The role of the right dorsolateral prefrontal cortex in the Tower of London task performance: repetitive transcranial magnetic stimulation study in patients with Parkinson’s disease

We studied whether one session of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over either the right or left dorsolateral prefrontal cortex would induce any measurable changes in the Tower of London spatial planning task performance in patients with Parkinson’s disease (PD). Ten patients with PD (with no dementia and/or depression) entered the randomized, sham-stimulation-controlled study with a crossover design. Active and placebo rTMS were applied over either the left or the right dorsolateral prefrontal cortex (in four separate sessions) in each patient. The order of sessions was randomized. The Tower of London task was performed prior to and immediately after each appropriate session. The “total problem-solving time” was our outcome measure. Only active rTMS of the right dorsolateral prefrontal cortex induced significant enhancement of the total problem-solving time, p = 0.038. Stimulation of the left prefrontal cortex or sham stimulations induced no significant effects. Only rTMS applied over the right dorsolateral prefrontal cortex induced positive changes in the spatial planning task performance in PD, which further supports the results of functional imaging studies indicating the causal engagement of the right-sided hemispheric structures in solving the task in this patient population.     

Prefrontal brain magnetic activity: effects of memory task demands

Changes in spatiotemporal profiles of brain magnetic activity were investigated in healthy volunteers as a function of varying demands for phonological storage of spoken pseudowords. Greater activity for the phonological memory task was restricted to the dorsolateral prefrontal cortex (DLPFC) in the left hemisphere. During performance of the memory task, activity was initially found in the left superior temporal gyrus (between 100 and 200 ms), followed by activity in the ventrolateral prefrontal, motor, and premotor cortices (between 200 and 300 ms). Activity in DLPFCs was first observed consistently across participants later, between 300 and 400 ms. The data are consistent with the purported role of posterior temporal cortices in phonological analysis and in the online storage of phonological information, the contribution of ventrolateral and motor processing areas in establishment and short-term maintenance of articulatory representations through rehearsal, and the role of DLPFCs in the executive control of the maintenance operation.     

Evidence for a dysfunctional retrosplenial cortex in patients with schizophrenia: a functional magnetic resonance imaging study with a semantic-perceptual contrast

We investigated whether the retrosplenial and the posterior cingulate cortex (RS-PCC) is functionally impaired in schizophrenia patients. Therefore, we measured functional magnetic resonance imaging (fMRI) signal changes associated with a synonym-judgment task known to activate, among other areas, the RS-PCC. Compared to 12 matched control subjects, 12 schizophrenia patients exhibited reliably weaker activations in the RS-PCC, the dorsolateral prefrontal cortex and the left orbitofrontal cortex (P < 0.05, corrected). Differences in frontal activations are in line with previous studies showing a structurally and functionally affected prefrontal cortex in schizophrenia. The impaired RS-PCC functionality in a semantic task may relate to verbal memory deficits frequently observed in schizophrenia patients, because this region is pivotal for gating information into the medial temporal lobe memory system.     

Neural activation during frequency-memory performance.

Lesion studies have demonstrated that frequency memory, or memory for the frequency of occurrence, is associated with prefrontal and not temporal lobe lesions. This study examined neural activation during performance on a frequency-memory-judgment task and a recognition-memory task, both using words. Relative to a control task, the authors observed peaks of activation during frequency-memory performance in the left ventrolateral prefrontal cortex (BA 45) and other areas typically associated with working memory (dorsolateral prefrontal cortex, posterior parietal cortex). Recognition performance was associated with activation in the same left ventrolateral prefrontal location as was observed with frequency memory. When comparing activation during frequency memory with activation during recognition memory, the authors found a suppression of activation in the hippocampus bilaterally during frequency memory. This study supports a neuroanatomical distinction between frequency and recognition memory.     

A comparison of rCBF patterns during letter and semantic fluency

To evaluate the functional neuroanatomies underlying letter and category fluency, 18 normal controls were studied with oxygen-15 water regional cerebral blood flow positron emission tomography. Three counterbalanced conditions each consisted of 6 trials (45 s each): letter fluency (generating words when cued with a particular letter), semantic fluency (generating words when cued with a particular category), and a control condition (generating days of the week and months of the year). Relative to the control, participants activated similar brain regions during both fluency tasks, including the anterior cingulate, left prefrontal regions, thalamus, and cerebellum; reductions were found in parietal and temporal regions. In a direct comparison of the 2 fluency tasks, inferior frontal cortex and temporoparietal cortex (hypothesized to participate in a phonologic loop for accessing word pronunciation) were activated more during letter than semantic fluency, whereas left temporal cortex (associated with access to semantic storage) was activated more during semantic than letter fluency. This study identifies subtle differences in the neural networks underlying letter and semantic fluency that may underlie the dissociation of these abilities in patients.     

Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?

BACKGROUND: Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation. METHOD: Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent. CONCLUSIONS: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.     

原发性失眠患者大脑背外侧前额叶的异常静息态功能连接

目的:利用功能连接方法观察原发性失眠患者静息态下的背外侧前额叶的异常功能连接。方法:采集33 例原 发性失眠患者以及33 例年龄、性别和受教育程度相匹配的健康对照的功能磁共振图像,以背外侧前额叶为感兴趣区 域,与全脑其他体素进行功能连接分析,得到两组之间功能连接的差异脑区,再对异常功能连接脑区与临床的量表分 数做相关分析。结果:与对照组相比,发现失眠患者左侧背外侧前额叶与左侧枕下回、右侧枕下回、右侧枕中回、右侧 颞叶、左侧额中回,左侧额下回以及右侧梭状回之间的功能连接增强（P<0.05,体素簇个数≥100,FDR校正）,与左侧前 扣带皮层、右侧海马旁回、右侧脑岛、右侧背外侧额上回、右侧顶上回、右侧中央后回以及右侧中央前回之间的功能连 接减弱（P<0.05,体素簇个数≥100,FDR校正）。并且左侧背外侧前额叶与左侧枕叶下回的功能连接值与睡眠状况自评 量表分数成正相关（P=0.035）。结论:原发性失眠患者背外侧前额叶与大脑多个脑区出现异常的功能连接,可能为理 解原发性失眠患者的神经机制提供一些新的影像学依据。     

Figural fluency: differential impairment in patients with left versus right frontal lobe lesions.

Based on an experimental study, Jones-Gotman and Milner demonstrated that patients with right frontal lobe lesions were impaired on design fluency. We sought a clinical adaptation and developed a psychometrically sound technique for design fluency. The present study explores the validity of the Ruff Figural Fluency Test (RFFT) in discriminating patients with either right frontal or nonright frontal lobe lesions. In the first of two studies, six subjects with circumscribed focal lesions were given the RFFT and the Jones-Gotman and Milner figural fluency task. In the second study, we identified a larger sample of 30 patients with focal lesions in the right frontal, left frontal, right posterior, or left posterior cortex. The results from both studies support the validity of the RFFT as a measure which is sensitive to right anterior dysfunction.     

Increased left prefrontal activation in patients with unipolar depression: an event-related, parametric, performance-controlled fMRI study

BACKGROUND: Executive deficits associated with frontal lobe dysfunction are prominent in depression. We applied a newly developed WM task to investigate the neural correlates of executive processes with functional magnetic resonance imaging (fMRI) at comparable performance levels analyzing correct trials only. METHODS: We studied 12 partially remitted, medicated inpatients meeting DSM-IV criteria for major depressive disorder and 17 healthy controls. We used a parametric version of a delayed match-to-sample WM task requiring manipulation of verbal material during a delay period in an event-related fMRI design. RESULTS: Depressed patients were generally slower and load-dependently less accurate than healthy controls. Patients showed significantly more activation of left dorsolateral prefrontal cortex with highest cognitive load. Additionally, they showed higher activation in ventromedial prefrontal cortex during the control condition. LIMITATIONS: The fact that patients were taking different antidepressant drugs could limit the explanatory power of the present results. CONCLUSIONS: Increased lateral prefrontal activation despite comparably successful performance - when only correct trials were analyzed - in patients with depression can be interpreted as evidence for compensatory recruitment of prefrontal cortical resources.     

Neonatal hippocampal lesions in rhesus macaques alter the monitoring, but not maintenance, of information in working memory

Neonatal hippocampal damage in rodents impairs medial prefrontal working memory functions. To examine whether similar impairment will follow the same damage in primates, adult monkeys with neonatal hippocampal lesions and sham-operated controls were trained on two working memory tasks. The session-unique delayed nonmatch-to-sample (SU-DNMS) task measures maintenance of information in working memory mediated by the ventral lateral prefrontal cortex. The object self-ordered (Obj-SO) task measures monitoring of information in working memory mediated by the dorsolateral prefrontal cortex. Adult monkeys with neonatal hippocampal lesions performed as well as sham-operated controls on the SU-DNMS task at either the 5- or 30-s delays but were severely impaired on the Obj-SO task. These results extend the earlier findings in rodents by demonstrating that early lesions of the hippocampus in monkeys impair working memory processes known to require the integrity of the dorsolateral prefrontal cortex while sparing lower order working memory processes such as recency. Although the present results suggest that the lack of functional hippocampal inputs may have altered the maturation of the dorsolateral prefrontal cortex, future studies will be needed to determine whether the nature of the observed working memory deficit is due to an absence of the hippocampus, a maldevelopment of the dorsolateral prefrontal cortex, or both.     

Cerebral oxygenation changes in the prefrontal cortex: effects of age and gender

Multi-channel near-infrared spectroscopy (NIRS) is an optical method, which allows non-invasive in vivo measurements of changes in the concentration of oxygenated (O(2)Hb) and deoxygenated (HHb) hemoglobin in living brain tissue, simultaneously from multiple measurement points. In the present study, 44 young and 42 elderly subjects were investigated by means of multi-channel NIRS (optical topography) during performance of the verbal fluency task (VFT). The aim of the study was to analyze the effects of the subjects' age and gender on functional brain activation during this cognitive task. In summary, the results clearly show that the VFT activated the left and right dorsolateral prefrontal cortex (increases in O(2)Hb and more localized decreases in HHb), with an obvious left-hemispheric dominance. The elderly subjects generally exhibited less activation and no left hemispheric lateralization effect. In contrast to a previous study, we did not find a clear influence of the subjects' gender on the brain activation pattern.     

Neural correlates of the judgment of lying: A functional magnetic resonance imaging study

Lie judgment is an estimation of the speaker's intention to deceive inevitably accompanied by moral judgment. To depict their neural substrates, we conducted a functional magnetic resonance imaging study. Eighteen subjects read short stories and made judgments in three different tasks: a control gender judgment task, a moral judgment task, and a lie judgment task. Compared with the control task, both the moral and lie judgment tasks activated the left temporal lobe, the medial prefrontal cortex, the lateral orbitofrontal cortex extending to the dorsolateral prefrontal cortex, the caudate nucleus, the left temporo-parietal junction (TPJ), and the right cerebellum. Neural activations were greater in the left middle frontal gyrus, the bilateral TPJ, and the right superior temporal sulcus in the lie judgment condition than in the moral judgment condition. In addition, the left TPJ showed greater activation when a protagonist told lies for anti-social rather than pro-social purposes. These data suggest that the judgment of lies is mediated by the neural substrates of moral judgment (conventionality) and those involved in detecting the intent to deceive (intentionality), and that the left TPJ might play a key role in processing both the conventional and the intentional information involved in the judgment of lying.     

Activation of brain regions using task-state FMRI in patients with mild traumatic brain injury: a meta-analysis

Activation likelihood estimation meta-analysis was performed to examine the activation characteristics of cognition-related brain regions in patients with mild traumatic brain injury (mTBI). The databases PubMed, Ovid, Cochrane Library, Google Scholar, CNKI, WFSD, and VIP were systematically searched. The software Ginger-ALE 3.0.2 was used for coordinate unification and meta-analysis. Seven studies with a total of 314 subjects were included. Meta-analysis results indicated that compared with healthy subjects, mTBI patients had enhanced activation in the left anterior angular gyrus, left occipital joint visual, left midbrain, right temporal angular gyrus, right cerebellar tonsil, left frontal insula, and right inferior frontal gyrus. mTBI patients had attenuated activation in the right dorsolateral prefrontal lobe, left cerebellar anterior lobe, left dorsolateral prefrontal lobe, right middle frontal gyrus, right posterior cingulate gyrus, left joint visual, left supramarginal gyrus, left middle frontal gyrus, right precuneus, left dorsolateral prefrontal cortex, right frontal eye field, right lower parietal gyrus, corpus callosum, right frontal pole region, and left prefrontal lobe. Further joint analysis revealed that the dorsolateral prefrontal lobe of the right middle frontal gyrus was a region of attenuated co-activation. The dorsolateral prefrontal lobe of the right middle frontal gyrus showing attenuated activation was the main brain region distinguishing mTBI patients from healthy subjects. Cognitive deficits could be associated with attenuated activation in the dorsolateral prefrontal lobe of the right middle frontal gyrus, which could be due to a decline in the recruitment ability of the neural network involved in controlling attention.     

Shared and distinct anatomical correlates of semantic and phonemic fluency revealed by lesion-symptom mapping in patients with ischemic stroke

Semantic and phonemic fluency tasks are frequently used to test executive functioning, speed and attention, and access to the mental lexicon. In semantic fluency tasks, subjects are required to generate words belonging to a category (e.g., animals) within a limited time window, whereas in phonemic fluency tasks subjects have to generate words starting with a given letter. Anatomical correlates of semantic and phonemic fluency are currently assumed to overlap in left frontal structures, reflecting shared executive processes, and to be distinct in left temporal and right frontal structures, reflecting involvement of distinct memory processes and search strategies. Definite evidence for this assumption is lacking. To further establish the anatomical correlates of semantic and phonemic fluency, we applied assumption-free voxel-based and region-of-interest-based lesion-symptom mapping in 93 patients with ischemic stroke. Fluency was assessed by asking patients to name animals (semantic), and words starting with the letter N and A (phonemic). Our findings indicate that anatomical correlates of semantic and phonemic fluency overlap in the left inferior frontal gyrus and insula, reflecting shared underlying cognitive processes. Phonemic fluency additionally draws on the left rolandic operculum, which might reflect a search through phonological memory, and the middle frontal gyrus. Semantic fluency additionally draws on left medial temporal regions, probably reflecting a search through semantic memory, and the right inferior frontal gyrus, which might reflect the application of a visuospatial mental imagery strategy in semantic fluency. These findings establish shared and distinct anatomical correlates of semantic and phonemic fluency.     

Functional correlates of distractor suppression during spatial working memory encoding

Executive working memory operations are related to prefrontal regions in the healthy brain. Moreover, neuroimaging data provide evidence for a functional dissociation of ventrolateral and dorsolateral prefrontal cortex. Most authors either suggest a modality-specific or a function-specific prefrontal cortex organization. In the present study we particularly aimed at the identification of different prefrontal cerebral areas that are involved in executive inhibitory processes during spatial working memory encoding. In an fMRI study (functional magnetic resonance imaging) we examined the neural correlates of spatial working memory processing by varying the amount of executive demands of the task. Twenty healthy volunteers performed the Corsi Block-Tapping test (CBT) during fMRI. The CBT requires the storage and reproduction of spatial target sequences. In a second condition, we presented an adapted version of the Block-Suppression-Test (BST). The BST is based on the original CBT but additionally requires the active suppression of visual distraction within the target sequences. In comparison to the CBT performance, particularly the left dorsolateral prefrontal cortex (BA 9) showed more activity during the BST condition. Our results show that the left dorsolateral prefrontal cortex plays a crucial role for executive controlled inhibition of spatial distraction. Furthermore, our findings are in line with the processing model of a functional dorsolateral-ventrolateral prefrontal cortex organization.     

Distinct control networks for cognition and emotion in the prefrontal cortex

The activation of dorsolateral prefrontal cortex (dlPFC) has been suggested to reflect the engagement of a control mechanism for top-down biasing of context processing in resource-demanding memory tasks. Here we tested the hypothesis that the dlPFC subserves a similar function also in attention and emotion tasks. 18 healthy young adults were tested in a functional magnetic resonance imaging (fMRI) study where the demands for context processing were manipulated in three different cognitive domains: auditory attention, episodic retrieval, and emotion regulation. We found that the right dlPFC was jointly sensitive to increased cognitive demands in the attention and memory tasks. By contrast, increased demands in the emotion task (reappraisal) were associated with increased activity in ventromedial PFC along with decreased amygdala activity. Our findings of divergent prefrontal control networks for cognitive and emotional control extend previous separations of cognition and emotion in the anterior cingulate cortex.     

Dissociating cortical regions activated by semantic and phonological tasks: a FMRI study in blind and sighted people

Previous neuroimaging studies of language processing in blind individuals described cortical activation of primary (V1) and higher tier visual areas, irrespective of the age of blindness onset. Specifically, participants were given nouns and asked to generate an associated verb. These results confirmed the presence of adaptations in the visual cortex of blind people and suggested that these responses represented linguistic operations. The present functional magnetic resonance imaging study attempted to further characterize these responses as being preferential for semantic or phonological processing. Three groups of participants (sighted, early onset, and late-onset blind) heard lists of related words and attended to either a common meaning (semantic task) or common rhyme (phonological task) that linked the words. In all three groups, the semantic task elicited stronger activity in the left anterior inferior frontal gyrus and the phonological task evoked stronger activity bilaterally in the inferior parietal cortex and posterior aspects of the left inferior frontal gyrus. Only blind individuals showed activity in occipital, temporal, and parietal components of visual cortex. The spatial extent of visual cortex activity was greatest in early blind, who exhibited activation in all ventral and dorsal visual cortex subdivisions (V1 through MT) for both tasks. Preferential activation appeared for the semantic task. Late blind individuals exhibited responses in ventral and dorsal V1, ventral V2, VP and V8, but only for the semantic task. Our findings support prior evidence of visual cortex activity in blind people engaged in auditory language processing and suggest that this activity may be related to semantic processing.     

Mapping of semantic, phonological, and orthographic verbal working memory in normal adults with functional magnetic resonance imaging.

Twelve neurologically normal participants (4 men and 8 women) performed semantic, phonological, and orthographic working memory tasks and a control task during functional magnetic resonance imaging. Divergent regions of the posterior left hemisphere used for decoding and storage of information emerged in each working memory versus control task comparison. These regions were consistent with previous literature on processing mechanisms for semantic, phonological, and orthographic information. Further, working memory versus control task differences extended into the left frontal lobe, including premotor cortex, and even into subcortical structures. Findings were consistent with R. C. Martin and C. Romani's (1994) contention that different forms of verbal working memory exist and further suggest that a reconceptualization of premotor cortex functions is needed.     

Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation

We studied the effect of repetitive transcranial magnetic stimulation (rTMS) on changes in regional cerebral blood flow (rCBF) as revealed by positron emission tomography (PET) while subjects performed a 2-back verbal working memory (WM) task. rTMS to the right or left dorsolateral prefrontal cortex (DLPFC), but not to the midline frontal cortex, significantly worsened performance in the WM task while inducing significant reductions in rCBF at the stimulation site and in distant brain regions. These results for the first time demonstrate the ability of rTMS to produce temporary functional lesions in elements of a neuronal network thus changing its distributed activations and resulting in behavioral consequences.     

Prefrontal [correction of Prefontal] cortex in long-term memory: an "interference" approach using magnetic stimulation

Neuroimaging has consistently shown engagement of the prefrontal cortex during episodic memory tasks, but the functional relevance of this metabolic/hemodynamic activation in memory processing is still to be determined. We used repetitive transcranial magnetic stimulation (rTMS) to transiently interfere with either left or right prefrontal brain activity during the encoding or retrieval of pictures showing complex scenes. We found that the right dorsolateral prefrontal cortex (DLPFC) was crucial for the retrieval of the encoded pictorial information, whereas the left DLPFC was involved in encoding operations. This 'interference' approach allowed us to establish whether a cortical area activated by a memory task actually contributes to behavioral performance.