Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals

Working memory dysfunctions are a prominent feature in schizophrenia. These impairments have been linked to alterations in prefrontal brain activation with studies reporting hypo- and hyperactivations. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes modulate working memory and its neural correlates. The aim of the present study was to test the influence of the NRG1 schizophrenia susceptibility gene on working memory and its neural correlates in healthy subjects. 429 healthy individuals performed a verbal and a spatial working memory task. A subsample of 85 subjects performed a 2-back version of the Continuous Performance Test (CPT) in a functional MRI study. The NRG1 SNP8NRG221533 (rs35753505) carrier status was determined and correlated with working memory performance and brain activation.There were no effects of genetic status on behavioural performance in the working memory tasks in the 429 subjects and in the fMRI task (n = 85). A linear effect of NRG1 SNP8NRG221533 carrier status on neuronal activation emerged in the fMRI experiment. Hyperactivation of the superior frontal gyrus (BA 10) was correlated with the number of risk alleles. The fMRI data suggest that performance measures between groups did not differ due to a compensational activation of BA 10 in risk-allele carriers. Our results are in line with functional imaging studies in patients with schizophrenia, which also showed a differential activation in lateral prefrontal areas.     

Neural substrates of letter fluency processing in young adults who were born very preterm: Alterations in frontal and striatal regions

Several studies have described poorer performance in executive-type tasks in individuals who were born very preterm compared to controls. As there is evidence that high-order executive functions may be underpinned by neuronal activity in frontal–striatal circuits, we investigated with functional MRI a group of young adults who were born very preterm (n = 28, gestational age < 33 weeks) and controls (n = 26) in order to detect possible alterations in brain activation during completion of a letter fluency task with differential cognitive loading (“easy” and “hard” letter trials). Structural MRI data were also collected to clarify whether any functional changes were associated with structural brain volume changes. Group membership, level of task difficulty and gestational age had significant effects on brain activation. In the absence of significant between-group differences in task performance, during “easy” letter trials, very preterm-born individuals showed attenuated activation in anterior cingulate gyrus, right caudate nucleus and left inferior frontal gyrus compared to controls. During “hard” letter trials, very preterm-born individuals showed both decreased and increased BOLD signal compared to controls, in left middle frontal and anterior cingulate gyrus, respectively. BOLD signal in caudate nucleus and anterior cingulate gyrus, in regions with peaks close to areas where between-group differences were observed, was linearly associated with gestational age. Analysis of structural MRI data showed altered grey matter distribution in the preterm-born group compared to controls. However, fMRI results were only partly explained by structural changes, and may reflect processes of functional plasticity for the successful completion of executive-type operations.     

精神分裂症空间工作记忆任务的fMRI研究

目的采用fMRI技术探讨精神分裂症患者空间工作记忆损害的神经机制。方法收集18例精神分裂症患者和18名正常受试者进行空间n-back任务的fMRI扫描。采用SPM 8进行数据预处理和统计分析,单样本t-检验用于分析两组各自脑激活结果,双样本t-检验用于工作记忆相关脑激活的组间比较。采用FDR方法进行多重比较校正。利用SPSS 17.0软件对工作记忆任务中的行为学结果 (正确率和反应时间)进行组间比较。结果与对照组相比,精神分裂症患者空间工作记忆任务反应时间延长(882.00±50.31)ms,正确率下降(83.60±2.90)%(P0.05)。精神分裂症患者在n-back空间工作记忆任务时所激活的脑区分布与对照组基本一致,主要包括双侧前额皮层、颞顶叶皮层及部分基底核团。但组间比较显示精神分裂症患者多个脑区激活强度及范围明显增加,包括双侧前额皮层背外侧、双侧后顶叶皮层、右侧中央前回、左侧颞中回、右扣带回和双侧小脑(FDR校正,P0.05)。结论执行空间工作记忆任务时精神分裂症患者脑区激活增加,但行为学表现下降,提示患者脑区活动效率低下,可能是工作记忆能力损害的神经基础。     

MRI of Functional Deactivation: Temporal and Spatial Characteristics of Oxygenation-Sensitive Responses in Human Visual Cortex

Magnetic resonance imaging (MRI) of neuronal “activation” relies on the elevation of blood flow and oxygenation and a related increase of the blood oxygenation level-dependent (BOLD) MRI signal. Because most cognitive paradigms involve both switches from a low degree of activity to a high degree of activity and vice versa, we have undertaken a baseline study of the temporal and spatial characteristics of positive and negative BOLD MRI responses in human visual cortex. Experiments were performed at 2.0 T using a multislice gradient-echo EPI sequence (TR = 1 s, mean TE = 54 ms, flip angle 50°) at 2 × 2-mm²spatial resolution. Activation and “deactivation” processes were accomplished by reversing the order of stimulus presentations in paradigms using homogeneous gray light and an alternating checkerboard as distinct functional states. For sustained stimulation (≥60 s) the two conditions resulted in markedly different steady-state BOLD MRI signal strengths. The transient responses to brief stimulation (≤18 s) differed insofar as activation processes temporally separate positive BOLD and negative undershoot effects by about 10 s, whereas negative BOLD effects and undershoot contributions overlap for deactivation processes. Apart from differences in stimulus features (e.g., motion) the used activation and deactivation protocols revealed similar maps of neuronal activity changes.     

Is there a "neural efficiency" in athletes? A high-resolution EEG study

“Neural efficiency” hypothesis posits that cortical activity is spatially focused in experts. Here we tested the hypothesis that compared to non-athletes, elite athletes are characterized by a reduced cortical activation during visuo-motor tasks related to the field of expertise, as a function of movement side. EEG data (56 channels; EB-Neuro) were continuously recorded in the following right-handed subjects: 11 non-athletes, 11 elite fencing athletes, and 11 elite karate athletes. During the EEG recordings, they observed pictures with fencing and karate attacks, and had to quickly click a right (left) keyboard button for the attacks at right (left) monitor side. The EEG data were averaged with respect to the movement onset, and were spatially enhanced by surface Laplacian estimation. The potentials related to the preparation (readiness potential) and initiation (motor potential) of the movements were measured. For the right movement, the potentials overlying supplementary motor and contralateral sensorimotor areas were higher in amplitude in the non-athletes than in the elite karate and fencing athletes. Furthermore, the amplitude of the motor potential over ipsilateral sensorimotor area was higher in the elite karate than fencing athletes, and its distribution over bilateral sensorimotor areas was less asymmetrical in the karate than in the other two groups. For the left movement, these potentials showed no difference between the groups. The present results suggest that “neural efficiency” hypothesis does not fully account for the organization of motor systems in elite athletes. “Neural efficiency” would depend on several factors including side of the movement, hemisphere, and kind of athletes.     

Does estrogen receptor gene polymorphism play a role in Parkinson's disease?

This study was designed to investigate the frequency of estrogen receptor (ER) gene polymorphism in Chinese patients with Parkinson's disease (PD). Polymerase chain reaction (PCR) method and restriction fragment length polymorphism (RFLP) were used to detect the ER gene polymorphisms in 158 PD patients and 146 healthy controls. In the PD and control groups, “x” accounted for 83.5% and 80.8%, respectively (P > 0.05). “xx” was found in 77.2% of the PD group and in 69.9% of the control group (P > 0.05). The frequency of “p” in the PD and control group was 67.7% and 64.0%, respectively (P > 0.05). “pp” was 51.9% in the PD group and 43.8% in the control group (P > 0.05). “ppxx” was found in 49.4% of the PD and 43.0% of the control subjects (P > 0.05). There was no significant difference in the “x”, “xx”, “p”, “pp” or “ppxx” between males and females within the PD or control groups. In conclusion, we found no significant differences in the genotype or allele frequencies between patients with Parkinson's disease and healthy subjects. These findings suggest that the estrogen receptor gene polymorphism may not play a key role in the pathogenesis PD in Chinese patients.     

Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating

Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eyeblink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human work demonstrates that frontal–striatal–thalamic (FST) circuitry modulates PPI. This study used functional magnetic resonance imaging (fMRI) to investigate FST circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions—dorsolateral prefrontal cortex (Brodmann areas 46, 9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus. In contrast, schizophrenia patients failed to show differential BOLD responses in FST circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.     

Neural correlates of relational and item-specific encoding during working and long-term memory in schizophrenia

Successful long-term memory (LTM) depends upon effective control of information in working memory (WM), and there is evidence that both WM and LTM are impaired by schizophrenia. This study tests the hypothesis that LTM deficits in schizophrenia may result from impaired control of relational processing in WM due to dorsolateral prefrontal cortex (DLPFC) dysfunction. fMRI was performed on 19 healthy controls and 20 patients with schizophrenia during WM tasks emphasizing relational (reorder trials) versus item-specific (rehearse trials) processing. WM activity was also examined with respect to LTM recognition on a task administered outside the scanner. Receiver operator characteristic analysis assessed familiarity and recollection components of LTM. Patients showed a disproportionate familiarity deficit for reorder versus rehearse trials against a background of generalized LTM impairments. Relational processing during WM led to DLPFC activation in both groups. However, this activation was less focal in patients than in controls, and patients with more severe negative symptoms showed less of a DLPFC increase. fMRI analysis of subsequent recognition performance revealed a group by condition interaction. High LTM for reorder versus rehearse trials was associated with bilateral DLPFC activation in controls, but not in patients who activated the left middle temporal and inferior occipital gyrus. Results indicate that although patients can activate the DLPFC on a structured relational WM task, this activation is less focal and does not translate to high retrieval success, suggesting a disruption in the interaction between WM and LTM processes in schizophrenia.     

人脑运动皮层功能磁共振成像研究

目的采用功能用磁共振成像（fMRI）回波平面（EPI）技术,研究人脑运动皮质血氧水平依赖（BOLD）的功能磁共振成像。方法27名正常健康志愿者,右手挤压橡皮圈,在运动和静止两种对比条件下,采集运动皮层的回波平面图像（BOLD-fMRI）。分析运动状态和非运动状态信号对比的脑功能图像。结果fMRI图像显示运动刺激下脑功能活动激活区主要位于对侧感觉运动皮质区、辅助运动区等。结论fMRI可用于研究活体人脑各功能区的活动,fMRI可对运动刺激下的人脑运动皮质进行初步定位。     

功能磁共振成像观察2型糖尿病患者工作记忆

目的 通过功能磁共振成像技术对2型糖尿病患者的工作记忆进行研究,探讨2型糖尿病患者工作记忆的受损状况.方法 采用1-back组块设计,对16例2型糖尿病患者及13名正常对照受试者,进行词语及客体工作记忆任务的fMRI检查,对反应时间、正确率及脑激活图进行分析.结果 2型糖尿病组患者的正确反应时间、正确率与对照组相比差异无统计学意义(P>0.05).与对照组相比,2型糖尿病组在词语工作记忆时,左侧额叶、左侧顶叶及海马旁回等脑区激活显著减弱(P<0.05),客体工作记忆时,右侧额叶、左侧顶叶及双侧枕叶等脑区激活减弱(P<0.05).结论 2型糖尿病患者存在词语及客体工作记忆损害,经典激活脑区存在损害.     

Imagery of a moving object: The role of occipital cortex and human MT/V5+

Visual imagery – similar to visual perception – activates feature-specific and category-specific visual areas. This is frequently observed in experiments where the instruction is to imagine stimuli that have been shown immediately before the imagery task. Hence, feature-specific activation could be related to the short-term memory retrieval of previously presented sensory information.Here, we investigated mental imagery of stimuli that subjects had not seen before, eliminating the effects of short-term memory. We recorded brain activation using fMRI while subjects performed a behaviourally controlled guided imagery task in predefined retinotopic coordinates to optimize sensitivity in early visual areas.Whole brain analyses revealed activation in a parieto-frontal network and lateral–occipital cortex. Region of interest (ROI) based analyses showed activation in left hMT/V5+. Granger causality mapping taking left hMT/V5+ as source revealed an imagery-specific directed influence from the left inferior parietal lobule (IPL). Interestingly, we observed a negative BOLD response in V1–3 during imagery, modulated by the retinotopic location of the imagined motion trace.Our results indicate that rule-based motion imagery can activate higher-order visual areas involved in motion perception, with a role for top-down directed influences originating in IPL. Lower-order visual areas (V1, V2 and V3) were down-regulated during this type of imagery, possibly reflecting inhibition to avoid visual input from interfering with the imagery construction. This suggests that the activation in early visual areas observed in previous studies might be related to short- or long-term memory retrieval of specific sensory experiences.     

Multi-task functional MRI in multiple sclerosis patients without clinical disability

While the majority of individuals with multiple sclerosis (MS) develop significant clinical disability, a subset experiences a disease course with minimal impairment even in the presence of significant apparent tissue damage on magnetic resonance imaging (MRI). Functional magnetic resonance imaging (fMRI) in MS patients with low disability suggests that increased use of the cognitive control system may limit the clinical manifestation of the disease. The current fMRI studies tested the hypothesis that nondisabled MS patients show increased recruitment of cognitive control regions while performing sensory, motor and cognitive tasks. Twenty two patients with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of ≤ 1.5 and 23 matched healthy controls were recruited. Subjects underwent fMRI while observing flashing checkerboards, performing right or left hand movements, or executing the 2-back working memory task. Compared to control subjects, patients demonstrated increased activation of the right dorsolateral prefrontal cortex and anterior cingulate cortex during the performance of the working memory task. This pattern of functional recruitment also was observed during the performance of non-dominant hand movements. These results support the mounting evidence of increased functional recruitment of cognitive control regions in the working memory system of MS patients with low disability and provide new evidence for the role of increased cognitive control recruitment in the motor system.     

Fatigue in Multiple Sclerosis Is Associated with Abnormal Cortical Activation to Voluntary Movement—EEG Evidence

Converging evidence is consistent with the view that fatigue in Multiple Sclerosis is independent from pyramidal tract involvement, suggesting a possible involvement of frontal areas. During voluntary movement, changes of the EEG rhythms can be observed over sensorimotor areas. Event-related desynchronization (ERD) of the 10 and 20 Hz frequency bands occurs during motor planning and execution and is followed after movement termination by event-related synchronization (ERS), expressing cortical idling or inhibition. We evaluated the pattern of cortical activation to voluntary movement in MS patients complaining of fatigue assessed using the Fatigue Severity Scale. Fifteen MS patients complaining of fatigue, 18 MS patients without fatigue, and 14 normal controls were studied. The two patients groups were similar for age, sex, disease duration, and were not disabled (score <1.5 at the Expanded Disability Status Scale). Twenty-nine channel EEG was recorded during about 60 self-paced extensions of the right thumb. The onset latency and amount of the contralateral sensorimotor (C3 electrode) 10 and 18–22 Hz ERD were similar in the three groups. ERD was more widespread anteriorly in the fatigue group compared with normal controls (P < 0.01 over Fz electrode). Postmovement contralateral sensorimotor 18–22 Hz ERS was significantly lower in fatigue MS patients compared with normal subjects (P < 0.005) and with nonfatigue MS patients (P = 0.02). These findings are consistent with a central origin of fatigue in MS and indicate cortical dysfunction even during a simple motor task, resulting in hyperactivity during movement execution and failure of the inhibitory mechanisms intervening after movement termination.     

Application of Cortical Unfolding Techniques to Functional MRI of the Human Hippocampal Region

We describe a new application of cortical unfolding to high-resolution functional magnetic resonance imaging (fMRI) of the human hippocampal region. This procedure includes techniques to segment and unfold the hippocampus, allowing the fusiform, parahippocampal, perirhinal, entorhinal, subicular, and CA fields to be viewed and compared across subjects. Transformation parameters derived from unfolding high-resolution structural images are applied to coplanar, functional images, yielding two-dimensional “unfolded” activation maps of hippocampi. The application of these unfolding techniques greatly enhances the ability of fMRI to localize and characterize signal changes within the medial temporal lobe. Use of this method on a novelty-encoding paradigm reveals a temporal dissociation between activation along the collateral sulcus and activation in the hippocampus proper.     

Problem-based learning in clinical practice: employment and education as development partners

In this project tutorial small group working sessions of problem-based learning were carried out in the long-term care practice period of nursing students. The purpose was to describe nursing students’ learning when tutorial work was carried out during their first clinical practice period. The students had one PBL cycle during their four weeks’ clinical practice consisting of two tutorial sessions where clinical mentors and the teacher worked together as tutors. The students were pre-tested before the clinical practice and post-tested afterwards using a questionnaire. The questionnaire had been used in pilot projects during 2004–2005. Altogether, 40 nursing students participated in the study. There were statistically significant differences between pre- and post-test in “PBL-learning skills” (p < 0.001) and “interaction with old patients” (p < 0.001). The means of items “Interested in work in long-term care” and “Own attitude towards long-term care” had increased between pre- and post-test. In conclusion it can be suggested that carrying out tutorials in nursing students’ clinical practice is beneficial.     

Encoding the future: Successful processing of intentions engages predictive brain networks

Evidence from cognitive, patient and neuroimaging research indicates that “remembering to remember” intentions, i.e., prospective memory (PM) retrieval, requires both general memory systems involving the medial temporal lobes and an executive system involving rostral PFC (BA 10). However, it is not known how prospective memories are initially formed. Using fMRI, we investigated whether brain activity during encoding of future intentions and present actions differentially predicted later memory for those same intentions (PM) and actions (retrospective memory). We identified two significant patterns of neural activity: a network linked to overall memory and another linked specifically to PM. While overall memory success was predicted by temporal lobe activations that included the hippocampus, PM success was also uniquely predicted by activations in additional regions, including left rostrolateral PFC and the right parahippocampal gyrus. This finding extends the role of these structures to the formation of individual intentions. It also provides the first evidence that PM encoding, like PM retrieval, is supported by both a common episodic memory network and an executive network specifically recruited by future-oriented processing.     

How well does structural equation modeling reveal abnormal brain anatomical connections? An fMRI simulation study

Many brain disorders result from alterations in the strength of anatomical connectivity between different brain regions. This study investigates whether such alterations can be revealed by examining differences in interregional effective connectivity between patient and normal subjects. We applied one prominent effective connectivity method – Structural Equation Modeling (SEM) – to simulated functional MRI (fMRI) timeseries from a neurobiologically realistic network model in which the anatomical connectivity is known and can be manipulated. These timeseries were simulated for two task conditions, a delayed match-to-sample (DMS) task and passive-viewing, and for “normal subjects” and “patients” who had one weakened anatomical connection in the neural network model. SEM results were compared between task conditions as well as between groups. A significantly reduced effective connectivity corresponding to the weakened anatomical connection during the DMS task was found. We also obtained a significantly reduced set of effective connections in the patient networks for anatomical connections “downstream” from the weakened linkage. However, some “upstream” effective connections were significantly larger in the patient group relative to normals. Finally, we found that of the SEM model measures we examined, the total error variance was the best at distinguishing a patient network from a normal network. These results suggest that caution is necessary in applying effective connectivity methods to fMRI data obtained from non-normal populations, and emphasize that functional interactions among network elements can appear as abnormal even if only part of a network is damaged.     

fMRI-acoustic noise alters brain activation during working memory tasks

Scanner noise during functional magnetic resonance imaging (fMRI) may interfere with brain function and change blood oxygenation level dependent (BOLD) signals, a problem that generally worsens at the higher field strengths. Therefore, we studied the effect of increased acoustic noise on fMRI during verbal working memory (WM) processing. The sound pressure level of scanner noise was increased by 12 dBA from "Quiet" to "Loud" echo planar imaging (EPI) scans by utilizing resonant vibration modes of the gradient coil. A WM paradigm with graded levels of task difficulty was used to further access WM load. Increased scanner noise produced increased BOLD responses (percent signal change) bilaterally in the cerebellum, inferior (IFG), medial (medFG), and superior (SFG) frontal, fusiform (FusG), and the lingual (LG) gyri, and decreased BOLD responses bilaterally in the anterior cingulate gyrus (ACG) and the putamen. This finding suggests greater recruitment of attention resources in these brain regions, probably to compensate for interference due to louder scanner noise. Increased working memory load increased the BOLD signals in IFG and the cerebellum, but decreased the BOLD signals in the putamen and the LG. These findings also support the idea that brain function requires additional attention resources under noisier conditions. Load- and acoustic-noise-related changes in BOLD responses correlated negatively in the WM network. This study demonstrates that MR noise affects brain activation pattern. Future comparisons between studies performed under different acoustic conditions (due to differing magnetic field strengths, pulse sequences, or scanner manufacturers) might require knowledge of the sound pressure level of acoustic noise during fMRI.     

Spatio-temporal dynamics of reach-related neural activity for visual and somatosensory targets

The parieto-frontal network plays a crucial role in the transformations that convert visual information into motor commands for hand reaching movements. Here we use electroencephalography to determine whether the planning of reaching movements to visual and somatosensory targets involves a similar spatio-temporal pattern of neural activity. Subjects performed reaching movements toward spatial locations defined either by visual (light-emitting diode) or somatosensory (vibration of a fingertip of the contralateral hand) stimuli. To identify the activations associated with sensorimotor transformations, we subtracted the event-related potentials recorded in a “static” task (the stimuli were presented but no movement was initiated) from those recorded in a “reach” task (a reach had to be initiated toward the spatial location of the stimuli). In the visual condition, reach-related activities were observed over parietal, premotor and sensorimotor areas contralateral to the reaching hand. Activation was first observed over parietal areas 140 ms after stimulus onset and progressed to frontal areas. The proprioceptive condition recruited a similar set of structures as for visual targets. However, the temporal pattern of activity within these cortical areas differed greatly. Activity was sustained over premotor and sensorimotor areas throughout the reaction time interval, occurring simultaneously with the parietal activation. These results suggest that a common cortical network serves to transform visual and somatosensory signals into motor commands, but that the interactions between the structures of this network differ. This raises the possibility that different coordinate frames are used to encode the motor error for the two target modalities.     

The use of surface electromyography as a tool in differentiating temporomandibular disorders from neck disorders

The aim of this study was to assess the electromyographic characteristics of the masticatory muscles (masseter and temporalis) of patients with either “temporomandibular joint disorder” or “neck pain”. Surface electromyography of the right and left masseter and temporalis muscles was performed during maximum teeth clenching in 38 patients aged 21–67 years who had either (a) temporomandibular joint disorder (24 patients); (b) “neck pain” (13 patients). Ninety-five control, healthy subjects were also examined. During clenching, standardized total muscle activities (electromyographic potentials over time) were significantly different in the three groups: 75 μV/μV s % in the temporomandibular joint disorder patients, 124 μV/μV s % in the neck pain patients, and 95 μV/μV s % in the control subjects (analysis of variance, P<0.001). The temporomandibular joint disorder patients also had significantly (P<0.001) more asymmetric muscle potentials (78%) than either neck pain patients (87%) or control subjects (92%). A linear discriminant function analysis allowed a significant separation between the two patient groups, with a single patient error of 18.2%. Surface electromyographic analysis during clenching allowed to differentiate between patients with a temporomandibular joint disorder and patients with a neck pain problem.