Activation of Multi-modal Cortical Areas Underlies Short-term Memory

We wanted to examine whether there are cortical fields active in short-term retention of sensory information, independent of the sensory modality. To control for selective attention, response selection and motor output, the cortical activity during short-term memory (STM) tasks was compared with that during detection (DT) tasks. Using positron emission tomography and [¹⁵O]-butanol as a tracer, we measured the regional cerebral blood flow in ten subjects during three STM tasks in which the subjects had to keep in mind: (i) the pitch of tones; (ii) frequencies of a vibrating stylus; and (iii) luminance levels of a monochrome light. Another group of ten subjects undertook three tasks in which subjects detected changes in similar stimuli. Six cortical fields were significantly more activated during STM than during DT. These fields were activated irrespective of sensory modality, and were located in the left inferior frontal gyrus, right superior frontal gyrus, right inferior parietal cortex, anterior cingulate, left frontal operculum and right ventromedial prefrontal cortex. Since the DT tasks and the STM tasks differed only with respect to the STM component, we conclude that the neuronal activity specifically related to retention of the stimuli during the delays was located in these six multi-modal cortical areas. Since no differences were observed in the sensory-specific association cortices, the results indicate further that the activity in the sensory-specific association cortices due to selective attention is not different from the activity underlying short-term retention of sensory information.     

Changes in cerebral blood flow during steady-state cycling exercise: a study using oxygen-15-labeled water with PET

Cerebral blood flow (CBF) during dynamic exercise has never been examined quantitatively using positron emission tomography (PET). This study investigated changes in CBF that occur over the course of a moderate, steady-state cycling exercise. Global and regional CBF (gCBF and rCBF, respectively) were measured using oxygen-15-labeled water (H₂¹⁵O) and PET in 10 healthy human subjects at rest (Rest), at the onset of exercise (Ex1) and at a later phase in the exercise (Ex2). At Ex1, gCBF was significantly (P<0.01) higher (27.9%) than at Rest, and rCBF was significantly higher than at Rest in the sensorimotor cortex for the bilateral legs (M1_Leg and S1_Leg), supplementary motor area (SMA), cerebellar vermis, cerebellar hemispheres, and left insular cortex, with relative increases ranging from 37.6% to 70.5%. At Ex2, gCBF did not differ from Rest, and rCBF was significantly higher (25.9% to 39.7%) than at Rest in only the M1_Leg, S1_Leg, and vermis. The areas showing increased rCBF at Ex1 were consistent with the central command network and the anatomic pathway for interoceptive stimuli. Our results suggest that CBF increases at Ex1 in parallel with cardiovascular responses then recovers to the resting level as the steady-state exercise continues.     

Individual differences in anxiety predict neural measures of visual working memory for untrustworthy faces

When facing strangers, one of the first evaluations people perform is to implicitly assess their trustworthiness. However, the underlying processes supporting trustworthiness appraisal are poorly understood. We hypothesized that visual working memory (VWM) maintains online face representations that are sensitive to physical cues of trustworthiness, and that differences among individuals in representing untrustworthy faces are associated with individual differences in anxiety. Participants performed a change detection task that required encoding and maintaining for a short interval the identity of one face parametrically manipulated to be either trustworthy or untrustworthy. The sustained posterior contralateral negativity (SPCN), an event-related component (ERP) time-locked to the onset of the face, was used to index the resolution of face representations in VWM. Results revealed greater SPCN amplitudes for trustworthy faces when compared with untrustworthy faces, indicating that VWM is sensitive to physical cues of trustworthiness, even in the absence of explicit trustworthiness appraisal. In addition, differences in SPCN amplitude between trustworthy and untrustworthy faces correlated with participants’ anxiety, indicating that healthy college students with sub-clinical high anxiety levels represented untrustworthy faces in greater detail compared with students with sub-clinical low anxiety levels. This pattern of findings is discussed in terms of the high flexibility of aversive/avoidance and appetitive/approach motivational systems.     

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

Using H₂¹⁵O 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.     

Reliability of CT perfusion-derived CBF in relation to hemodynamic compromise in patients with cerebrovascular steno-occlusive disease: a comparative study with 15O PET

In the bolus tracking technique with computed tomography (CT) or magnetic resonance imaging, cerebral blood flow (CBF) is computed from deconvolution analysis, but its accuracy is unclear. To evaluate the reliability of CT perfusion (CTP)-derived CBF, we examined 27 patients with symptomatic or asymptomatic unilateral cerebrovascular steno-occlusive disease. Results from three deconvolution algorithms, standard singular value decomposition (sSVD), delay-corrected SVD (dSVD), and block-circulant SVD (cSVD), were compared with ¹⁵O positron emission tomography (PET) as a reference standard. To investigate CBF errors associated with the deconvolution analysis, differences in lesion-to-normal CBF ratios between PET and CTP were correlated with prolongation of arterial-tissue delay (ATD) and mean transit time (MTT) in the lesion hemisphere. Computed tomography perfusion results strongly depended on the deconvolution algorithms used. Standard singular value decomposition showed ATD-dependent underestimation of CBF ratio, whereas cSVD showed overestimation of the CBF ratio when MTT was severely prolonged in the lesions. The computer simulations reproduced the trend observed in patients. Deconvolution by dSVD can provide lesion-to-normal CBF ratios less dependent on ATD and MTT, but requires accurate ATD maps in advance. A practical and accurate method for CTP is required to assess CBF in patients with MTT-prolonged regions.     

Functional significance of central D1 receptors in cognition: beyond working memory

The role of dopamine D1 receptors in prefrontal cortex function, including working memory, is well acknowledged. However, relatively little is known about their role in other cognitive or emotional functions. We measured both D1 and D2 receptors in the brain using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in cognitive and emotional functions beyond working memory. We found an inverted U-shaped relation between prefrontal D1 receptor availability and Wisconsin Card Sorting Test performance, indicating that too little or too much D1 receptor stimulation impairs working memory or set shifting. In addition, variability of D1 receptor availability in the amygdala and striatum was related to individual differences in emotional responses and decision-making processes, respectively. These observations suggest that the variability of available D1 receptors might be associated with individual differences in brain functions that require phasic dopamine release. An interdisciplinary approach combining molecular imaging of dopamine neurotransmission with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders such as schizophrenia, addiction and Parkinson's disease, as well as novel therapeutics for cognitive impairments observed in them.     

Learning of Sequential Finger Movements in Man: A Combined Kinematic and Positron Emission Tomography (PET) Study

The cerebral structures participating in learning of a manual skill were mapped with regional cerebral blood flow (rCBF) measurements and positron emission tomography in nine healthy volunteers. The task was a complicated right-hand finger movement sequence. The subjects were examined at three stages: during initial practice of the finger movement sequence, in an advanced stage of learning, and after they had learnt the finger movement sequence. Quantitative evaluation of video tapes and electromyographic records of the right forearm and hand muscles demonstrated that the finger movements significantly accelerated and became more regular. Significant mean rCBF increases were induced in the left motor hand area, the left premotor cortex, the left supplementary motor area, the left sensory hand area, the left supplementary sensory area and the right anterior lobe of the cerebellum. During the learning process significant depressions of the mean rCBF occurred bilaterally in the superior parietal lobule, the anterior parietal cortex and the pars triangularis of the right inferior frontal cortex. The mean rCBF increases in these structures during the initial stage of learning were related to somatosensory feedback processing and internal language for the guidance of the finger movements. These activations disappeared when the subjects had learnt the finger movement sequence. Conversely, the mean rCBF significantly rose during the course of learning in the midsector of the putamen and globus pallidus on the left side. It is suggested that during the learning phase of this movement sequence, the basal ganglia were critically involved in the establishment of the final motor programme.     

The neural substrate for working memory of tactile surface texture

Fine surface texture is best discriminated by touch, in contrast to macro geometric features like shape. We used functional magnetic resonance imaging and a delayed match‐to‐sample task to investigate the neural substrate for working memory of tactile surface texture. Blindfolded right‐handed males encoded the texture or location of up to four sandpaper stimuli using the dominant or non‐dominant hand. They maintained the information for 10–12 s and then answered whether a probe stimulus matched the memory array. Analyses of variance with the factors Hand, Task, and Load were performed on the estimated percent signal change for the encoding and delay phase. During encoding, contralateral effects of Hand were found in sensorimotor regions, whereas Load effects were observed in bilateral postcentral sulcus (BA2), secondary somatosensory cortex (S2), pre‐SMA, dorsolateral prefrontal cortex (dlPFC), and superior parietal lobule (SPL). During encoding and delay, Task effects (texture > location) were found in central sulcus, S2, pre‐SMA, dlPFC, and SPL. The Task and Load effects found in hand‐ and modality‐specific regions BA2 and S2 indicate involvement of these regions in the tactile encoding and maintenance of fine surface textures. Similar effects in hand‐ and modality‐unspecific areas dlPFC, pre‐SMA and SPL suggest that these regions contribute to the cognitive monitoring required to encode and maintain multiple items. Our findings stress both the particular importance of S2 for the encoding and maintenance of tactile surface texture, as well as the supramodal nature of parieto‐frontal networks involved in cognitive control. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Differential functional connectivity of prefrontal and medial temporal cortices during episodic memory retrieval

Some theories of brain function emphasize the interactions between brain areas as the major determinant of cognitive and behavioral operations. We explored such interactions in a PET study of episodic memory retrieval having three retrieval conditions, with differing levels of retrieval success. Functional connectivity of voxels located within Brodmann areas 10 and 45/47 in the right prefrontal cortex (RPFC) and the left hippocampus (LGH) with the rest of the brain was estimated using partial least squares. Area 10 and LGH showed an opposite pattern of functional connectivity, with a large expanse of bilateral limbic cortices that was equivalent in all tasks. However, during high retrieval, area 45/47 was included in this pattern. The results suggest that activity in portions of the RPFC reflects either memory retrieval mode or retrieval success, depending on other brain regions to which it is functionally linked. Hum. Brain Mapping 5:323–327, 1997. © 1997 Wiley-Liss, Inc.     

Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study.

BACKGROUND: This study examined cerebral function in posttraumatic stress disorder (PTSD) during the updating of working memory to trauma-neutral, verbal information. METHODS: Ten PTSD and matched control subjects completed a visuoverbal target detection task involving continuous updating (Variable target condition) or no updating (Fixed target condition) of target identity, with updating activity estimated by condition comparison. RESULTS: Normal updating activity using this paradigm involved bilateral activation of the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobe. The PTSD group lacked this activation in the left hemisphere and was significantly different from control subjects in this regard, but showed additional activation in the superior parietal lobe, bilaterally. CONCLUSIONS: The pattern of parietal activation suggests a dependence on visuospatial coding for working memory representation of trauma-neutral, verbal information. Group differences in the relative involvement of the DLPFC indicate less dependence in PTSD on the executive role normally attributed to the left DLPFC for monitoring and manipulation of working memory content in posterior regions of the brain.     

Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study

Summary Patients with combat-related posttraumatic stress disorder (PTSD) show altered cognitive and affective processing and symptomatic responding following exposure to trauma reminders. Previous symptom provocation studies using brain imaging have involved Vietnam veterans. In this study neural correlates were investigated in patients with PTSD resulting from trauma in more recent war zones. ¹⁵Oxygen water and positron emission tomography were used to measure regional cerebral blood flow (rCBF) in patients with war- and combat-related chronic PTSD during exposure to combat and neutral sounds. Self-reports and heart rate confirmed symptomatic responding during traumatic stimulation. The war-related condition, as compared to the neutral, increased rCBF in the right sensorimotor areas (Brodmann areas 4/6), extending into the primary sensory cortex (areas 1/2/3), and the cerebellar vermis. RCBF also increased in the right amygdala and in the periaqueductal gray matter adjacent to the pons. During provocation rCBF was lowered in the right retrosplenial cortex (areas 26/29/30 extending into area 23). Symptom provocation in PTSD promote sensorimotor, amygdaloid and midbrain activation. We conclude that perceptually induced symptom activation in PTSD is associated with an emotionally determined motor preparation and propose that subcortically initiated rather than cortically controlled memory mechanisms determine this pattern. Received: 14 November 2001 / Accepted: 1 March 2002     

Verbal and spatial working memory in older individuals: A positron emission tomography study

Recent reviews of a substantial number of studies have partially resolved questions concerning the brain regions used by working memory for manipulation and representation. We report a large single experiment in middle-aged to older adults (n = 89), classified by hypertensive status. Our design addresses the question of regions related to manipulation and representation, most particularly comparing spatial and verbal working memory. A control, memory search, and 2-back running memory task were performed with identical stimuli and responses during whole-brain 15O water positron emission tomography (PET) scans. Letter or spatial position instructions created verbal or spatial working memory versions of the tasks. We assessed agreement with the literature using regions of interest that were defined by clusters of activation empirically derived from the literature by Wager and Smith (Wager, T.D. and Smith, E.E., Neuroimaging studies of working memory: a meta-analysis, Cognitive, Affective and Behavioral Neuroscience, 3 (2003) 255-274). Our results largely confirmed conclusions from the review on the organization of working memory into dorsal prefrontal manipulation and ventrolateral prefrontal maintenance areas and representation in dorsal and ventral paths. Specific verbal versus spatial comparisons were also concordant with prior work establishing posterior lateralized representation for different contents by working memory. The similarity of results between this older sample and results derived by others from younger participants is notable.     

Dynamic scanning of 15O-butanol with positron emission tomography can identify regional cerebral activations

To determine task-specific activations of the human brain in individual subjects, we applied pixel-by-pixel t-map statistics to the regional cerebral perfusion data obtained sequentially by dynamic scanning of [¹⁵O]-butanol with positron emission tomography (PET). The listmode data were binned into frames of 2 sec, and multiple corresponding pixel-by-pixel activation-minus-control subtractions were used for t-map calculation. The subtraction frames covering 10–40 sec after tracer arrival in the brain showed the activation-related increase of regional cerebral perfusion. A mismatch of the activation and control data by 2 sec resulted in a mean error of <5% of the integrated activity increase. To validate these results, we simulated images with a spatial resolution and signal-to-noise ratio equivalent to that of the [¹⁵O]-butanol subtraction images. By means of these simulated images, we determined the minimal data requirements for t-map analysis, the degree of spatial correlations in the image matrix, and the distribution of noise in the t-maps. The simulation results provided a measure to estimate the significance of regional cerebral perfusion changes recorded with [¹⁵O]-butanol. The location and spatial extent of regional cerebral activations obtained from dynamic data corresponded closely to those obtained with quantitative measurements of regional cerebral blood flow (rCBF). Our results show that statistical parametric mapping of [¹⁵O]-butanol scanning data allows the detection of significant, task-specific brain activations in single activation-control comparisons in individual subjects. Hum. Brain Mapping 5:364–378, 1997. © 1997 Wiley-Liss, Inc.     

Paradoxical reduction of cerebral blood flow after acetazolamide loading: a hemodynamic and metabolic study with 15O PET

Paradoxical reduction of cerebral blood flow (CBF) after administration of the vasodilator acetazolamide is the most severe stage of cerebrovascular reactivity failure and is often associated with an increased oxygen extraction fraction (OEF). In this study, we aimed to reveal the mechanism underlying this phenomenon by focusing on the ratio of CBF to cerebral blood volume (CBV) as a marker of regional cerebral perfusion pressure (CPP). In 37 patients with unilateral internal carotid or middle cerebral arterial (MCA) steno-occlusive disease and 8 normal controls, the baseline CBF (CBF_b), CBV, OEF, cerebral oxygen metabolic rate (CMRO₂), and CBF after acetazolamide loading in the anterior and posterior MCA territories were measured by ¹⁵O positron emission tomography. Paradoxical CBF reduction was found in 28 of 74 regions (18 of 37 patients) in the ipsilateral hemisphere. High CBF_b (>47.6 mL/100 mL/min, n = 7) was associated with normal CBF_b/CBV, increased CBV, decreased OEF, and normal CMRO₂. Low CBF_b (<31.8 mL/100 mL/min, n = 9) was associated with decreased CBF_b/CBV, increased CBV, increased OEF, and decreased CMRO₂. These findings demonstrated that paradoxical CBF reduction is not always associated with reduction of CPP, but partly includes high-CBF_b regions with normal CPP, which has not been described in previous studies.     

The vascular mean transit time: a surrogate for the penumbra flow threshold?

Depicting the salvageable tissue is increasingly used in the clinical setting following stroke. As absolute cerebral blood flow (CBF) is difficult to measure using perfusion magnetic resonance or computed tomography and has limitations as a penumbral marker, time-based variables, particularly the mean transit time (MTT), are routinely used as surrogates. However, a direct validation of MTT as a predictor of the penumbra threshold using gold-standard positron emission tomography (PET) is lacking. Using ¹⁵O-PET data sets obtained from two independent acute stroke samples (N=7 and N=30, respectively), we derived areas under the curve (AUCs), optimal thresholds (OTs), and 90%-specificity thresholds (90%-Ts) from receiver operating characteristic curves for absolute MTT, MTT delay, and MTT ratio to predict three penumbra thresholds (‘classic'': CBF <20 mL/100 g per min; ‘normalized'': CBF ratio <0.5; and ‘stringent'': both CBF <20 mL/100 g per min and oxygen extraction fraction >0.55). In sample 1, AUCs ranged from 0.79 to 0.92, indicating good validity; OTs ranged from 7.8 to 8.3 seconds, 2.8 to 4.7 seconds, and 151% to 267% for absolute MTT, MTT delay, and MTT ratio, respectively, while as expected, 90%-Ts were longer. There was no significant difference between sample 1 and sample 2 for any of the above measurements, save for a single MTT parameter with a single penumbra threshold. These consistent findings from gold-standard PET obtained in two independent cohorts document that MTT is a very good surrogate to CBF for depicting the penumbra threshold.     

Neuroimaging findings in Alzheimer's disease

In the present article, the neuroimaging findings in Alzheimer's disease are summarized and experimental data from animals relating to metabolic changes in Alzheimer's disease (AD), particularly in the frontobasal cholinergic projections onto the cerebral cortex, are reviewed. Changes in glucose metabolism as well as in cerebral blood flow (CBF) are specific for AD, in which the parietotemporal association cortex shows metabolic suppression. This finding is used as a diagnostic aid in the clinical application of single photon emission computed tomography. In rare cases, limited suppression of metabolism and blood flow is also found in the unilateral medial temporal lobe or parietal lobe. Statistically, approximately 80% of cases of AD show a typical parietotemporal suppression pattern of CBF. This cortical metabolic and circulatory suppression has been attributed to cholinergic deprivation from the basal forebrain Mynert nucleus. Animal experiments have revealed transient cortical suppression of glucose metabolism in the frontal cortex after destruction of the basal forebrain cholinergic neurons by ibotenic acid. This suppression persists for approximately 1 week and returns to normal 1 month after operation. Thus, the typical neuroimaging findings in AD would not be due to deficient cholinergic projections from the basal forebrain.     

Rapid quantitative CBF and CMRO2 measurements from a single PET scan with sequential administration of dual 15O-labeled tracers

Positron emission tomography (PET) with ¹⁵O tracers provides essential information in patients with cerebral vascular disorders, such as cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen (CMRO₂). However, most of techniques require an additional C¹⁵O scan for compensating cerebral blood volume (CBV). We aimed to establish a technique to calculate all functional images only from a single dynamic PET scan, without losing accuracy or statistical certainties. The technique was an extension of previous dual-tracer autoradiography (DARG) approach, but based on the basis function method (DBFM), thus estimating all functional parametric images from a single session of dynamic scan acquired during the sequential administration of H₂¹⁵O and ¹⁵O₂. Validity was tested on six monkeys by comparing global OEF by PET with those by arteriovenous blood sampling, and tested feasibility on young healthy subjects. The mean DBFM-derived global OEF was 0.57±0.06 in monkeys, in an agreement with that by the arteriovenous method (0.54±0.06). Image quality was similar and no significant differences were seen from DARG; 3.57%±6.44% and 3.84%±3.42% for CBF, and −2.79%±11.2% and −6.68%±10.5% for CMRO₂. A simulation study demonstrated similar error propagation between DBFM and DARG. The DBFM method enables accurate assessment of CBF and CMRO₂ without additional CBV scan within significantly shortened examination period, in clinical settings.     

Regional cerebral blood flow measured by99mTc-HMPAO SPECT differs in subgroups of Alzheimer's disease

Summary Alzheimer's disease (AD) is a heterogeneous entity. Identifying AD subtypes might have impact in patients' response to different treatment strategies. We designed a study to examine regional cerebral blood flow (rCBF) in AD subtypes. To identify AD subtypes, we performed a cluster analysis including performance on memory, language, visuospatial, praxis, and executive functions. The rCBF measured by^99mTc-HMPAO SPECT was referred to the cerebellum. We examined 35 patients fulfilling the NINCDS-ADRDA criteria of probable AD and 13 age and sex-matched healthy cognitively intact controls. AD patients were at the early stage of the disease, their mean Mini-Mental Status (MMS) score (S.D.) was 22.5 (3.6). The cluster analysis revealed two AD subgroups: AD1 (N=12) and AD2 (N=23). The subgroups did not differ in age, sex, or global clinical severity as assessed by MMS and Brief Cognitive Rating Scale (BCRS). Both subgroups had equally impaired memory. The AD2 group was inferior to the AD1 group on verbal, visuospatial, praxic, and executive functions. The AD1 group showed reduced rCBF ratios in the temporal and parietal cortices and the amygdala compared to controls. The AD2 group differed from controls in the rCBF ratios of frontal, temporal, parietal, occipital, basal ganglia, and amygdaloid regions bilateral and from AD1 in the rCBF ratios of frontal and temporal cortices. In AD patients, the rCBF ratios did not correlate with MMS or BCRS scores. In contrast, several significant correlations were found between decreases rCBF ratios and impairment of memory and other cognitive functions. In conclusion, a cluster analysis on neuropsychological test performance identified two AD subgroups that differed on the neuropsychological profile and on the rCBF in spite of similar global clinical severity.