Malle A. Tagamets

A Parametric Approach to Orthographic Processing in the Brain: An fMRI Study

Brain activation studies of orthographic stimuli typically start with the premise that different types of orthographic strings (e.g., words, pseudowords) differ from each other in discrete ways, which should be reflected in separate and distinct areas of brain activation. The present study starts from a different premise: Words, pseudowords, letterstrings, and false fonts vary systematically across a continuous dimension of familiarity to English readers. Using a one-back matching task to force encoding of the stimuli, the four types of stimuli were visually presented to healthy adult subjects while fMRI activations were obtained. Data analysis focused on parametric comparisons of fMRI activation sites. We did not find any region that was exclusively activated for real words. Rather, differences among these string types were mainly expressed as graded changes in the balance of activations among the regions. Our results suggests that there is a widespread network of brain regions that form a common network for the processing of all orthographic string types.

Functional interactions of the inferior frontal cortex during the processing of words and word-like stimuli.

The hypothesis that ventral/anterior left inferior frontal gyrus (LIFG) subserves semantic processing and dorsal/posterior LIFG subserves phonological processing was tested by determining the pattern of functional connectivity of these regions with regions in left occipital and temporal cortex during the processing of words and word-like stimuli. In accordance with the hypothesis, we found strong functional connectivity between activity in ventral LIFG and activity in occipital and temporal cortex only for words, and strong functional connectivity between activity in dorsal LIFG and activity in occipital and temporal cortex for words, pseudowords, and letter strings, but not for false font strings. These results demonstrate a task-dependent functional fractionation of the LIFG in terms of its functional links with posterior brain areas.

Effect of methylphenidate on executive functioning in adults with attention-deficit/hyperactivity disorder: normalization of behavior but not related brain activity.

BACKGROUND We examined the effect of prolonged methylphenidate (MPH) treatment on the functional neuroanatomy of executive functioning in adult men with attention-deficit/hyperactivity disorder (ADHD). METHODS Positron emission tomography with [(15)O] water measured alterations of regional cerebral blood flow (rCBF) during the Paced Auditory Serial Addition Task and a control task in 10 ADHD and 11 normal control men. Attention-deficit/hyperactivity disorder men were imaged unmedicated and after a clinically optimal dose of MPH for 3 weeks. RESULTS Methylphenidate improved ADHD task performance, reduced rCBF in the prefrontal cortex (PFC), and increased rCBF in the right thalamus and precentral gyrus. Comparisons between the ADHD and normal control groups showed that normal control participants exhibited greater anterior cingulate cortex and temporal gyrus rCBF than ADHD participants under both conditions. Executive functioning was associated with greater subcortical (basal ganglia and cerebellar vermis) activation in the ADHD than normal control group under both conditions. CONCLUSIONS Methylphenidate does not normalize task-related activity in ADHD. Task-related rCBF decreases in the PFC may be due to improved filtering out of task-irrelevant stimuli by way of MPH-mediated dopamine release in the PFC.

A Positron Emission Tomography Study Of Methylphenidate in Adults with ADHD: Alterations in Resting Blood Flow and Predicting Treatment Response

A hallmark symptom of attention-deficit hyperactivity disorder (ADHD) is an excess of motoric behavior or hyperactivity. Methylphenidate (MPH) is known to reduce hyperactivity in individuals with ADHD. Yet little is known about how it alters neural activity and how this relates to its clinical effects. The goal of this study is to examine MPH-induced changes during resting brain metabolism, and to examine how these changes correlate with measures of behavioral response to the drug. Measures of regional cerebral blood flow (rCBF) using positron emission tomography (PET) were acquired at rest for ten adult subjects with ADHD during both an unmedicated state and after a 3-week period of chronic dosing with a clinically optimal dose of MPH. Compared with the on-MPH condition, the off-MPH condition was associated with relative increases in rCBF bilaterally in the precentral gyri, left caudate nucleus, and right claustrum. The on-MPH condition was associated with relative increases in rCBF in the cerebellar vermis. A correlational analysis measured the relation between rCBF in the off-medication condition to change in ADHD ratings between the off- and on-MPH condition to identify brain regions associated with treatment response. The degree of change in the ratings was negatively correlated with rCBF increases in the midbrain, cerebellar vermis, and the precentral and middle frontal gyri in the off-MPH condition. The majority of these brain regions are involved in the planning and execution of motor behavior. These data suggest that MPH modulates brain regions associated with motor function to achieve a reduction in ADHD symptoms.

Investigating the neural basis for functional and effective connectivity. Application to fMRI

Viewing cognitive functions as mediated by networks has begun to play a central role in interpreting neuroscientific data, and studies evaluating interregional functional and effective connectivity have become staples of the neuroimaging literature. The neurobiological substrates of functional and effective connectivity are, however, uncertain. We have constructed neurobiologically realistic models for visual and auditory object processing with multiple interconnected brain regions that perform delayed match-to-sample (DMS) tasks. We used these models to investigate how neurobiological parameters affect the interregional functional connectivity between functional magnetic resonance imaging (fMRI) time-series. Variability is included in the models as subject-to-subject differences in the strengths of anatomical connections, scan-to-scan changes in the level of attention, and trial-to-trial interactions with non-specific neurons processing noise stimuli. We find that time-series correlations between integrated synaptic activities between the anterior temporal and the prefrontal cortex were larger during the DMS task than during a control task. These results were less clear when the integrated synaptic activity was haemodynamically convolved to generate simulated fMRI activity. As the strength of the model anatomical connectivity between temporal and frontal cortex was weakened, so too was the strength of the corresponding functional connectivity. These results provide a partial validation for using fMRI functional connectivity to assess brain interregional relations.

Disruption of anterior insula modulation of large-scale brain networks in schizophrenia.

BACKGROUND Systems level modeling of functional magnetic resonance imaging data has demonstrated dysfunction of several large-scale brain networks in schizophrenia. Anomalies across multiple functional networks associated with schizophrenia could be due to diffuse pathology across multiple networks or, alternatively, dysfunction at converging control(s) common to these networks. The right anterior insula has been shown to modulate activity in the central executive and default mode networks in healthy individuals. We tested the hypothesis that right anterior insula modulation of central executive and default mode networks is disrupted in schizophrenia and associated with cognitive deficits. METHODS In 44 patients with schizophrenia and 44 healthy control subjects, we used seed-based resting state functional connectivity functional magnetic resonance imaging analysis to examine connectivity between right insular subregions and central executive/default mode network regions. We also performed two directed connectivity analyses of resting state data: Granger analysis and confirmatory structural equation modeling. Between-group differences in path coefficients were used to evaluate anterior insula modulation of central executive and default mode networks. Cognitive performance was assessed with the rapid visual information processing task, a test of sustained attention. RESULTS With multiple connectivity techniques, we found compelling, corroborative evidence of disruption of right anterior insula modulation of central executive and default mode networks in patients with schizophrenia. The strength of right anterior insula modulation of these networks predicted cognitive performance. CONCLUSIONS Individuals with schizophrenia have impaired right anterior insula modulation of large-scale brain networks. The right anterior insula might be an emergent pathophysiological gateway in schizophrenia.

Specific motion processing pathway deficit during eye tracking in schizophrenia: A performance-matched functional magnetic resonance imaging study

BACKGROUND The neural mechanisms underlying smooth pursuit eye movement (SPEM) abnormalities in schizophrenia are not well understood. Previous evidence suggests that a deficit in the processing of internal representations of object motion (extraretinal motion) contributes to SPEM deficits in patients. Functional magnetic resonance imaging (fMRI) activation was compared between patients and control subjects to determine whether schizophrenia patients exhibit abnormal cerebral activation in regions associated with extraretinal motion processing during SPEM. METHODS Patients and control subjects were selected based on matched performance in the closed-loop gain. Despite similar performance on closed-loop pursuit gain, patients showed consistent deficits in extraretinal motion based on predictive pursuit. In the magnet, subjects were tested using a traditional smooth-pursuit task that elicits closed-loop response. RESULTS Patients had reduced pursuit-related activation in several known extraretinal motion processing areas including frontal and supplemental eye fields, medial superior temporal cortex, and anterior cingulate. Patients also showed increased activation in medial occipitotemporal cortex. CONCLUSIONS These results provide functional anatomic evidence supporting reduced function in the extraretinal motion processing pathway in schizophrenia. Increased activation in medial occipitotemporal cortex suggests an increased dependence on immediate retinal motion information, which may be used to compensate for reduced extraretinal signaling during sustained visual tracking.

Relating neuronal dynamics for auditory object processing to neuroimaging activity: a computational modeling and an fMRI study

We investigated the neural basis of auditory object processing in the cerebral cortex by combining neural modeling and functional neuroimaging. We developed a large-scale, neurobiologically realistic network model of auditory pattern recognition that relates the neuronal dynamics of cortical auditory processing of frequency modulated (FM) sweeps to functional neuroimaging data of the type obtained using PET and fMRI. Areas included in the model extend from primary auditory to prefrontal cortex. The electrical activities of the neuronal units of the model were constrained to agree with data from the neurophysiological literature regarding the perception of FM sweeps. We also conducted an fMRI experiment using stimuli and tasks similar to those used in our simulations. The integrated synaptic activity of the neuronal units in each region of the model, convolved with a hemodynamic response function, was used as a correlate of the simulated fMRI activity, and generally agreed with the experimentally observed fMRI data in the brain areas corresponding to the regions of the model. Our results demonstrate that the model is capable of exhibiting the salient features of both electrophysiological neuronal activities and fMRI values that are in agreement with empirically observed data. These findings provide support for our hypotheses concerning how auditory objects are processed by primate neocortex.

Interpreting PET and fMRI measures of functional neural activity: the effects of synaptic inhibition on cortical activation in human imaging studies

Human brain imaging methods such as postiron emission tomography and functional magnetic resonance imaging have recently achieved widespread use in the study of both normal cognitive processes and neurological disorders. While many of these studies have begun to yield important insights into human brain function, the relationship between these measurements and the underlying neuronal activity is still not well understood. One open question is how neuronal inhibition is reflected in these imaging results. In this paper, we describe how large-scale modeling can be used to address this question. Specifically, we identify three factors that may play a role in how inhibition affects imaging results: (1) local connectivity; (2) context; and (3) type of inhibitory connection. Simulation results are presented that show how the interaction among these three factors can explain seemingly contradictory experimental results. The modeling suggests that neuronal inhibition can raise brain imaging measures if there is either low local excitatory recurrence or if the region is not otherwise being driven by excitation. Conversely, with high recurrence or actively driven excitation, inhibition can lower observed values.

Working Memory in Attention Deficit/Hyperactivity Disorder is Characterized by a Lack of Specialization of Brain Function

Working memory impairments are frequent in Attention Deficit/Hyperactivity Disorder (ADHD) and create problems along numerous functional dimensions. The present study utilized the Visual Serial Addition Task (VSAT) and functional magnetic resonance imaging (fMRI) to explore working memory processes in thirteen typically developing (TD) control and thirteen children with ADHD, Combined type. Analysis of Variance (ANOVA) was used to examine both main effects and interactions. Working memory-specific activity was found in TD children in the bilateral prefrontal cortex. In contrast the within-group map in ADHD did not reveal any working-memory specific regions. Main effects of condition suggested that the right middle frontal gyrus (BA6) and the right precuneus were engaged by both groups during working memory processing. Group differences were driven by significantly greater, non-working memory-specific, activation in the ADHD relative to TD group in the bilateral insula extending into basal ganglia and the medial prefrontal cortex. A region of interest analysis revealed a region in left middle frontal gyrus that was more active during working memory in TD controls. Thus, only the TD group appeared to display working memory-modulated brain activation. In conclusion, children with ADHD demonstrated reduced working memory task specific brain activation in comparison to their peers. These data suggest inefficiency in functional recruitment by individuals with ADHD represented by a poor match between task demands and appropriate levels of brain activity.