Metabolic connectivity as index of verbal working memory

Positron emission tomography (PET) data are commonly analyzed in terms of regional intensity, while covariant information is not taken into account. Here, we searched for network correlates of healthy cognitive function in resting state PET data. PET with [¹⁸F]-fluorodeoxyglucose and a test of verbal working memory (WM) were administered to 35 young healthy adults. Metabolic connectivity was modeled at a group level using sparse inverse covariance estimation. Among 13 WM-relevant Brodmann areas (BAs), 6 appeared to be robustly connected. Connectivity within this network was significantly stronger in subjects with above-median WM performance. In respect to regional intensity, i.e., metabolism, no difference between groups was found. The results encourage examination of covariant patterns in FDG-PET data from non-neurodegenerative populations.     

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     

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.     

Common prefrontal activations during working memory,episodic memory,and semantic memory

Regions of the prefrontal cortex (PFC) are typically activated in many different cognitive functions. In most studies, the focus has been on the role of specific PFC regions in specific cognitive domains, but more recently similarities in PFC activations across cognitive domains have been stressed. Such similarities may suggest that a region mediates a common function across a variety of cognitive tasks. In this study, we compared the activation patterns associated with tests of working memory, semantic memory and episodic memory. The results converged on a general involvement of four regions across memory tests. These were located in left frontopolar cortex, left mid-ventrolateral PFC, left mid-dorsolateral PFC and dorsal anterior cingulate cortex. These findings provide evidence that some PFC regions are engaged during many different memory tests. The findings are discussed in relation to theories about the functional contribution of the PFC regions and the architecture of memory.     

Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia.

BACKGROUND: Patients with schizophrenia demonstrate poor verbal memory, ascribed to impaired prefrontal and hippocampal function. Healthy adults can increase recall accuracy following encoding interventions, such as item repetition and the formation of semantic associations. We examined the effects of these interventions on both memory performance and retrieval-related hippocampal activity in healthy adults and patients with schizophrenia. METHODS: Twelve patients with schizophrenia and twelve healthy control subjects participated. During study, subjects counted either the number of meanings or T-junctions in words seen only once or repeated four times. At test, O15-positron emission tomography scans were acquired while subjects completed word-stems with previously studied items. RESULTS: Control subjects recalled more words overall, but both groups demonstrated similar performance benefits following deeper encoding. Both item repetition and the use of a semantic encoding task were associated with memory retrieval-related hippocampal recruitment in control but not schizophrenic participants. Patients with schizophrenia demonstrated greater activation of prefrontal cortical areas during word retrieval. CONCLUSIONS: Despite a lack of hippocampal recruitment, patients with schizophrenia showed intact modulation of memory performance following both encoding interventions. Impaired hippocampal recruitment, in concert with greater prefrontal activation, may reflect a specific deficit in conscious recollection in schizophrenia.     

Hemispheric differences in neural systems for face working memory: A PET-rCBF study

Neural systems that participate in working memory for faces were investigated in an experiment designed to distinguish face perception areas from working memory areas. Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) while subjects performed a sensorimotor control task, a face perception control task, and five working memory tasks with parametrically varied retention intervals, ranging from 1 to 21 sec. Striate and ventral occipitotemporal extrastriate areas demonstrated a simple negative correlation between rCBF and retention delay, indicating that these areas participate principally in perceptual operations performed during visual stimulation. By contrast, right and left frontal areas demonstrated rCBF increases that were significantly more sustained across delays than were increases in ventral extrastriate areas, but the relation between rCBF and retention interval differed significantly by hemisphere. Whereas right frontal rCBF showed a nonsignificant tendency to diminish at longer delays, left inferior frontal, middle frontal, and anterior cingulate cortex, as well as left parietal and inferior temporal cortex, demonstrated their largest rCBF increases at the longest delays. These results indicate that right frontal and left frontal, parietal, and temporal areas all participate in face working memory, but that left hemisphere areas are associated with a more durable working memory representation or strategy that subjects rely on increasingly with longer retention intervals. One possible explanation for this hemispheric difference is that left hemisphere activity is associated with a face representation that embodies the result of more analysis and elaboration, whereas right frontal activity is associated with a simpler, icon-like image of a face that is harder to maintain in working memory. © 1995 Wiley-Liss, Inc.     

Cortical control of complex sequential movement studied by functional neuroimaging techniques

Recent advances in functional neuroimaging techniques permit non-invasive visualization of the human brain functions. In the central mechanism for controlling complex sequential movement, several candidate brain regions have been suggested to participate in a different way by the previous studies. The motor executive areas including the bilateral primary sensorimotor area and supplementary motor area, appear to play an executive role in running motor sequences, regardless of their length, and increase their activity associated with implicit or procedural learning of motor sequence. In contrast, the fronto-parietal network including the bilateral premotor, prefrontal and posterior parietal cortices appears to be related to the length of sequence performed and increases its activity associated with explicit or declarative learning of motor sequence. Although these techniques provide useful information on human physiology and pathophysiology in various brain functions, in order to explore functional relevance of findings it is important to combine functional neuroimaging studies with other modalities of physiological techniques.     

Modulation of human medial temporal lobe activity by form,meaning, and experience

Clinically, the hallmark of the human amnesic syndrome is an impaired ability to consciously recollect or remember daily events. If the medial region of the temporal lobes, including the hippocampus and related structures, is critical for establishing these new memories, then this brain region should be active whenever events are experienced, regardless of whether subjects are asked explicitly to learn and remember. Here we show that the medial temporal region is active during encoding and that the hemisphere activated and the amount of activation depend on the type of stimulus presented (objects or words), whether the stimulus can be encoded for meaning (real objects and words versus nonsense objects and words), and task experience (first versus the second time a task is performed). These findings demonstrate that the medial temporal lobe memory system is engaged automatically when we attend to a perceptual event and that the location and amount of activation depend on stimulus characteristics (physical form, meaning) and experience. Hippocampus 1997;7:587–593. © 1997 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.     

"Central command" and insular activation during attempted foot lifting in paraplegic humans

The relationship between cardiovascular regulation and brain activation was investigated during attempted foot lifting in paraplegic subjects and during rhythmic handgrip exercise at one-third of maximum voluntary contraction force. Brain areas of interest were the primary sensory-motor area and the insula, a hypothesized center for a central nervous feed-forward mechanism involved in cardiovascular control ("central command"). This mechanism is complementary to the usual known feedback pathways such as skeletal muscle afferent signals. Regional cerebral blood flow (rCBF) was measured in eight normal and three paraplegic subjects using positron emission tomography (PET) and oxygen-15-labeled water. Statistical parametric maps were calculated from the images comparing rest and handgrip. Paraplegics were also scanned during attempted foot lifting, a condition without sensory feedback. During activation tasks, heart rate and mean arterial pressure increased. PET activation responses (P < 0.05, corrected for multiple comparisons) were found in the contralateral primary sensory-motor area, the supplementary motor area, ipsilateral cerebellum, and bilaterally in the insula. A conjunction analysis showing responses common to handgrip and attempted foot lifting revealed activation in the right central insula (P < 0.05, corrected) in concordance with the concept of a central command feed-forward hypothesis.     

Changes of effective connectivity between the lateral and medial parts of the prefrontal cortex during a visual task

Structural equation modelling was used to study the change of connectivity during a visual task with continuous variation of the attention load. The model was based on areas defined by the haemodynamic responses described elsewhere [Mazoyer, P., Wicker, B. & Fonlupt, P. (2002) A neural network elicited by parametric manipulation of the attention load. Neuroreport, 13, 2331-2334], including occipitotemporal, parietal, temporal and prefrontal (lateral and medial areas) cortices. We have studied stationary- (which does not depend on the attentional load) and attention-related coupling between areas. This allowed the segregation of two subsystems. The first could reflect a system performing the integration step of the visual signal and the second a system participating in response selection. The major finding is the mutual negative influence between the lateral and medial parts of the prefrontal cortex. This negative influence between these two brain regions increased with the attention load. This is interpreted as a modification of the balance between integration and decision processes that are needed for the task to be efficiently completed.     

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.     

Vibratory stimulation increases and decreases the regional cerebral blood flow and oxidative metabolism: a positron emission tomography (PET) study

The aim of this study was to examine the hypothesis, if the activation of some cerebral structures due to physiological stimulation is accompanied by deactivations of other structures elsewhere in the brain. A vibratory stimulus was applied to the right hand palm of healthy volunteers and the regional cerebral blood flow (rCBF) and regional cerebral oxygen metabolism (rCMRO2) were measured with positron emission tomography (PET). Regional analysis and voxel-by-voxel plots indicated that the stimulation induced increases and decreases of the rCBF were coupled to increases and decreases of the rCMRO2. The increases were localized in the left primary somatosensory area (SI), the left secondary somatosensory area (SII), the left retroinsular field (RI), the left anterior parietal cortex, the left primary motor area (MI), and the left supplementary motor area (SMA). The decreases occurred bilaterally in the superior parietal cortex, in paralimbic association areas, and the left globus pallidus. The increases and decreases of the rCBF and rCMRO2 were balanced in such a way that the mean global CBF and CMRO2 did not change compared with rest. We conclude that the decreases of the cerebral oxidative metabolism indicated regional depressions of synaptic activity.     

Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto‐temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto‐temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1‐week of antipsychotic treatment. Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto‐temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1‐week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto‐temporal dysconnectivity. Patterns of fronto‐temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. Hum Brain Mapp 36:1442–1457, 2015. © 2014 Wiley Periodicals, Inc.     

Memory loss due to transient hypoperfusion in the medial temporal lobes including hippocampus

A typical case of transient global amnesia (TGA) was investigated with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) with 1.5-tesler scans. During the amnesic episode, a marked decrease of cerebral blood flow was observed in the areas confined to the territory of the bilateral posterior cerebral arteries including the hippocampus. After the episode, cerebral blood flow returned to normal and a circumscribed lesion was detected in the middle portion of CA 1 field of the left hippocampus. The SPECT findings prove direct evidence that the medial temporal structures are involved in the establishment of new memories, as well as in process of recalling only recently acquired memories, but not in retrieval of memories acquired long ago. The MRI findings indicate that a unilateral partial damage to CA 1 sector of the hippocampus does not develop a definite memory impairment and that high-resolution MRI study on the hippocampus is necessary in TGA patients.     

Metabolic evidence for episodic memory plasticity in the nonepileptic temporal lobe of patients with mesial temporal epilepsy

Purpose: Metabolic changes have been described in the nonepileptic temporal lobe of patients with unilateral mesiotemporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS). To better understand the functional correlate of this metabolic finding, we have sought to characterize brain regions in patients with MTLE that show correlation between unilateral episodic memory performances, as assessed by intracarotid amobarbital test (IAT), and interictal regional cerebral metabolism measured by [¹⁸F]‐fluorodeoxyglucose positron emission tomography (FDG‐PET). Methods: Resting FDG‐PET was performed interictally in 26 patients with unilateral MTLE caused by HS (16 female, mean age: 36 years; 16 left HS). Using statistical parametric mapping (SPM8), we performed a group comparison analysis comparing brain metabolism in the patients and in 54 adult controls (27 female, mean age: 32 years), with FDG‐PET data of right HS patients being flipped. IAT scores of nonepileptic hemisphere functions (amobarbital injection ipsilateral to HS) were used as covariates of interest in a correlation analysis with regional brain metabolism. Key Findings: The group comparison analysis revealed significant hypometabolic areas in a widespread temporofrontal network ipsilateral to HS. In addition, a significant increase in metabolism was found in mesial and lateral temporal regions contralateral to HS. Significant positive correlations were found between IAT scores of nonepileptic hemisphere functions and mesial temporal metabolism in this hemisphere. Significance: This study demonstrates the existence of significant increase in relative regional cerebral glucose metabolism in mesial and lateral temporal regions contralateral to the epileptic focus in patients with unilateral MTLE associated with HS. The positive correlation in these brain regions between IAT scores and metabolism supports the role of disease‐induced plasticity mechanisms contralateral to HS in the preservation of episodic memory processes.     

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.     

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.     

Age-related differences in the functional connectivity of the hippocampus during memory encoding

The purpose of the current experiment was to examine the functional connectivity of the hippocampus during encoding in young and old adults, and the way in which this connectivity was related to recognition performance. Functional connectivity was defined as the correlation between activity in the hippocampus and activity in the rest of the brain, as measured by neuroimaging. During encoding of words and pictures of objects in young adults, hippocampal activity was correlated with activity in the ventral prefrontal and extrastriate regions, and increased activity in all these regions was associated with better recognition. In contrast, older adults showed correlations between hippocampal activity and the dorsolateral prefrontal and parietal regions, and positive correlations between activity in these regions and better memory performance. This ventral/dorsal distinction suggests a shift in the cognitive resources used with age from more perceptually based processes to those involved in executive and organizational functions. The results of this study provide evidence that aging is associated with alterations in hippocampal function, including how it is functionally connected with prefrontal cortex, and that these alterations have an impact on memory performance.     

Cerebral blood flow during anticipation of public speaking in social phobia: a PET study.

BACKGROUND: The aim was to examine the neural correlates of anxiety elicited by the anticipation of public speaking in individuals with social phobia.Positron emission tomography and (15)O-water was used to measure regional cerebral blood flow in subjects with DSM-IV defined social phobia during anxiety anticipation. Heart rate and subjective anxiety were also recorded. While being scanned, subjects were speaking alone either before or after speaking in public. To evaluate anticipatory anxiety we compared individuals speaking alone before they were speaking in front of an audience with those who did the reverse. RESULTS: Heart rate and subjective anxiety measures confirmed anticipatory anxiety in social phobics who performed their private speech before their public. This was accompanied by enhanced cerebral blood flow in the right dorsolateral prefrontal cortex, left inferior temporal cortex, and in the left amygdaloid-hippocampal region. Brain blood flow was lower in the left temporal pole and bilaterally in the cerebellum in the anticipation group. CONCLUSIONS: Brain regions with altered perfusion presumably reflect changes in neural activity associated with worry about anticipated public performance. We speculate that anticipatory anxiety in social phobics originates in an affect sensitive fear network encompassing the amygdaloid-hippocampal region, prefrontal, and temporal areas.     

How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain?

Transcranial direct current stimulation (tDCS) of the primary motor hand area (M1) can produce lasting polarity-specific effects on corticospinal excitability and motor learning in humans. In 16 healthy volunteers, O positron emission tomography (PET) of regional cerebral blood flow (rCBF) at rest and during finger movements was used to map lasting changes in regional synaptic activity following 10 min of tDCS (+/-1 mA). Bipolar tDCS was given through electrodes placed over the left M1 and right frontopolar cortex. Eight subjects received anodal or cathodal tDCS of the left M1, respectively. When compared to sham tDCS, anodal and cathodal tDCS induced widespread increases and decreases in rCBF in cortical and subcortical areas. These changes in rCBF were of the same magnitude as task-related rCBF changes during finger movements and remained stable throughout the 50-min period of PET scanning. Relative increases in rCBF after real tDCS compared to sham tDCS were found in the left M1, right frontal pole, right primary sensorimotor cortex and posterior brain regions irrespective of polarity. With the exception of some posterior and ventral areas, anodal tDCS increased rCBF in many cortical and subcortical regions compared to cathodal tDCS. Only the left dorsal premotor cortex demonstrated an increase in movement related activity after cathodal tDCS, however, modest compared with the relatively strong movement-independent effects of tDCS. Otherwise, movement related activity was unaffected by tDCS. Our results indicate that tDCS is an effective means of provoking sustained and widespread changes in regional neuronal activity. The extensive spatial and temporal effects of tDCS need to be taken into account when tDCS is used to modify brain function.