Positive evidence against human hippocampal involvement in working memory maintenance of familiar stimuli

Subjects (n = 40) performed a delayed item recognition task for visually presented letters with three set sizes (1, 3 or 6 letters). Accuracy was close to ceiling at all set sizes, so we took set size as a proxy for WM load (i.e. the amount of information being maintained in WM). Functional magnetic resonance imaging (fMRI) signal associated with the delay period increased in a nearly linear fashion with WM load in the left inferior frontal gyrus/anterior insula (possibly Broca's area, BA 44/45), right anterior insula, bilateral caudate, bilateral precentral gyrus (BA 6), bilateral middle frontal gyrus (BA 9/46), bilateral inferior parietal lobule (with foci in both BA 39 and 40), left superior parietal lobule (BA 7), medial frontal gyrus (BA 6), anterior cingulate gyrus (BA 32) and bilateral superior frontal gyrus (BA 8). These results lend support to the idea that at least some of the cortical mechanisms of WM maintenance, potentially rehearsal, exhibit a scaling with WM load. In contrast, the delay-related fMRI signal in hippocampus followed an inverted U-shape, being greatest during the intermediate level of WM load, with relatively lower values at the lowest and highest levels of WM load. This pattern of delay-related fMRI activity, orthogonal to WM load, is seemingly not consonant with a role for hippocampus in WM maintenance of phonologically codable stimuli. This finding could possibly be related more to the general familiarity of the letter stimuli than their phonological codability per se.     

Repetitive transcranial magnetic stimulation effects on brain function and cognition among elders with memory dysfunction. A randomized sham-controlled study

In the present study, we aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on memory performance and brain activity in elders presenting with subjective memory complaints and a memory performance within the low normal range. Forty participants underwent 2 functional magnetic resonance imaging (fMRI) sessions, in which they were administered 2 equivalent face-name memory tasks. Following each fMRI, subjects were asked to pair faces with their corresponding proper name. In-between, high-frequency rTMS was applied randomly using real or sham stimulation in a double-blind design. Only subjects who received active rTMS improved in associative memory significantly. This was accompanied by additional recruitment of right prefrontal and bilaterial posterior cortical regions at the second fMRI session, relative to baseline scanning. Our findings reflect a potentiality of rTMS to recruit compensatory networks, which participate during the memory-encoding process. Present results represent the first evidence that rTMS is capable of transitorily and positively influencing brain function and cognition among elders with memory complaints.     

Age-related changes in neural activity during visual target detection measured by fMRI

We used functional magnetic resonance imaging (fMRI) of a visual target detection (oddball) task to investigate age differences in neural activation for the detection of two types of infrequent events: visually simple items requiring a response shift (targets) and visually complex items that did not entail a response shift (novels). Targets activated several prefrontal regions (e.g. middle frontal gyrus), as well as deep gray matter regions (caudate, putamen, thalamus and insula). Prefrontal activation was similar for younger and older adults, whereas deep gray matter activation was relatively greater for the older adults. Novels activated occipital regions (fusiform and lateral occipital gyri), and this activation was relatively reduced for older adults. The changes in behavioral performance across the task conditions were similar for the two age groups, although the older adults' responses were slower overall. Regression analyses of the relation between neural activation and task performance (response time) indicated that whereas performance was mediated most directly by prefrontal cortex for younger adults, older adults' performance was influenced to a greater extent by deep gray matter structures. Older adults may place relatively greater emphasis on the attentional control of response regulation, in compensation for the age-related decline in visual processing efficiency.     

Task-dependency of the neural correlates of episodic encoding as measured by fMRI.

Using event-related functional magnetic resonance imaging (fMRI), the neural correlates of memory encoding can be studied by contrasting item-related activity elicited in a study task according to whether the items are remembered or forgotten in a subsequent memory test. Previous studies using this approach have implicated the left prefrontal cortex in the successful encoding of verbal material into episodic memory when the study task is semantic in nature. In the current study, we asked whether the neural correlates of episodic encoding differ depending on type of study task. Seventeen volunteers participated in an event-related fMRI experiment in which at study, volunteers were cued to make either animacy or syllable judgements about words. A recognition memory test followed after a delay of approximately 15 min. For the animacy task, words that were subsequently remembered showed greater activation in left and medial prefrontal regions. For the syllable task, by contrast, successful memory for words was associated with activations in bilateral intraparietal sulcus, bilateral fusiform gyrus, right prefrontal cortex and left superior occipital gyrus. These findings suggest that the brain networks supporting episodic encoding differ according to study task.     

Identification and differential vulnerability of a neural network in sleep deprivation

The study aimed to identify task-related brain activation networks whose change in expression exhibits subject differences as a function of differential susceptibility to sleep deprivation. Brain activity during a non-verbal recognition memory task was investigated in an event-related functional MRI paradigm both prior to and after 48 h of sleep deprivation. Nineteen healthy subjects participated. Regional covariance analysis was applied to data. An activation network pattern was identified whose expression decreased from pre- to post-sleep deprivation in 15 out 19 subjects (P < 0.05). Differential decrease in expression correlated with worsening performance in recognition accuracy (P < 0.05). Sites of de-activation were found in the posterior cerebellum, right fusiform gyrus and precuneus, and left lingual and inferior temporal gyri; increased activation was found in the bilateral insula, claustrum and right putamen. A network whose expression decreased after sleep deprivation and correlated with memory performance was identified. We conclude that this activation network plays a role in cognitive function during sleep deprivation.     

Frontal and parietal contributions to probabilistic association learning

Neuroimaging studies have shown both dorsolateral prefrontal (DLPFC) and inferior parietal cortex (iPARC) activation during probabilistic association learning. Whether these cortical brain regions are necessary for probabilistic association learning is presently unknown. Participants' ability to acquire probabilistic associations was assessed during disruptive 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC, left iPARC, and sham using a crossover single-blind design. On subsequent sessions, performance improved relative to baseline except during DLPFC rTMS that disrupted the early acquisition beneficial effect of prior exposure. A second experiment examining rTMS effects on task-naive participants showed that neither DLPFC rTMS nor sham influenced naive acquisition of probabilistic associations. A third experiment examining consecutive administration of the probabilistic association learning test revealed early trial interference from previous exposure to different probability schedules. These experiments, showing disrupted acquisition of probabilistic associations by rTMS only during subsequent sessions with an intervening night's sleep, suggest that the DLPFC may facilitate early access to learned strategies or prior task-related memories via consolidation. Although neuroimaging studies implicate DLPFC and iPARC in probabilistic association learning, the present findings suggest that early acquisition of the probabilistic cue-outcome associations in task-naive participants is not dependent on either region.     

Segregation of areas related to visual working memory in the prefrontal cortex revealed by rTMS

The functional organization of working memory (WM) in the human prefrontal cortex remains unclear. Storage and processing functions might be segregated in ventral and dorsal areas of the prefrontal cortex, respectively. If so, storage functions might be spared, irrespective of informational domain, following damage or dysfunction in dorsolateral areas. Alternatively, WM and prefrontal function in general might be segregated according to informational domains (e.g. spatial versus object-based information). In the present study we used repetitive transcranial magnetic stimulation (rTMS) to directly test these competing hypotheses. We applied rTMS to transiently and selectively disrupt the function of the dorsomedial, dorsolateral or ventral prefrontal cortex in normal human volunteers performing either a spatial or a face-recognition delayed-response task. Performance in the spatial task was impaired by rTMS of the dorsomedial prefrontal cortex. Performance in the face-recognition (non-spatial) task was impaired by rTMS of the ventral prefrontal cortex. Transient disruption of the dorsolateral prefrontal cortex affected performance in both tasks. These findings provide evidence of domain-specific segregation of WM functions in widely separated areas of prefrontal cortex.     

Striatal dopamine and working memory

Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks.     

Brain activity during stimulation of the trigeminal nerve with noxious heat.

OBJECTIVE: The aim of this study was to observe areas of brain activation with painful hot stimulation to the trigeminal nerve. STUDY DESIGN: Nine healthy pain-free women (mean age 26.2 +/- 6.9 yrs) with a natural, regular menstrual cycle participated in the study. Whole-brain functional magnetic resonance imaging (fMRI) data were acquired for each participant on day 2 or 3 after the onset of menses using echo-planar imaging at 1.5T with near-isotropic spatial resolution and a temporal resolution of 4 s. RESULTS: Whole-brain fMRI with a Peltier thermode inside the head coil yielded a feasible imaging protocol with little disturbance from the thermode. Painful thermal stimulation of the left trigeminal system activated discrete brain regions within the insula, cingulate gyrus, thalamus, inferior parietal lobe/postcentral gyrus, right middle and inferior frontal gyri, cuneus, precuneus, and precentral gyrus. CONCLUSION: Painful stimulation of the trigeminal nerve resulted in activation of similar brain areas generally known for pain processing of painful peripheral stimulation.     

Functional cerebral reorganization for auditory spatial processing and auditory substitution of vision in early blind subjects

Early blind (EB) individuals can recognize bidimensional shapes using a prosthesis substituting vision with audition (PSVA) and activate right dorsal extrastriate visual cortex during the execution of this task. The present study used repetitive transcranial magnetic stimulation (rTMS) to further examine the functional role of this structure in the successful use of the PSVA. Moreover, we investigated which auditory parameter used in the prosthesis (pitch, intensity, or spatial location) might contribute to this occipital activation. Results revealed that rTMS applied to right dorsal extrastriate cortex in EB subjects interferes with both the PSVA use and the auditory spatial location task but not with pitch and intensity discriminations. By contrast, rTMS targeting the same cortical areas in sighted subjects did not affect performance on any auditory tasks. Early visual deprivation thus leads to functional cerebral cross-modal reorganization in the processing of auditory information and auditory-to-visual sensory substitution. The findings also point to the specific involvement of the dorsal visual stream for auditory spatial processing in blind subjects. Moreover, this suggests that sensory substitution prostheses can be developed using these additional neural resources to perform tasks that partially compensate for the loss of vision.     

Probing the pathophysiology of auditory/verbal hallucinations by combining functional magnetic resonance imaging and transcranial magnetic stimulation

Functional magnetic resonance imaging and repetitive transcranial magnetic stimulation (rTMS) were used to explore the pathophysiology of auditory/verbal hallucinations (AVHs). Sixteen patients with schizophrenia-spectrum disorder were studied with continuous or near continuous AVHs. For patients with intermittent hallucinations (N = 8), blood oxygenation level-dependent (BOLD) activation maps comparing hallucination and nonhallucination periods were generated. For patients with continuous hallucinations (N = 8) correlations between BOLD signal time course in Wernicke's area, and other regions were used to map functional coupling to the former. These maps were used to identify 3-6 cortical sites per patient that were probed with 1-Hz rTMS and sham stimulation. Delivering rTMS to left temporoparietal sites in Wernicke's area and the adjacent supramarginal gyrus was accompanied by a greater rate of AVH improvement compared with sham stimulation and rTMS delivered to anterior temporal sites. For intermittent hallucinators, lower levels of hallucination-related activation in Broca's area strongly predicted greater rate of response to left temporoparietal rTMS. For continuous hallucinators, reduced coupling between Wernicke's and a right homologue of Broca's area strongly predicted greater left temporoparietal rTMS rate of response. These findings suggest that dominant hemisphere temporoparietal areas are involved in expressing AVHs, with higher levels of coactivation and/or coupling involving inferior frontal regions reinforcing underlying pathophysiology.     

Blood-oxygenation-level-dependent functional magnetic resonance imaging for evaluating cerebral regions of female sexual arousal response

Objectives. To evaluate, for the first time, the cerebral regions associated with female sexual arousal evoked by visual stimulation using noninvasive blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI).Methods. A total of 6 healthy right-handed female volunteers (mean age 33 years, range 25 to 41) underwent fMRI on a 1.5-T MR scanner, in which the BOLD technique was used to create fMR images reflecting local brain activities. Real-time visual stimulation was performed with alternatively combined erotic and nonerotic films to identify the activated brain regions associated with sexual response. The perceived sexual arousal response was assessed using a scale ranging from 1 (no change) to 5 (maximal increase).Results. The mean score for perceived sexual arousal by erotic visual stimulation was 2.7 on the 5-point scale and was unchanged by nonerotic stimulation. During the visual task, the occipital cortex was activated by both the erotic and the nonerotic films; however, the following cerebral areas were significantly (P <0.05) activated, varying from 4 of 6 to 6 of 6 women: inferior frontal lobe, cingulate gyrus, insula gyrus, corpus callosum, thalamus, caudate nucleus, globus pallidus, and inferior temporal lobe.Conclusions. This study is the first to evaluate noninvasive BOLD-fMRI in identifying cerebral regions associated with sexual arousal response evoked by visual stimulation in women.     

静息态fMRI评估急性酒精暴露对恒河猴脑功能的影响

目的采用静息态fMRI基于分数低频振荡幅度(fALFF)方法评估急性酒精暴露后恒河猴脑功能改变。方法分别对7只健康雄性恒河猴于静脉注射酒精前及注射后10、28、46min进行BOLD fMRI序列及3D结构像扫描,采用fALFF算法获得并比较4个时间点fALFF差异的脑区。结果 4个时间点fALFF总体差异显著的脑区为右侧中央后回、右侧岛叶、右侧小脑、左侧海马旁回、双侧额下回、小脑蚓部、右枕叶、楔前叶、左侧缘上回(P均0.05);静脉注射酒精后fALFF值减低的脑区为双侧额上回、右侧额下回、右侧梭状回、右侧角回、双侧颞上回、右枕叶、左侧外侧沟、左侧中央后回、左侧楔状叶、左侧丘脑、左侧岛叶、前扣带回(P均0.05);静脉注射酒精后fALFF值增高的脑区为右侧额下回、右侧颞中回(P均0.05)。结论酒精暴露急性期脑代谢活动发生显著变化,主要涉及默认网络、奖赏及情绪加工系统、视听皮层等。     

Imaging the brain activity changes underlying impaired visuospatial judgments: simultaneous FMRI, TMS, and behavioral studies

Damage to parietal cortex impairs visuospatial judgments. However, it is currently unknown how this damage may affect or indeed be caused by functional changes in remote but interconnected brain regions. Here, we applied transcranial magnetic stimulation (TMS) to the parietal cortices during functional magnetic resonance imaging (fMRI) while participants were solving visuospatial tasks. This allowed us to observe both the behavioral and the neural effects of transient parietal activity disruption in the active healthy human brain. Our results show that right, but not left, parietal TMS impairs visuospatial judgment, induces neural activity changes in a specific right-hemispheric network of frontoparietal regions, and shows significant correlations between the induced behavioral impairment and neural activity changes in both the directly stimulated parietal and remote ipsilateral frontal brain regions. The revealed right-hemispheric neural network effect of parietal TMS represents the same brain areas that are functionally connected during the execution of visuospatial judgments. This corroborates the notion that visuospatial deficits following parietal damage are brought about by a perturbation of activity across a specific frontoparietal network, rather than the lesioned parietal site alone. Our experiments furthermore show how concurrent fMRI and magnetic brain stimulation during active task execution hold the potential to identify and visualize networks of brain areas that are functionally related to specific cognitive processes.     

Parieto-frontal interactions in visual-object and visual-spatial working memory: evidence from transcranial magnetic stimulation.

This study aimed to investigate whether transcranial magnetic stimulation (TMS) can induce selective working memory (WM) deficits of visual-object versus visual-spatial information in normal humans. Thirty-five healthy subjects performed two computerized visual n-back tasks, in which they were required to memorize spatial locations or abstract patterns. In a first series of experiments, unilateral or bilateral TMS was delivered on posterior parietal and middle temporal regions of both hemispheres after various delays during the WM task. Bilateral temporal TMS increased reaction times (RTs) in the visual-object, whereas bilateral parietal TMS selectively increased RTs in the visual-spatial WM task. These effects were evident at a delay of 300 ms. Response accuracy was not affected by bilateral or unilateral TMS of either cortical region. In a second group of experiments, bilateral TMS was applied over the superior frontal gyrus (SFG) or the dorsolateral prefrontal cortex (DLPFC). TMS of the SFG selectively increased RTs in the visual-spatial WM task, whereas TMS of the DLPFC interfered with both WM tasks, in terms of both accuracy and RTs. These effects were evident when TMS was applied after a delay of 600 ms, but not one of 300 ms. These findings confirm the segregation of WM buffers for object and spatial information in the posterior cortical regions. In the frontal cortex, the DLPFC appears to be necessary for WM computations regardless of the stimulus material.     

Right parietal cortex plays a critical role in change blindness

There is increasing evidence from functional magnetic resonance imaging (fMRI) that visual awareness is not only associated with activity in ventral visual cortex but also with activity in the parietal cortex. However, due to the correlational nature of neuroimaging, it remains unclear whether this parietal activity plays a causal role in awareness. In the experiment presented here we disrupted activity in right or left parietal cortex by applying repetitive transcranial magnetic stimulation (rTMS) over these areas while subjects attempted to detect changes between two images separated by a brief interval (i.e. 1-shot change detection task). We found that rTMS applied over right parietal cortex but not left parietal cortex resulted in longer latencies to detect changes and a greater rate of change blindness compared with no TMS. These results suggest that the right parietal cortex plays a critical role in conscious change detection.     

A developmental fMRI study of reading and repetition reveals changes in phonological and visual mechanisms over age

In this study of reading development, children (ages 7-10) and adults (ages 18-32) performed overt single-word reading and aural repetition tasks on high-frequency word stimuli during functional magnetic resonance imaging. Most regions showed similar activity across age groups. These widespread regions of similarity indicate that children and adults use largely overlapping mechanisms when processing high-frequency words. Significant task-related differences included greater activity in occipital cortex for the read task, and greater activity in temporal cortex for the repeat task; activity levels in these regions were similar for adults and children. However, age group differences were found in several posterior regions, including a set of regions implicated in adult reading: the left supramarginal gyrus, the left angular gyrus, and bilateral anterior extrastriate cortex. The angular and supramarginal gyrus regions, hypothesized to play a role in phonology, showed decreased activity in adults relative to children for high-frequency words. The extrastriate regions had significant activity for both the visual read task and auditory repeat task in children, but just for the read task in adults, showing significant task and age interactions. These results are consistent with decreasing reliance on phonological processing, and increasing tuning of visual mechanisms, with age.     

Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited

Evidence implicates subtle neuronal pathology of the prefrontal cortex (PFC) in schizophrenia, but how this pathology is reflected in physiological neuroimaging experiments remains controversial. We investigated PFC function in schizophrenia using functional magnetic resonance imaging (fMRI) and a parametric version of the n-back working memory (WM) task. In a group of patients who performed relatively well on this task, there were three fundamental deviations from the 'healthy' pattern of PFC fMRI activation to varying WM difficulty. The first characteristic was a greater magnitude of PFC fMRI activation in the context of slightly impaired WM performance (i.e. physiological inefficiency). The second was that the significant correlations between behavioral WM performance and dorsal PFC fMRI activation were in opposite directions in the two groups. Third, the magnitude of the abnormal dorsal PFC fMRI response was predicted by an assay of N-acetylaspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9, 46) to varying WM difficulty - supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. These data suggest that under certain conditions the physiological ramifications of dorsal PFC neuronal pathology in schizophrenia includes exaggerated and inefficient cortical activity, especially of dorsal PFC.     

Enhanced excitability of the human visual cortex induced by short-term light deprivation

Long-term deprivation of visual input for several days or weeks leads to marked changes in the excitability and function of the occipital cortex. The time course of these changes is poorly understood. In this study, we addressed the question whether a short period of light deprivation (minutes to a few hours) can elicit such changes in humans. Noninvasive transcranial magnetic stimulation (TMS) of the human occipital cortex can evoke the perception of flashes or spots of light (phosphenes). To assess changes in visual cortex excitability following light deprivation, we measured the minimum intensity of stimulation required to elicit phosphenes (phosphene threshold) and the number of phosphenes elicited by different TMS stimulus intensities (stimulus-response curves). A reduced phosphene threshold was detected 45 min after the onset of light deprivation and persisted for the entire deprivation period (180 min). Following re-exposure to light, phosphene thresholds returned to predeprivation values over 120 min. Stimulus-response curves were significantly enhanced in association with this intervention. In a second experiment, we studied the effects of light deprivation on functional magnetic resonance imaging (fMRI) signals elicited by photic stimulation. fMRI results showed increased visual cortex activation after 60 min of light deprivation that persisted following 30 min of re-exposure to light. Our results demonstrated a substantial increase in visual cortex excitability. These changes may underlie behavioral gains reported in humans and animals associated with light deprivation.     

Impaired face discrimination in acquired prosopagnosia is associated with abnormal response to individual faces in the right middle fusiform gyrus

The middle fusiform gyrus (MFG) and the inferior occipital gyrus (IOG) are activated by both detection and identification of faces. Paradoxically, patients with acquired prosopagnosia following lesions to either of these regions in the right hemisphere cannot identify faces, but can still detect faces. Here we acquired functional magnetic resonance imaging (fMRI) data during face processing in a patient presenting a specific deficit in individual face recognition, following lesions encompassing the right IOG. Using an adaptation paradigm we show that the fMRI signal in the rMFG of the patient, while being larger in response to faces as compared to objects, does not differ between conditions presenting identical and distinct faces, in contrast to the larger response to distinct faces observed in controls. These results suggest that individual discrimination of faces critically depends on the integrity of both the rMFG and the rIOG, which may interact through re-entrant cortical connections in the normal brain.