Functional connectivity in an fMRI study of semantic and phonological processes and the effect of l-Dopa
Introduction
Understanding the effects of pharmacological manipulation on semantic networks may have implications ranging from language perception (Angwin et al., 2004, Kischka et al., 1996) to problem solving (Beversdorf et al., 1999, Beversdorf et al., 2002, Silver et al., 2004). This may also reveal insight into the impairments exhibited by some patient populations (Arnott, Chenery, Murdoch, & Silburn, 2001). In order to understand these complex behaviors, one must first begin to understand how these manipulations affect brain regions associated with language processing.
Studies of patients with brain lesions have shown that the representations of word meaning and form can be differentiated (for a review see Rapp & Caramazza, 1995). However functional deficits are often associated with large lesions and make it difficult to relate specific deficits to specific anatomical regions. Evidence form neuroimaging studies complements the findings from brain damaged patients and makes it possible to identify specific brain areas associated with a specific task (Cabeza and Nyberg, 2000, Crosson et al., 2003, Devlin et al., 2003, Fiez and Petersen, 1998, Martin, 2003, McDermott et al., 2003, Poldrack et al., 1999, Price, 2000, Thompson-Schill et al., 1997). The findings of these studies revealed the existence of a vast network of brain structures that contribute to these language processes, including anterior and posterior, cortical and subcortical brain regions. In examining different aspects of language processing, such as phonological and semantic processing, no task is ‘process-pure’. All phonological tasks can involve some semantic processing and all semantic tasks can include some phonological processing. However, whereas brain activation associated with these two language processes overlaps to a marked degree, some differences in brain activation have been revealed between tasks directed at semantic and phonological processing. The left inferior prefrontal cortex (LIPC) participates in a network that activates during controlled processing of both semantic and non-semantic information (Bookheimer, 2002, Devlin et al., 2003, Gabrieli et al., 1998, Poldrack et al., 1999, Price, 2000, Thompson-Schill et al., 1997, Wagner et al., 2001), whereas posterior regions appear to have a relatively greater involvement in retrieval of stored information such as word meaning (posterior middle temporal gyrus-BA21) (Demb et al., 1995, Gold and Buckner, 2002, McDermott et al., 2003, Poldrack et al., 1999, Shivde and Thompson-Schill, 2004) or sound (parietal cortex-BA7/40) (McDermott et al., 2003, Shivde and Thompson-Schill, 2004). These studies go further and reveal some regional specificity within the prefrontal cortex: anterior LIPC (BA 45/47/10) is involved more in semantic processing (Gold and Buckner, 2002, McDermott et al., 2003, Demb et al., 1995, Poldrack et al., 1999, Shivde and Thompson-Schill, 2004) and posterior LIPC (BA 44/6) in phonological processing (Gold and Buckner, 2002, Poldrack et al., 1999, McDermott et al., 2003, Shivde and Thompson-Schill, 2004). McDermott et al. (2003) have also found that areas of the middle frontal gyrus (BA6, pre-SMA) bilateral fusiform gyrus (BA37) and bilateral cerebellum are similarly activated by both phonological and semantic tasks relative to baseline (fixating on a cross-hair). Subcortical structures have also been found to contribute to both semantic and phonological processing. Crosson et al. (2003) showed that the left dorsal caudate and the ventral anterior thalamus contribute to retrieval of words from pre-existing lexical stores, due to direct connections with the pre-SMA. They have also suggested that right basal ganglia activity contributes by suppressing right frontal activity from interfering with language production.
Although, the areas of the brain involved in semantic and phonological processing have been identified and further specifications of functional distinctions within these areas have been made, the interaction between these areas during language processing has not been extensively reported to our knowledge. Therefore, we intended to contribute by adding information about the functional connectivity in the brain during language processes, specifically semantic and phonological processing.
Complex cognitive functions and behaviors are mediated by interconnected neural networks (Mesulam, 1990). The anatomical connections can be characterized by using diffusion weighted imaging. In contrast, the functional interaction between brain regions activated during performance of a task can be characterized by using fMRI to examine functional connectivity. Functional connectivity has been defined as the “temporal correlation between spatially remote neurophysiological events” (Friston, 1994a). In neuroimaging, functional connectivity offers indirect evidence of communication or collaboration between areas of the brain but offers “no insight into how these correlations are mediated” (Friston, 1994a). Functional connectivity is calculated by extracting fMRI time series from brain regions of interest. Then correlation coefficients (cc) are calculated between the time series of two regions of interest in order to determine to what degree they are functionally connected (Arfanakis et al., 2000). Such methodology has been used to examine functional connectivity within the motor, visual and auditory systems (Arfanakis et al., 2000), and during visual delayed recognition (Rissman, Gazzaley, & D’Esposito, 2004). This methodology has also revealed decreased functional connectivity during sentence comprehension and working memory in high functioning autism (Just et al., 2004, Koshino et al., 2005), a clinical population characterized by impairments in utilization of context, resulting in atypical performance consistent with ‘underconnectivity’ on tasks involving the semantic and associative networks (Beversdorf et al., 2000). Therefore, we wished to examine functional connectivity for semantic and phonological processes.
Behavioral research has demonstrated a role of the catecholamine neurotransmitter systems in modulation of cognition, more specifically of language networks. l-Dopa is converted into both dopamine and norepinephrine. These act to “amplify strong signals and dampen weak ones” (Dehaene, Jonides, Smith, & Spitzer, 1999), and therefore they increase the signal-to-noise ratio of cortical information processing. This is supported by evidence that dopamine enhances N-methyl-d-aspartate (NMDA) mediated excitatory postsynaptic currents (EPSCs) in layer V of the rat prefrontal cortex, while reducing non-NMDA mediated components of EPSCs, thus selectively enhancing sustained synaptic inputs (Seamans, Durstewitz, Christie, Stevens, & Sejnowski, 2001). These findings are proposed as a mechanism for the dopaminergic role in sustaining working memory (Winterer and Weinberger, 2004, Durstewitz and Seamans, 2002). This also suggests that increased levels of catecholamines may increase the focus of activation in semantic networks, and therefore it should decrease the spread of activation. Previous behavioral research demonstrated that administration of l-Dopa resulted in restriction of the semantic network in a lexical priming experiment (Angwin et al., 2004, Kischka et al., 1996). This result along with studies of semantic network spread in neurologically impaired patients such as schizophrenic patients and patients with Parkinson’s disease, suggests that dopamine may play a role in modulation of semantic processing (Spitzer et al., 1993, Spitzer et al., 1994, Watters and Patel, 1999). Therefore, we also wished to explore whether administration of l-Dopa also affects the interaction between language network components in semantic and phonological categorization tasks, as revealed by functional connectivity.
Section snippets
Research participants
Sixteen participants, 8 male and 8 female, mean age 28.3 years (range 21–49 years), average educational level 15 years, were recruited to participate in these studies. The sample size in this within-subject design would be expected to yield a significant effect of l-Dopa since previous experiments on semantic priming yielded significant results with a similar number of between-subject comparisons (Kischka et al., 1996). They were all native English speakers, right handed, as assessed with the
Behavioral results
Mean response times (RT) were calculated for each participant for each of the four testing conditions, and are presented in Table 1. A repeated measures 2*2 (task*drug) ANOVA was carried out to detect the effect of either drug or task on response times. A significant main effect was found for task [F(1,15) = 64.5, p < 0.00005] with a longer response time recorded for the semantic task (mean RT = 668 ms, SD = 11) as compared to the phonological task (mean RT = 602, SD = 12). Neither a main effect of drug,
Discussion
fMRI was used to study functional connectivity associated with semantic and phonological processing and whether this is affected by l-Dopa. Brain activation maps of the semantic and phonological networks were obtained and functional connectivity was calculated as the degree of correlation between the activation time series data of pairs of brain areas commonly activated by the two tasks.
Behavioral data, consisting of response times to the stimuli, were recorded. These results demonstrate that
Acknowledgments
This research was funded by the Alumni Grants for Graduate Research and Scholarship (AGGRS) from The Ohio State University Graduate School and by Davis Medical Research Grant from the Ohio State University Medical Center. Dr. Beversdorf is also funded by a Biomedical Research Grant from the National Alliance for Autism Research (1033/DB//01-201-005-00-00) and by grants from NIDA (R21 DA015734) and NINDS (K23 NS43222).
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