A test-retest study of cerebral blood flow during somatosensory stimulation in depressed patients with schizophrenia and major depression

Six depressed patients with schizophrenia and 6 depressed patients with major depression were investigated before and during somatosensory stimulation (SS) with Tc-99m HMPAO SPECT. 8 controls were investigated only under resting conditions. The results can be summarized as follows: 1. Both psychiatric patient groups were hypofrontal (dorsolateral prefrontal cortex) compared to controls. 2. Hypofrontality was further enhanced by SS, significantly only in affective psychoses in the right inferior frontal lobe and in the right frontal hemisphere in total, in schizophrenia in the left dorsolateral prefrontal cortex. 3. Within the frontal lobes different regions were affected by SS in the two diagnostic groups. 4. In the right inferior parietal lobe SS response was significantly different in the two illnesses with schizophrenia showing a relative decrease, affective psychoses showing a relative increase of activity. 5. SS produced an increase of cerebral blood flow in subcortical regions (statistically significant contralateral to SS in thalamus and basal ganglia, ipsilateral to SS in cerebellum), a pattern which was common to all psychiatric patients. 6. Somatosensory cortex flow was not changed by SS. In conclusion, we could not fully confirm our hypotheses that similar blood flow abnormalities in different illnesses during SS are only caused by similarities in depressive psychopathology. Instead, depressed patients with schizophrenia were different from depressed patients with major depression in showing decreased activity in interrelating brain regions participating in an attentional network.     

Control of maximum sarcoplasmic reticulum Ca load in intact ferret ventricular myocytes. Effects Of thapsigargin and isoproterenol

Functional neuroanatomical correlates subserving maintenance rehearsal relative to a reading control task were investigated with positron emission tomography imaging of cerebral blood flow in 6 healthy older participants and 6 patients with mild Alzheimer's disease (AD). Rehearsal and reading rates and number of unique words rehearsed did not differ significantly for the 2 groups. The right dorsolateral prefrontal cortex was activated in both groups during rehearsal, highlighting this region's role in short-term maintenance of verbal information. A shift in cortical processing resources to more anterior brain regions with increased rehearsal list length was seen, likely reflecting greater demands on frontal cortex as cognitive load grows. Whereas controls showed unilateral right frontal activation during rehearsal, AD patients demonstrated bilateral frontal activation, possibly reflecting compensatory recruitment of neural resources.     

Compensatory recruitment of neural resources during overt rehearsal of word lists in Alzheimer's disease.

Functional neuroanatomical correlates subserving maintenance rehearsal relative to a reading control task were investigated with positron emission tomography imaging of cerebral blood flow in 6 healthy older participants and 6 patients with mild Alzheimer's disease (AD). Rehearsal and reading rates and number of unique words rehearsed did not differ significantly for the 2 groups. The right dorsolateral prefrontal cortex was activated in both groups during rehearsal, highlighting this region's role in short-term maintenance of verbal information. A shift in cortical processing resources to more anterior brain regions with increased rehearsal list length was seen, likely reflecting greater demands on frontal cortex as cognitive load grows. Whereas controls showed unilateral right frontal activation during rehearsal, AD patients demonstrated bilateral frontal activation, possibly reflecting compensatory recruitment of neural resources. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia

Hypofrontality or reduced activity in the prefrontal cortex, measured as reduced frontal perfusion or glucose uptake, has gained the status of an established finding in the medical literature on schizophrenia. Many relevant studies, however, have potential sources of bias, such as small subject numbers, or unreliable performance of activation tasks by the patients during the scanning procedure. Seventy patients with non-affective and non-organic psychoses were recruited--most qualifying for DSM III-R schizophrenia or schizophreniform psychosis (n = 60)--together with 20 healthy volunteers. They underwent single photon emission computed tomography with 99mTc-exametazime, carried out at rest. Tracer uptake was normalised to the occipital cortex. Group differences in tracer uptake were predicted in anterior regions of interest (prefrontal cortex and mesial frontal/cingulate cortex). Actively psychotic (including schizophrenic) patients not taking any drugs showed increased uptake in the prefrontal cortex. Reduced tracer uptake occurred in the mesial frontal cortex of schizophrenic patients, particularly if they were taking drugs. Relatively increased prefrontal tracer uptake associated with relatively decreased mesial frontal uptake characterised the patients in comparison with the controls. Generalised hypofrontality is, therefore, not a feature of schizophrenic patients at rest whether taking drugs or not.     

Functional imaging, affective disorder and dementia

Perfusion imaging has had modest success thus far in mood disorder. The most consistent findings in both primary major depression and in secondary depression have been reductions in inferior frontal cortex, adjacent cingulate cortex, temporal cortex and basal nuclei. They are compatible with a primary network for the integration of emotional experience in inferior frontal cortex, striatum and amygdala which is partially supported by the findings from relevant lesions and activation studies in normal controls. There are additional findings implicating dorso-lateral prefrontal and adjacent medial/limbic cortex in some patient groups. In elderly men particularly, reductions in prefrontal cortex appear to correlate with cognitive impairment. In dementia, perfusion imaging with single photon emission tomography (SPET) is becoming established as an important clinical tool ancillary to neuropsychological testing. Quantitation and statistical definitions of regional abnormality will be worthwhile innovations as camera systems become more technically advanced.     

Frontostriatal deficits in unipolar major depression

Recent accounts of major depression have tended to focus on dysfunction of frontothalamic-striatal reentrant circuits as a possible source of the disorder. Evidence of frontostriatal involvement in unipolar major depression from lesion and neuropsychological studies, and functional and structural imaging studies is examined. The high incidence of depressive symptomatology following left frontal and basal ganglia lesions implicate these as possible sites of dysfunction. Neuropsychological evidence indicates similar deficits in patients with major depression, perhaps with dorsolateral prefrontal deficits most prominent. Structural imaging studies report frontal and basal ganglia (BG) abnormalities particularly in cases of late-age onset depression. Resting state functional imaging studies show deficits in dorsolateral, anterior cingulate (medial frontal), and BG structures. Activation imaging studies show less consistent evidence of dorsolateral deficit, while anterior cingulate deficit is more consistently demonstrated. Variability in findings across studies may reflect differences between subtypes of depression and differences in methodology. Possible involvement of the BG in the psychomotor retardation of depression is examined. It is concluded that, while there is evidence of frontostriatal deficit in major depression, the exact nature of such deficits is uncertain. Issues such as component vs. system dysfunction need to be addressed.     

"Willed action": a functional MRI study of the human prefrontal cortex during a sensorimotor task

Functional MRI (fMRI) was used to examine human brain activity within the dorsolateral prefrontal cortex during a sensorimotor task that had been proposed to require selection between several responses, a cognitive concept termed "willed action" in a positron emission tomography (PET) study by Frith et al. [Frith, C. D., Friston, K., Liddle, P. F. & Frackowiak, R. S. J. (1991) Proc. R. Soc. London Ser. B 244, 241-246]. We repeated their sensorimotor task, in which the subject chooses to move either of two fingers after a stimulus, by fMRI experiments in a 2.1-T imaging spectrometer. Echo-planar images were acquired from four coronal slices in the prefrontal cortex from nine healthy subjects. Slices were 5 mm thick, centers separated by 7 mm, with nominal in-plane spatial resolution of 9.6 x 5.0 mm2 for mean data. Our mean results are in agreement with the PET results in that we saw similar bilateral activations. The present results are compared with our previously published fMRI study of a verbal fluency task, which had also been proposed by Frith et al. to elicit a "willed action" response. We find a clear separation of activation foci in the left dorsolateral prefrontal cortex for the sensorimotor (Brodmann area 46) and verbal fluency (Brodmann area 45) tasks. Hence, assigning a particular activated region to "willed action" is not supported by the fMRI data when examined closely because identical regions are not activated with different modalities. Similar modality linked activations can be observed in the original PET study but the greater resolution of the fMRI data makes the modality linkages more definite.     

The neuropsychology of the prefrontal cortex

Single photon emission computed tomography with the xenon inhalation technique is used to compare activation of regional cerebral blood flow in frontal brain regions during the performance of four widely used neuropsychological tests: the Continuous Performance Test, the Wisconsin Card Sorting Test, the Tower of London, and Porteus Mazes. Healthy normal volunteers performing these tasks show significant increases in frontal regions during the Continuous Performance Test, the Wisconsin Card Sorting Test, and the Tower of London, but not the Porteus Mazes. Activation produced by the Continuous Performance Test and the Tower of London are mesial and bilateral and may reflect stimulation of midline attentional circuits. The Wisconsin Card Sorting Test produces a left dorsolateral area of prefrontal activation. These findings indicate that regional activation of the frontal lobes occurs in response to cognitive challenges produced through performance of standard neuropsychological tests.     

Emotion-Modulated Performance and Activity in Left Dorsolateral Prefrontal Cortex.

Functional MRI (fMRI) was used to examine the relationship between processing of pleasant and unpleasant stimuli and activity in prefrontal cortex. Twenty volunteers identified the colors in which pleasant, neutral, and unpleasant words were printed. Pleasant words prompted more activity bilaterally in dorsolateral prefrontal cortex (DLPFC) than did unpleasant words. In addition, pleasant words prompted more activity in left than in right DLPFC. Response speed to pleasant words was correlated with DLPFC activity. These data directly link positive affect, enhanced performance, and prefrontal activity, providing some of the first fMRI evidence supporting models of emotional valence and frontal brain asymmetry based on electroencephalography (EEG). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues: evidence for high variability and distinct regulation in diabetes

A recent positron emission tomography (PET) study on brain mechanisms in classical, or Pavlovian, conditioning is reviewed. The PET data were compared with skin conductance data recorded off-line. The participants were five men who participated in three different experimental phases. In the first (habituation) phase, a tone was repeated 24 times at random intervals. In the second (acquisition) phase, the tone was paired with a brief shock to the wrist. In the third (extinction) phase, the tone was presented alone again. Statistical parametric mapping analysis of the PET data showed significantly increased activation of the right hemisphere in the orbitofrontal cortex, dorsolateral prefrontal cortex, inferior and superior frontal cortices, and inferior and middle temporal cortices. In the left hemisphere, only Area 19 and the superior frontal cortex showed significant activation. The findings are discussed within a theoretical framework that argues for different brain mechanisms in acquisition and extinction in classical conditioning.     

Acute effects of cocaine on human brain activity and emotion

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.     

Dynamic pattern of brain activation during sequencing of word strings evaluated by fMRI

An impaired ability to recite highly automated word strings (e.g., the names of the months of the year) in reverse order concomitant with preserved production of the conventional sequence has been considered a salient sign of frontal lobe dysfunction. Using functional magnetic resonance imaging (fMRI), the spatial and temporal pattern of brain activation during covert performance of these tasks was evaluated in healthy subjects. As compared to the response obtained during forward recitation, re-sequencing of the word string yielded additional activation of the bilateral middle and inferior frontal gyri, the posterior parietal cortex and the left anterior cingulate gyrus. The prefrontal responses are in accordance with the clinical findings referred to. However, the set of activated areas, as a whole, presumably reflects contribution of the various components of the working memory system to the sequencing of word strings. During successive periods of task administration, subjects showed a linear increase of production speed. Analysis of corresponding dynamic changes of regional hemodynamic responses revealed a significant increase at the level of the left inferior parietal cortex and a decrease within the mesial aspect of the left superior frontal gyrus. Presumably, the former finding reflects increasing demands on the phonological short-term memory store, due to faster updating of its content under increased word production rate. Decreasing activation within the superior frontal gyrus might indicate contribution of this area to the initiation of the cognitive processes subserving the sequencing of verbal items. These findings demonstrate the capability of fMRI as a powerful tool for the analysis of dynamic brain activation.     

Olfactory-evoked regional cerebral blood flow in Alzheimer's disease.

Olfaction is impaired in Alzheimer's disease (AD). It was hypothesized that AD would reduce olfactory-evoked perfusion in mesial temporal olfactory (piriform) cortex, where neuropathology begins. Seven AD patients and 8 elderly controls (ECs) underwent olfactory threshold and identification tests and olfactory stimulation during positron emission tomography. Odor identification was impaired in AD, but threshold was not. Olfactory stimulation in ECs activated right and left piriform areas and right anterior ventral temporal cortex. AD patients had less activation in right piriform and anterior ventral temporal cortex but not in the left piriform area. Although orbital cortex did not activate in ECs, there was a significant between-groups difference in this area. Right piriform activation correlated with odor identification. Impaired odor identification likely reflects sensory cortex dysfunction rather than cognitive impairment. Given olfactory bulb projections to the mesial temporal lobe, olfactory stimulation during functional imaging might detect early dysfunction in this region. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deep brain stimulation of the subthalamic nucleus selectively improves learning of weakly associated cue combinations during probabilistic classification learning in Parkinson's disease.

Objective: Evidence from functional imaging and clinical studies on patients with Parkinson's disease (PD) or Huntington's disease (HD) suggests that the basal ganglia play a crucial role in learning on the weather prediction task (WPT). Using deep brain stimulation (DBS) on versus off methodology, the aim of this study was to investigate the effect of altering the output from the basal ganglia to the prefrontal cortex on implicit probabilistic classification learning on the WPT by patients with PD. Method: Eleven PD patients with bilateral DBS of the subthalamic nucleus (STN) and 13 matched controls completed 200 trials of the WPT on 2 separate occasions, with the patients tested with DBS of the STN on or off. Results: DBS of the STN had no effect on overall WPT learning. However, STN DBS selectively improved implicit learning of cue combinations that were weakly (implicitly), rather than strongly (explicitly), associated with the WPT outcome. Conclusions: Results suggest that the STN plays a role in implicit probabilistic classification learning by altering basal ganglia output to the frontal cortex. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Dissociating working memory from task difficulty in human prefrontal cortex

A functional magnetic resonance imaging (fMRI) study was conducted to determine whether prefrontal cortex (PFC) increases activity in working memory (WM) tasks as a specific result of the demands placed on WM, or to other processes affected by the greater difficulty of such tasks. Increased activity in dorsolateral PFC (DLPFC) was observed during task conditions that placed demands on active maintenance (long retention interval) relative to control conditions matched for difficulty. Furthermore, the activity was sustained over the entire retention interval and did not increase when task difficulty was manipulated independently of WM requirements. This contrasted with the transient increases in activity observed in the anterior cingulate, and other regions of frontal cortex, in response to increased task difficulty but not WM demands. Thus, this study established a double-dissociation between regions responsive to WM versus task difficulty, indicating a specific involvement of DLPFC and related structures in WM function.     

Functional anatomy of musical processing in listeners with absolute pitch and relative pitch

We used both structural and functional brain imaging techniques to investigate the neural basis of absolute pitch (AP), a specialized skill present in some musicians. By using positron emission tomography, we measured cerebral blood flow during the presentation of musical tones to AP possessors and to control musicians without AP. Listening to musical tones resulted in similar patterns of increased cerebral blood flow in auditory cortical areas in both groups, as expected. The AP group also demonstrated activation of the left posterior dorsolateral frontal cortex, an area thought to be related to learning conditional associations. However, a similar pattern of left dorsolateral frontal activity was also observed in non-AP subjects when they made relative pitch judgments of intervals, such as minor or major. Conversely, activity within the right inferior frontal cortex was observed in control but not in AP subjects during the interval-judgment task, suggesting that AP possessors need not access working memory mechanisms in this task. MRI measures of cortical volume indicated a larger left planum temporale in the AP group, which correlated with performance on an pitch-naming task. Our findings suggest that AP may not be associated with a unique pattern of cerebral activity but rather may depend on the recruitment of a specialized network involved in the retrieval and manipulation of verbal-tonal associations.     

Differential Prefrontal Cortex Activation During Inhibitory Control in Adolescents With and Without Childhood Attention-Deficit/Hyperactivity Disorder.

The authors examined inhibitory control processes in 8 adolescents diagnosed with attention-deficit/ hyperactivity disorder (ADHD) during childhood and in 8 adolescent control participants using functional MRI with the Stimulus and Response Conflict Tasks (K. W. Nassauer & J. M. Halperin, 2003). No group differences in performance were evident on measures of interference control and/or response competition created by location and direction stimuli. However, the ADHD group demonstrated significantly greater activation of the left ventrolateral prefrontal cortex during interference control as well as greater activation of the left anterior cingulate cortex, right ventrolateral prefrontal cortex, and left basal ganglia during the dual task of interference control and response competition. The magnitude of the prefrontal and basal ganglia activation was positively correlated with severity of ADHD. Response competition alone did not yield group differences in activation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vivo imaging of brain nicotinic acetylcholine receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography

The distribution and kinetics of 5-[123I]iodo-A-85380, a novel ligand for brain nicotinic acetylcholine receptors (nAChRs), were evaluated in the Rhesus monkey using single photon emission computed tomography (SPECT). Peak levels of radioactivity were measured in brain at 90 min after injection of the tracer. Accumulation of radioactivity was highest in the thalamus, intermediate in the frontal cortex and basal ganglia, and lowest in the cerebellum. The ratio of specific to nonspecific binding (V3") in the thalamus, estimated from the (thalamic-cerebellar)/cerebellar radioactivity ratio, reached a value of 6 at 4 h post-injection. Specific binding was reduced by subcutaneous injection of 1 mg/kg cytisine at 2.25 h after injection of radiotracer. At 2.5 h after cytisine administration, radioactivity in the thalamus was reduced by 84%, in the frontal cortex, by 76%, and in the basal ganglia, by 57% of the level measured at the time of cytisine administration, demonstrating that the binding was reversible. On the basis of these findings, together with other data indicating high affinity, receptor subtype selectivity, low nonspecific binding and lack of toxicity in animals, 5-[123I]iodo-A-85380 appears to be a promising ligand for SPECT imaging of nAChRs in the human brain.     

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.     

Neural Mechanisms of Affective Interference in Schizotypy.

Negatively valenced stimuli foster cognitive impairment in schizotypy and schizophrenia. To identify relevant brain mechanisms, the authors had 16 positive-schizotypy and 16 control participants perform an emotional Stroop task, judging the ink color of negative and neutral words during functional magnetic resonance imaging (fMRI) of regional brain activity. Schizotypy individuals showed increased right and decreased left activity in dorsolateral prefrontal cortex, indicating a deficit in maintenance of attentional set in the presence of negative emotional distractors. They also showed abnormal activity in ventral limbic areas, including decreased activity in nucleus accumbens and increased activity in hippocampus and amygdala, a circuit involved in the integration of cognitive and affective processes. These results indicate that aspects of emotion-cognition processes and the brain mechanisms that implement them are similar in schizotypy and schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)