Hoi-Chung Leung

An event-related functional MRI study comparing interference effects in the Simon and Stroop tasks

The Stroop and Simon tasks typify a class of interference effects in which the introduction of task-irrelevant stimulus characteristics robustly slows reaction times. Behavioral studies have not succeeded in determining whether the neural basis for the resolution of these interference effects during successful task performance is similar or different across tasks. Event-related functional magnetic resonance imaging (fMRI) studies were obtained in 10 healthy young adults during performance of the Stroop and Simon tasks. Activation during the Stroop task replicated findings from two earlier fMRI studies. These activations were remarkably similar to those observed during the Simon task, and included anterior cingulate, supplementary motor, visual association, inferior temporal, inferior parietal, inferior frontal, and dorsolateral prefrontal cortices, as well as the caudate nuclei. The time courses of activation were also similar across tasks. Resolution of interference effects in the Simon and Stroop tasks engage similar brain regions, and with a similar time course. Therefore, despite the widely differing stimulus characteristics employed by these tasks, the neural systems that subserve successful task performance are likely to be similar as well.

Sustained Mnemonic Response in the Human Middle Frontal Gyrus during On-Line Storage of Spatial Memoranda

The mapping of cognitive functions to neural systems is a central goal of cognitive neuroscience. On the basis of homology with lesion and physiological studies in nonhuman primates, Brodmanns area (BA) 46/9 in the middle frontal gyrus (MFG) has been proposed as the cortical focus for both the storage as well as processing components of working memory in the human brain, but the evidence on the segregation of these components and their exact areal localization has been inconsistent. In order to study this issue and increase the temporal resolution of functional mapping, we disambiguated the storage component of working memory from sensory and motor responses by employing functional magnetic resonance imaging (fMRI) in spatial delayed-response (DR) tasks with long delay intervals and different conditions of demand. We here show that BA 46 can support a sustained mnemonic response for as long as 24 sec in a high-demand task and the signal change in this area exceeded that in the other prefrontal areas examined. Our findings support a conservation of functional architecture between human and nonhuman primate in showing that the MFG is prominently engaged in the storage of spatial information.

Common and Differential Ventrolateral Prefrontal Activity during Inhibition of Hand and Eye Movements

The inferior frontal cortex, particularly the ventrolateral prefrontal cortex (VLPFC) in the right hemisphere, has been implicated to serve as a general inhibitory mechanism in the cognitive control of behavior. Because this notion was primarily based on studies of response inhibition in manual tasks, it has yet to be validated in other response modalities. We conducted a functional magnetic resonance imaging study to examine whether the VLPFC is commonly activated during inhibition of responses by hand and by eye within the same subjects. We used the stop-signal task, a relatively pure measure of response inhibition, as the behavioral paradigm. Results from 12 subjects showed that both the right and the left caudal VLPFC and anterior insula, rostral to the premotor area, are activated during inhibition of both manual and saccadic responses. Within the posterior VLPFC, activations overlapped to a significant extent across the two response modalities, although a weaker functionally differentiation was also found along the dorsoventral axis. Other areas such as medial superior frontal gyrus (pre-supplementary motor area/supplementary eye field), dorsolateral prefrontal cortex, and inferior parietal cortex were also activated during canceling both hand and eye movements. Our findings suggest that a common VLPFC network is involved in response inhibition, although the specific control of the different response modalities may be partially segregated within the lateral prefrontal cortex.

Frontal activations associated with accessing and evaluating information in working memory: an fMRI study

To investigate the involvement of frontal cortex in accessing and evaluating information in working memory, we used a variant of a Sternberg paradigm and compared brain activations between positive and negative responses (known to differentially tax access/evaluation processes). Participants remembered two trigrams in each trial and were then cued to discard one of them and maintain the other one as the target set. After a delay, a probe letter was presented and participants made decisions about whether or not it was in the target set. Several frontal areas--anterior cingulate (BA32), middle frontal gyrus (bilateral BA9, right BA10, and right BA46), and left inferior frontal gyrus (BA44/45)--showed increased activity when participants made correct negative responses relative to when they made correct positive responses. No areas activated significantly more for the positive responses than for the negative responses. It is suggested that the multiple frontal areas involved in the test phase of this task may reflect several component processes that underlie more general frontal functions.

Impairment of Working Memory Maintenance and Response in Schizophrenia: Functional Magnetic Resonance Imaging Evidence

BACKGROUND Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases. METHODS Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load. RESULTS Task accuracy was similar in patients and healthy participants. However, patients showed reductions in brain activation during maintenance and response phases but not during the encoding phase. The reduced prefrontal activity during the maintenance phase of working memory was attributed to a greater rate of decay of prefrontal activity over time in patients. Cortical deficits in patients did not appear to be related to antipsychotic treatment. In patients and in healthy subjects, the time-dependent reduction in prefrontal activity during working memory maintenance correlated with poorer performance on the memory task. CONCLUSIONS Overall, these data highlight that basic research insights into the distinct neurobiologies of the maintenance and response phases of working memory are of potential importance for understanding the neurobiology of cognitive impairment in schizophrenia and advancing its treatment.

The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity

Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.

The effect of memory load on cortical activity in the spatial working memory circuit

Accumulating evidence from electrophysiology and neuroimaging studies suggests that spatial working memory is subserved by a network of frontal and parietal regions. In the present study, we parametrically varied the memory set size (one to four spatial locations) of a delayed-response task and applied time-resolved fMRI to study the influence of memory load upon the spatial working memory circuit. Our behavioral results showed that performance deteriorates (lower accuracy and longer reaction time) as memory load increases. Memory load influenced cortical activity during the cue, delay, and response phases of the delayed-response task. Although delay-related activity in many regions increased with increasing memory load, it also was significantly reduced in the middle frontal gyrus and frontal eye fields and leveled off in the parietal areas when memory load increased further. Delayrelated activity in the left posterior parietal cortex was also lower during the error trials, in comparison with the correct trials. Our findings indicate that the delay period activity in the spatial working memory circuit is load sensitive and that the attenuation of this signal is the neural manifestation of performance limitation in the face of excessive memory load.

Rule-Guided Executive Control of Response Inhibition: Functional Topography of the Inferior Frontal Cortex

Background The human inferior frontal cortex (IFC) is a large heterogeneous structure with distinct cytoarchitectonic subdivisions and fiber connections. It has been found involved in a wide range of executive control processes from target detection, rule retrieval to response control. Since these processes are often being studied separately, the functional organization of executive control processes within the IFC remains unclear. Methodology/Principal Findings We conducted an fMRI study to examine the activities of the subdivisions of IFC during the presentation of a task cue (rule retrieval) and during the performance of a stop-signal task (requiring response generation and inhibition) in comparison to a not-stop task (requiring response generation but not inhibition). We utilized a mixed event-related and block design to separate brain activity in correspondence to transient control processes from rule-related and sustained control processes. We found differentiation in control processes within the IFC. Our findings reveal that the bilateral ventral-posterior IFC/anterior insula are more active on both successful and unsuccessful stop trials relative to not-stop trials, suggesting their potential role in the early stage of stopping such as triggering the stop process. Direct countermanding seems to be outside of the IFC. In contrast, the dorsal-posterior IFC/inferior frontal junction (IFJ) showed transient activity in correspondence to the infrequent presentation of the stop signal in both tasks and the left anterior IFC showed differential activity in response to the task cues. The IFC subdivisions also exhibited similar but distinct patterns of functional connectivity during response control. Conclusions/Significance Our findings suggest that executive control processes are distributed across the IFC and that the different subdivisions of IFC may support different control operations through parallel cortico-cortical and cortico-striatal circuits.

Neuronal representation of occluded objects in the human brain.

Occluding surfaces frequently obstruct the object of interest yet are easily dealt with by the visual system. Here, we test whether neural areas known to participate in motion perception and eye movements are regions that also process occluded motion. Functional magnetic resonance imaging (fMRI) was used to assess brain activation while subjects watched a moving ball become occluded. Areas activated during occluded motion included the intraparietal sulcus (IPS) as well as middle temporal (MT) regions analogous to monkey MT/MST. A second experiment showed that these results were not due to motor activity. These findings suggest that human cortical regions involved in perceiving occluded motion are similar to regions that process real motion and regions responsible for eye movements. The intraparietal sulcus may be involved in predicting the location of an unseen target for future hand or eye movements.

Load response functions in the human spatial working memory circuit during location memory updating.

Previous studies have emphasized that the dorsolateral prefrontal cortex is important for manipulating information in working memory, although activations in other frontal and parietal areas are commonly observed under the same conditions. We conducted an fMRI experiment to examine brain responses as a parametric function of memory updating, which is considered as an elemental process in working memory. In a variant spatial delayed-response task, human subjects performed updating operations over a 9-second delay period, during which they mentally transform the location of a memorized target in a 4 by 4 grid according to 3 to 12 instruction cues. Activity increased monotonically with increasing updating load in numerous cortical and subcortical regions including the rostrodorsal premotor (rdPM), lateral precentral sulcus, lateral prefrontal, posterior associative, striatal and cerebellar areas. The rdPM and superior parietal were particularly sensitive to the updating manipulation. There were several main findings. First, updating spatial working memory involved mostly the same cortical and subcortical regions that were activated during maintenance of spatial information. Second, the updating load response functions of regions in the spatial working memory circuit showed a strong linear component. However, none shows significant increases in activity from 9 to 12 updating operations. Third, activity in the right rdPM and anterior inferior frontal gyrus correlated positively with working memory performance in the high updating load condition. Our findings suggest that updating and maintenance of spatial information may share similar processes and that the rostrodorsal premotor cortex and anterior inferior frontal gyrus may be important for the success of tracking spatial information in working memory.