoclonal antibodies

To evaluate the hypothesis that self-paced movements are mediated primarily by the supplementary motor area, whereas externally triggered movements are mainly affected by the lateral premotor cortex, different movements in 6 healthy volunteers were studied while changes in regional cerebral blood flow (rCBF) were measured using positron emission tomography (PET) and 15O-labeled water. Subjects made a series of finger opposition movements initiated in a self-paced manner every 4 to 6 seconds, and separately, made continuous finger opposition movements at a frequency of 2 Hz paced by a metronome. The primary motor cortex, lateral area 6, cerebellum on both sides, and caudal cingulate motor area, and the putamen and thalamus on the contralateral side were more active during the metronome-paced movements. The increases in rCBF in these areas are likely the result of the larger number of movements per minute made with the externally triggered task. The anterior supplementary motor area and rostral cingulate motor area in the midline, prefrontal cortices bilaterally, and lobus parietalis inferior on the ipsilateral side were more active during the self-paced movements. Increases in rCBF in those areas, which include medial premotor structures, may be related to the increased time devoted to planning the movement in this condition.     

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 frequency and distribution of spontaneous attention shifts between social and nonsocial stimuli in autistic, typically developing, and nonautistic developmentally delayed infants

Spontaneous shifts of attention were observed in autistic, typically developing, and nonautistic developmentally delayed infants. Three types of attention shifting behaviour were observed; (1) between an object and another object, (2) between an object and a person, and (3) between a person and another person. The two control groups shifted attention more frequently between an object and a person than between an object and another object or between a person and another person. The infants with autism showed a different pattern, shifting attention between an object and another object more than any other type of shift. Furthermore, infants with autism showed fewer shifts of attention between an object and a person, and between person and person, than did the two control groups. They also spent less time overall looking at people and looked more briefly at people and for longer durations at objects, compared to the two control groups. These results indicate an abnormality in social orientation in autism even at the early age of 20 months.     

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.     

Anatomy of motor learning. I. Frontal cortex and attention to action

We used positron emission tomography to study new learning and automatic performance in normal volunteers. Subjects learned sequences of eight finger movements by trial and error. In a previous experiment we showed that the prefrontal cortex was activated during new learning but not during during automatic performance. The aim of the present experiment was to see what areas could be reactivated if the subjects performed the prelearned sequence but were required to pay attention to what they were doing. Scans were carried out under four conditions. In the first the subjects performed a prelearned sequence of eight key presses; this sequence was learned before scanning and was practiced until it had become overlearned, so that the subjects were able to perform it automatically. In the second condition the subjects learned a new sequence during scanning. In a third condition the subjects performed the prelearned sequence, but they were required to attend to what they were doing; they were instructed to think about the next movement. The fourth condition was a baseline condition. As in the earlier study, the dorsal prefrontal cortex and anterior cingulate area 32 were activated during new learning, but not during automatic performance. The left dorsal prefrontal cortex and the right anterior cingulate cortex were reactivated when subjects paid attention to the performance of the prelearned sequence compared with automatic performance of the same task. It is suggested that the critical feature was that the subjects were required to attend to the preparation of their responses. However, the dorsal prefrontal cortex and the anterior cingulate cortex were activated more when the subjects learned a new sequence than they were when subjects simply paid attention to a prelearned sequence. New learning differs from the attention condition in that the subjects generated moves, monitored the outcomes, and remembered the responses that had been successful. All these are nonroutine operations to which the subjects must attend. Further analysis is needed to specify which are the nonroutine operations that require the involvement of the dorsal prefrontal and anterior cingulate cortex.