Chapter 6 Functional neuro imaging in Parkinson s disease 6.1 Introduction This dissertation contains an event related functional Magnetic Resonance Imaging (fmri) study examining brain activations during the reading of violated and non violated sentences in individuals with and without Parkinson s disease (PD). The paradigm used is related to the one frequently used in Event Related Potential (ERP) experiments. In these ERP studies, subjects read or hear correct sentences mixed with sentences that contain a violation of the semantics or syntax of the sentence. In the next sections, first a brief introduction to the ERP and fmri technique is given. Subsequently, the studies evaluating sentence comprehension in PD are reported separately for ERP and fmri. Prior to presenting these linguistic imaging studies in PD, which are relatively scarce, an overview is provided on ERP measurements in basal ganglia (BG) lesioned patients and relevant fmri studies showing activation in the BG and frontal cortex during violation processing. Throughout this chapter the reader is referred to reviews dealing with the topics for more detailed information. 6.2 Event Related Potentials (ERPs) 6.2.1 Basic concepts and language related ERP components ERPs are extracted from the Electro encephalogram (EEG). In contrast to fmri, which measures the delayed hemodynamic response associated with neural firing, EEG indirectly measures neural activity via electrical potential charges at the scalp. When the EEG is timelocked to a specific stimulus (e.g., a particular word in a sentence) the brain response to this stimulus can be measured and is called the ERP. The ERP technique lacks spatial resolution, but has a good temporal resolution in terms of msec (Coles & Rugg, 1995; Picton, Lins, & Scherg, 1995). Language related ERP components have been identified (for an overview see Kutas & Van Petten, 1994; Osterhout & Holcomb, 1995) and correlate with different aspects of language processing during comprehension. In 1980, Kutas and Hillyard reported for the first time a large negative ERP component elicited by semantically inappropriate words in sentence context (e.g., He spread the warm bread with socks ). This negativity had an onset at about 200 250 msec and a peak around 400 msec, hence was called the N400 component. Compared to correct sentences, semantic violations increase the amplitude of the N400. This difference in N400 amplitude between a correct and an 83
incorrect sentence is referred to as an N400 effect. Subsequent studies showed that the N400 amplitude can also be modulated by rather unexpected but semantically correct sentences. For example, He mailed the letter without a thought elicited a more negative N400 than the more expected He mailed the letter without a stamp (Kutas & Hillyard, 1984). More recently, Hagoort, Hald, Bastiaansen and Petersson (2004) demonstrated that in sentence context, words that violate expectations about the real world also elicit a more negative N400 than expected words such as in the sentence, The Dutch trains are white and very crowded compared to the correct real world knowledge The Dutch trains are yellow and very crowded (Hagoort et al., 2004). To summarize, evidence shows that the N400 reflects the ease with which a word is integrated into the context of the sentence. Clearly different from the semantic N400 are the ERP components in response to syntactic violations: the anterior negativities and the late posterior positivities. A number of studies have reported on the early negativity with a left lateralized anterior scalp distribution (Friederici, Pfeifer, & Hahne, 1993; Neville, Nicol, Barss, Forster, & Garrett, 1991). The timing of these negativities differs as a function of the syntactic violations involved. Violations of word category elicit an early left anterior negativity effect, or ELAN, occurring between 100 and 300 ms post stimulus (Friederici, Hahne, & Mecklinger, 1996; Gunter, Friederici, & Hahne, 1999; Hahne & Friederici, 1999; Neville et al., 1991), whereas morphosyntactic violations such as number agreement, gender agreement, and inflectional violations elicit the later left anterior negativity (LAN) effect occurring between 300 and 500 ms (Gross, Say, Kleingers, Clahsen, & Münte, 1998; Gunter, Friederici, & Schriefers, 2000; Hahne & Jescheniak, 2001, Penke et al., 1997; Vos, Gunter, Kolk, & Mulder, 2001). It has been suggested that the (E)LAN reflects highly automatic first pass parsing processes (Friederici, 1995, 2002; Hagoort, 2003; Hahne & Friederici, 1999) that are already present during early language development (Oberecker, Friederich, & Friederici, 2005). However, other researchers claim that the early negativities reflect working memory (WM) load (Kluender & Kutas, 1993). Supporting the latter view are studies reporting anterior negativities in response to grammatically correct sentences with a larger WM demand (King & Kutas, 1995; Kluender & Kutas, 1993; Weckerly & Kutas, 1999). The second syntax relevant ERP component that is more under the control of attention is a late centroparietally distributed potential with a positive polarity occurring between 500 and 1200 msec and commonly referred to as the P600 (alternatively Syntactic Positive Shift ). The P600 effect has been reported in different languages for a range of syntactic violations such as violations of phrase structure (Friederici et al., 1996; Neville et al., 1991), verb subcategorization (Osterhout, 1997; Osterhout, Holcomb, & Swinney, 1994), number (Vos et al., 2001; Osterhout, McKinnon, Bersick, & Corey, 1996; Hagoort et al, 1993) and gender agreement (Gunter, Friederici, & Schriefers, 2000; Osterhout & Mobley, 1995; Osterhout, Bersick, & McLaughlin, 1997). However, for the P600 to be present there is no need for the sentence to include a syntactic violation. The P600 effect has also been observed in sentences when a preferred syntactic analysis can no longer be maintained, like in syntactically ambiguous sentences (Friederici, Hahne, & Mecklinger, 1996; Frisch, Schlesewsky, Saddy, & Alpermann, 2002; Kaan & Swaab, 2003; Mecklinger, Schriefers, Steinhauer, & Friederici, 1995; Osterhout & Holcomb, 1992; Osterhout & Holcomb, 1993), or when syntactic complexity is increased (Friederici, Hahne, & 84
Saddy, 2002; Kaan, Harris, Gibson, & Holcomb, 2000; Kaan & Swaab, 2003). The functional interpretation of the P600 varies from being the index of syntactic processes (Hagoort et al., 1993), to indicating secondary syntactic processes such as reanalysis and repair (Friederici & Mecklinger, 1996), or as reflecting syntactic integration processes in general (Kaan et al., 2000). Important to note is that this qualitatively distinction of syntactic ((E)LAN/P600) versus semantic (N400) processing, has recently been shown to be untenable (for reviews see Bornkessel Schlesewsky & Schlesewsky, 2008 and Kuperberg, 2007). More specifically, semantic processing can be reflected by other ERP components than the N400. For example, P600 effects have been shown in connection with verb argument animacy violations and implausible sentences (Kim & Osterhout, 2005; Kolk et al., 2003; Van Herten et al., 2005). In the following section, ERP studies in patients with BG lesions and PD will be discussed. 6.2.2 ERP studies in patients with basal ganglia lesions and Parkinson s disease Using ERPs, Friederici, Von Cramon and Kotz (1999) investigated early automatic and late controlled syntactic processes in patients with left focal ischaemic/haemorrhagic vascular BG lesions compared to patients with lesions in the left cortical hemisphere. A dissociation in ERP effects between the cortical and subcortical patient group was found. Summarizing the findings of the study, the ELAN, reflecting early automatic processes, was absent in patients with left frontal cortical lesions, but present in patients with lesions in the BG. In contrast, the P600, reflecting late integrational processes, was present in the cortical patients, but was somewhat reduced in the BG patients. This dissociation confirmed the suggestion already proposed for healthy control (HC) subjects (Hahne & Friederici, 1999) that only the left fronto lateral cortex and not necessarily the BG are involved in the early automatic syntactic processes. It was also concluded that the P600 and not the ELAN is under attentional control. Kotz et al. (2002) reported a study evaluating this putative influence of attention on the ERP components in small groups of patients with cortical lesions including and excluding the BG (among other patient groups) by conducting an additional non linguistic odd ball task. Patients with cortical lesions including the BG show no P600 as a result of the syntactic violation conditions, while patients with cortical lesions excluding the BG do show a P600. In addition, both groups showed a P300 in response to deviant tones, supporting a linguistic basis for the syntactic deficits in patients with lesions in the BG. In a follow up study, Kotz, Frisch, Von Cramon and Friederici (2003) reported the ERP results of fourteen braindamaged patients with and without BG lesions. In the experiment, participants listened to sentences with violations of the verb argument structure (e.g., *Das Zimmer wurde gearbeitet/ *'The room was worked ) and equivalent correct sentences (e.g., Im Zimmer wurde gearbeitet/ 'In the room [people] had worked ). As predicted and in line with previous findings (Friederici et al., 1999; Kotz et al., 2002), a P600 effect was only found in patients without BG lesions. Furthermore, all patients showed a P300 effect in response to deviant tones in the non linguistic odd ball experiment. In addition, this study also found an extended N400 like negativity effect in the BG group, which points to the modulatory role of the BG in lexical semantic processing such as thematic role assignment (e.g., Crosson, 1999; Nadeau & Crosson, 1997). Kotz et al. (2003) argued that the extended N400 effect in BG 85
lesioned patients was due to their general cognitive slowing that also impairs lexicalsemantic processing during language comprehension. This reasoning confirms the hypothesis put forward by Grossman et al. (2002) concerning PD patients that predicts that the dysfunctional striatum influences the speed of information processing. From the above discussed findings, it may be concluded that the BG do not play a role during automatic syntactic processing, but rather during controlled syntactic processing and lexical semantic processes. Additionally, other ERP studies have shown that neurodegeneration of the BG due to PD influences the language related ERP components dramatically. In a study by Kotz et al. (2002), the eight PD patients included showed an intact ELAN, but a strongly reduced P600. In another study, Friederici et al. (2003) compared PD patients to non brain damaged subjects (NBDS). As predicted, the PD patients showed an intact ELAN and a reduced P600. According to Friederici et al. (2003), the alteration in the P600 reflected distortions of the late controlled syntactic integration processes in PD. This reduction in amplitude points to a failure in the activation of the generators of this ERP component in PD patients. The reduction in PD patients P600 amplitude points to a lack of integrity of the cortico striatocortical circuits responsible for its generation. On the basis of the patient studies described above it can be concluded that the frontal cortex and the BG are differently involved in sentence processing or are active during different stages of auditory sentence processing. The left frontal cortex and the left anterior temporal cortex both contribute to the early automatic processing underlying the (E)LAN, whereas the left BG contribute to the late controlled syntactic integration processes underlying the P600 as evidenced by the reduction of the P600 effect in patients with focal BG lesions or PD (Friederici & Kotz, 2003; Friederici et al., 2003). 6.3 Functional Magnetic Resonance Imaging (fmri) 6.3.1 Basic concepts behind fmri The goal of this section is to introduce the basic physical concepts of fmri, so as to better understand the results of later mentioned experiments making use of this neuro imaging method in language paradigms in HC and PD subjects (see Chapters 7 and 8). Functional MRI reveals indirect neuronal activation during the execution of a task or presentation of a stimulus when compared with a control state with lower or different functional involvement (Mangia et al., 2008). As a result of neuronal activity, extra oxygen is needed in the active brain tissue. This oxygen utilization causes an increase in blood flow to compensate for the increased metabolic activity (Roy & Sherrington, 1890). Oxygen is provided by an increased supply of oxygenated hemoglobin (oxyhemoglobin). This effect is called the Hemodynamic Response Function (HRF). However, extra oxygen consumption does not lead to a decrease of local oxygen concentration, since more oxygen is provided than necessary (Fox & Raichle, 1986). Thus, increased neuronal activity leads to an increased amount of oxyhemoglobin relative to deoxygenated hemoglobin (deoxyhemoglobin). 86
Given that deoxyhemoglobin is paramagnetic and becomes magnetized in the presence of a magnetic field, the magnetic field is disrupted and the subsequent signal is dephasing. Oxyhemoglobin on the other hand, is diamagnetic, causing no distortion of the magnetic field (Pauling & Coryell, 1936). Since there is more oxygenated blood than deoxygenated blood in a region of neuronal activation, the result is a net decrease in paramagnetic deoxyhemoglobin. The magnetic properties of an active oxygenated brain region will decrease and increase the magnetic resonance signal. The mismatch between oxygen demand and the increase in oxygenated blood flow is called the Blood Oxygenation Level Dependent (BOLD) effect and forms the physiological basis of fmri (Ogawa, Lee, Kay, & Tank, 1990). Summarized, the BOLD effect is not directly related to electrical neuronal activity but rather indirectly detects metabolic changes which affect the hemodynamic response to neuronal activity. Due to its high spatial resolution, the technique has provided new insights into the human brain s functional organization (Logothetis, 2008). fmri provides the means to do repeated measurements (every 2 4 sec) of brain activity at 64x64x64 (almost 30.000) points or volume (3D) pixels (voxels) throughout the brain. Each voxel represents physiological responses from a small portion of the brain (typically 3x3x3 mm). The analysis of such data seeks to identify voxel by voxel whether any brain regions show a significant difference in brain activity between two different conditions. In the experiments reported in Chapters 7 and 8, Statistical Parametric Mapping version 5 (SPM5, 2005, Wellcome Department of Cognitive Neurology, London, UK, www.fil.ion.ucl.ac.uk/spm5) was used. By using SPM, voxels that show differences between conditions can be presented as a map of t values (Friston et al., 1995). 6.3.2 fmri violation studies fmri is a noninvasive imaging technique, which offers spatial resolution superior to that of ERP, and is therefore ideal to identify the neural source underlying (morpho)syntactic violations. ERPs recorded at the scalp are distant from subcortical activation and therefore less suitable to detect BG activation (Wahl et al., 2008). Moreover, it is unlikely that subcortical structures produce far field potentials, due to their lack of a layered neuronal organization (Menon et al., 1997). Several fmri imaging studies have confirmed the involvement of both the frontal cortex and the BG in syntactic violation processing (Indefrey, Hagoort, Herzog, Sietz, & Brown, 2001; Moro et al., 2001; Ni et al., 2000; Newman, Pancheva, Ozawa, Neville, & Ullman, 2001; Newman, Just, Keller, Roth, & Carpenter, 2003; Kuperberg et al., 2000, Kuperberg, Holcomb, Sitnikova, Greve, Dale, & Caplan, 2003; Raettig, Frisch, Friederici, & Kotz, 2010; Rüschemeyer, Fiebach, Kempe, & Friederici, 2005). Comparison of these violation studies is complicated, since they differ in the type of tasks performed by the subjects, the type of stimulus presentation implemented (i.e., blocked or event related), the choice of control tasks and, finally, in the use of real words or pseudowords as stimuli. In addition, most of these studies were primarily aimed at distinguishing semantic (content) and syntactic (form) 87
representations of language in the brain instead of investigating brain activation underlying morphosyntactic or verb argument structure processing. In the event related odd ball experiment described by Ni et al. (2000), a judgment task unrelated to the target anomaly was used to isolate regions of the brain activated by auditory morphosyntactic anomalies (e.g., *Trees can grew ) compared to semantic anomalies (e.g., *Trees can eat ). The morphosyntactic anomalies activated the bilateral inferior frontal gyrus (IFG, Brodmann Area (BA) 44) and middle frontal gyrus (MFG, BA 46), the left IFG (BA 45), the left medial aspect of superior frontal gyrus (SFG, BA 8) and superior aspects of MFG, adjacent to superior frontal sulcus (SFS, BA 6). In the right hemisphere, activation of the head of the caudate nucleus (Caud) was evident. Similar findings were obtained in a study using H 2 15 O Positron Emission Tomography (PET) by Moro et al. (2001). Access to the semantic system was neutralized by using visually presented pseudoword sentences containing anomalies either at the phonotactic, morphosyntactic or the syntactic level. The activated areas reported for the morphosyntactic condition involved the bilateral IFG (BA 44/45) and the right cerebellum. During the syntactic anomaly condition activation in the left IFG (BA 45), the right homologue of Broca s area (BA 44/45) and a selective activation of the left Caud were found. Indefrey et al. (2001) and Kuperberg et al. (2003) tested finiteness violations in pseudoword and real word sentences respectively. Indefrey et al. (2001) described activation in the left MFG (BA 9) when syntactic processing is compared to phonological processing. Kuperberg et al. (2003) reported a different activation pattern in the bilateral inferior parietal lobule, intraparietal sulcus and precuneus for the finiteness violations. Finally, recently, a study in German was published that reports on both violation types that are also the focus of fmri studies presented in Chapters 7 and 8 of this thesis. The stimuli were presented auditorily and were limited to simple passive sentences (Raettig, Frisch, Friederici, & Kotz, 2010). The first type of violated sentences contained a morphosyntactic mismatch between the auxiliary and the main verb [e.g., *Im Haus wurde bald streichen und renoviert, * In the house was soon painted and renovated ]. This inflectional violation elicited an increase in brain activity in the left middle temporal gyrus (MTG) to posterior superior temporal gyrus (STG). Their second violation, a verb argument structure violation [e.g., *Das Konzert wurde bald gehustet und unterbrochen, * The concert was soon coughed and disturbed ], is comparable to the violation described in Friederici and Frisch (2000) and elicited brain activations in the left IFG (BA 44). To sum up, data collected from imaging studies suggest that the bilateral IFG and nuclei of the BG are involved in the detection of violations. However, this is not consistently found in all the above described studies, which might be explained by the methodological differences. Furthermore, in addition to the areas that are in the focus of our study, activation in other frontal, temporal and parietal areas was observed as well. 88
6.3.3 fmri study on language processing in Parkinson s disease patients Several studies using PET and fmri have investigated the pattern of brain activation during language processing in NBDS. However, to our knowledge only a few imaging studies have investigated specifically the underlying neural activity during language processing in PD patients. In an fmri study, Grossman et al. (2003) found striatal activation in the brains of healthy senior volunteers for sentences with a long noun gap linkage compared with sentences with a short linkage. PD patients had less activation than HC subjects in the striatum for the long noun gap linkage sentences. Moreover, PD patients engaged significantly more brain regions associated with WM than healthy subjects to achieve the same level of comprehension accuracy as the control subjects. According to Grossman et al. (2003) the striatum contributes to cognitive resources such as WM and informationprocessing speed. In other words, the PD patients sentence comprehension difficulties have been ascribed to their restricted striatal recruitment and are therefore based on cognitive resource limitations. Recently, Péran et al. (2009) investigated the neuronal substrates of action related word production in PD patients and found a relationship between motor system dysfunction in PD and the extent of activation in verb generation (see also Chapter 3). 89
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