Charting the effects of TMS with fMRI: Modulation of cortical recruitment within the distributed network supporting semantic control.

Semantic memory comprises our knowledge of the meanings of words and objects but only some of this knowledge is relevant at any given time. Thus, semantic control processes are needed to focus retrieval on relevant information. Research on the neural basis of semantic control has strongly implicated left inferior frontal gyrus (LIFG) but recent work suggests that a wider network supports semantic control, including left posterior middle temporal gyrus (pMTG), right inferior frontal gyrus (RIFG) and pre-supplementary motor area (pre-SMA). In the current study, we used repetitive transcranial magnetic stimulation (1Hz offline TMS) over LIFG, immediately followed by fMRI, to examine modulation of the semantic network. We compared the effect of stimulation on judgements about strongly-associated words (dog-bone) and weaker associations (dog-beach), since previous studies have found that dominant links can be recovered largely automatically with little engagement of LIFG, while more distant connections require greater control. Even though behavioural performance was maintained in response to TMS, LIFG stimulation increased the effect of semantic control demands in pMTG and pre-SMA, relative to stimulation of a control site (occipital pole). These changes were accompanied by reduced recruitment of both the stimulated region (LIFG) and its right hemisphere homologue (RIFG), particularly for strong associations with low control requirements. Thus repetitive TMS to LIFG modulated the contribution of distributed regions to semantic judgements in two distinct ways.

Neural substrates of figurative language during natural speech perception: an fMRI study.

Many figurative expressions are fully conventionalized in everyday speech. Regarding the neural basis of figurative language processing, research has predominantly focused on metaphoric expressions in minimal semantic context. It remains unclear in how far metaphoric expressions during continuous text comprehension activate similar neural networks as isolated metaphors. We therefore investigated the processing of similes (figurative language, e.g., "He smokes like a chimney!") occurring in a short story. Sixteen healthy, male, native German speakers listened to similes that came about naturally in a short story, while blood-oxygenation-level-dependent (BOLD) responses were measured with functional magnetic resonance imaging (fMRI). For the event-related analysis, similes were contrasted with non-figurative control sentences (CS). The stimuli differed with respect to figurativeness, while they were matched for frequency of words, number of syllables, plausibility, and comprehensibility. Similes contrasted with CS resulted in enhanced BOLD responses in the left inferior (IFG) and adjacent middle frontal gyrus. Concrete CS as compared to similes activated the bilateral middle temporal gyri as well as the right precuneus and the left middle frontal gyrus (LMFG). Activation of the left IFG for similes in a short story is consistent with results on single sentence metaphor processing. The findings strengthen the importance of the left inferior frontal region in the processing of abstract figurative speech during continuous, ecologically-valid speech comprehension; the processing of concrete semantic contents goes along with a down-regulation of bilateral temporal regions.

Where the mass counts: common cortical activation for different kinds of nonsingularity.

Typically, plural nouns are morphosyntactically marked for the number feature, whereas mass nouns are morphosyntactically singular. However, both plural count nouns and mass nouns can be semantically interpreted as nonsingular. In this study, we investigated the hypothesis that their commonality in semantic interpretation may lead to common cortical activation for these different kinds of nonsingularity. To this end, we examined brain activation patterns related to three types of nouns while participants were listening to a narrative. Processing of plural compared with singular nouns was related to increased activation in the left angular gyrus. Processing of mass nouns compared with singular count nouns was related to increased activity bilaterally in the superior temporal cortex and also in the left angular gyrus. No significant activation was observed in the direct comparison between plural and mass nouns. We conclude that the left angular gyrus, also known to be relevant for numerical cognition, is involved in the semantic interpretation of different kinds of nonsingularity.

Executive semantic processing is underpinned by a large-scale neural network: revealing the contribution of left prefrontal, posterior temporal, and parietal cortex to controlled retrieval and selection using TMS.

To understand the meanings of words and objects, we need to have knowledge about these items themselves plus executive mechanisms that compute and manipulate semantic information in a task-appropriate way. The neural basis for semantic control remains controversial. Neuroimaging studies have focused on the role of the left inferior frontal gyrus (LIFG), whereas neuropsychological research suggests that damage to a widely distributed network elicits impairments of semantic control. There is also debate about the relationship between semantic and executive control more widely. We used TMS in healthy human volunteers to create "virtual lesions" in structures typically damaged in patients with semantic control deficits: LIFG, left posterior middle temporal gyrus (pMTG), and intraparietal sulcus (IPS). The influence of TMS on tasks varying in semantic and nonsemantic control demands was examined for each region within this hypothesized network to gain insights into (i) their functional specialization (i.e., involvement in semantic representation, controlled retrieval, or selection) and (ii) their domain dependence (i.e., semantic or cognitive control). The results revealed that LIFG and pMTG jointly support both the controlled retrieval and selection of semantic knowledge. IPS specifically participates in semantic selection and responds to manipulations of nonsemantic control demands. These observations are consistent with a large-scale semantic control network, as predicted by lesion data, that draws on semantic-specific (LIFG and pMTG) and domain-independent executive components (IPS).

The neural organization of semantic control: TMS evidence for a distributed network in left inferior frontal and posterior middle temporal gyrus.

Assigning meaning to words, sounds, and objects requires stored conceptual knowledge plus executive mechanisms that shape semantic retrieval according to the task or context. Despite the essential role of control in semantic cognition, its neural basis remains unclear. Neuroimaging and patient research has emphasized the importance of left inferior frontal gyrus (IFG)--however, impaired semantic control can also follow left temporoparietal lesions, suggesting that this function may be underpinned by a large-scale cortical network. We used repetitive transcranial magnetic stimulation in healthy volunteers to disrupt processing within 2 potential sites in this network--IFG and posterior middle temporal cortex. Stimulation of both sites selectively disrupted executively demanding semantic judgments: semantic decisions based on strong automatic associations were unaffected. Performance was also unchanged in nonsemantic tasks--irrespective of their executive demands--and following stimulation of a control site. These results reveal that an extended network of prefrontal and posterior temporal regions underpins semantic control.

Heterogeneity of the left temporal lobe in semantic representation and control: priming multiple versus single meanings of ambiguous words.

Semantic judgments involve both representations of meaning plus executive mechanisms that guide knowledge retrieval in a task-appropriate way. These 2 components of semantic cognition-representation and control-are commonly linked to left temporal and prefrontal cortex, respectively. This simple proposal, however, remains contentious because in most functional neuroimaging studies to date, the number of concepts being activated and the involvement of executive processes during retrieval are confounded. Using functional magnetic resonance imaging, we examined a task in which semantic representation and control demands were dissociable. Words with multiple meanings like "bank" served as targets in a double-prime paradigm, in which multiple meaning activation and maximal executive demands loaded onto different priming conditions. Anterior inferior temporal gyrus (ITG) was sensitive to the number of meanings that were retrieved, suggesting a role for this region in semantic representation, while posterior middle temporal gyrus (pMTG) and inferior frontal cortex showed greater activation in conditions that maximized executive demands. These results support a functional dissociation between left ITG and pMTG, consistent with a revised neural organization in which left prefrontal and posterior temporal areas work together to underpin aspects of semantic control.

Genetic variation in the schizophrenia-risk gene neuregulin 1 correlates with brain activation and impaired speech production in a verbal fluency task in healthy individuals.

Impaired performance in verbal fluency tasks is an often replicated finding in schizophrenia. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and temporal areas. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes for the disorder, such as NRG1, modulate verbal fluency performance and its neural correlates. Four hundred twenty-nine healthy individuals performed a semantic and a lexical verbal fluency task. A subsample of 85 subjects performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (MRI). NRG1 (SNP8NRG221533; rs35753505) status was determined and correlated with verbal fluency performance and brain activation. For the behavioral measure, there was a linear effect of NRG1 status on semantic but not on lexical verbal fluency. Performance decreased with number of risk-alleles. In the fMRI experiment, decreased activation in the left inferior frontal and the right middle temporal gyri as well as the anterior cingulate gyrus was correlated with the number of risk-alleles in the semantic verbal fluency task. NRG1 genotype does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in schizophrenia and may explain some of the cognitive and brain activation variation found in the disorder. More generally, NRG1 might be one of several genes that influence semantic language capacities.

Neural correlates of narrative shifts during auditory story comprehension.

The ability to segment continuous linguistic information online into larger, meaningful units is a key element in narrative comprehension. Narrative shifts, i.e. transitions between individual units, are postulated to continuously update the mental situation model. Their cerebral correlates, however, have hardly been investigated. Under highly naturalistic conditions this study seeks to identify the neural correlates of implicit processing of narrative shifts during continuous speech comprehension. 16 male native German speakers listened passively to a German novella for 23 min while BOLD signal was recorded with fMRI. Text comprehension was tested in a short post-scan interview asking for critical episodes of the story. Narrative shifts were defined on the basis of a macropropositional analysis. Compared to listening to text passages of the narrative that neither contained narrative shifts nor structurally similar linguistic control events (i.e., sentence boundaries), narrative shifts evoked increased BOLD signal changes in the right temporal gyrus, precuneus and posterior/middle cingulate cortex bilaterally. When narrative shifts were contrasted with sentence boundaries, activation in the right precuneus and cingulate cortex remained significant. The results strengthen the relevance of medial parietal structures for natural language comprehension. More precisely, the precuneus and posterior cingulate appear to be the neural substrate for updating mental story representations and can be regarded as critical parts of a more complex, distributed neural network underlying story comprehension.

The influence of multiple primes on bottom-up and top-down regulation during meaning retrieval: evidence for 2 distinct neural networks.

Meaning retrieval of a word can proceed fast and effortlessly or can be characterized by a controlled search for candidate lexical items and a subsequent selection process. In the current study, we facilitated meaning retrieval by increasing the number of words that were related to the final target word in a triplet (e.g., lion-stripes-tiger). To induce higher search and selection demands, we presented ambiguous words as targets (i.e., homonyms like ball) in half of the trials. Hereby, the dominant (game), low-frequent (dance), or both meanings of the homonym were primed. Participants performed a relatedness judgment during functional magnetic resonance imaging. Activation in a bilateral network (angular gyrus, rostromedial prefrontal cortex) increased linearly with multiple related primes, whereas the posterior left inferior prefrontal cortex (pLIPC) showed the reverse activation pattern for unambiguous trials. When homonyms served as targets, pLIPC responded strongest when both meanings or low-frequent concepts were addressed. Additional anterior left inferior prefrontal cortex activation was observed for the latter trials only. The data support an interaction between 2 distinct cerebral networks that can be linked to automatic bottom-up support and top-down control during meaning retrieval. They further imply a functional specialization of the LIPC along an anterior-posterior dimension.

Task-dependent modulations of prefrontal and hippocampal activity during intrinsic word production.

Functional imaging studies of single word production have consistently reported activation of the lateral prefrontal and cingulate cortex. Its contribution has been shown to be sensitive to task demands, which can be manipulated by the degree of response specification. Compared with classical verbal fluency, free word association relies less on response restrictions but to a greater extent on associative binding processes, usually subserved by the hippocampus. To elucidate the relevance of the frontal and medial-temporal areas during verbal retrieval tasks, we applied varying degrees of response specification. During fMRI data acquisition, 18 subjects performed a free verbal association (FVA), a semantic verbal fluency (SVF) task, and a phonological verbal fluency (PVF) task. Externally guided word production served as a baseline condition to control for basic articulatory and reading processes. As expected, increased brain activity was observed in the left lateral and bilateral medial frontal cortices for SVF and PVF. The anterior cingulate gyrus was the only structure common to both fluency tasks in direct comparison to the less restricted FVA task. The hippocampus was engaged during associative and semantic retrieval. Interestingly, hippocampal activity was selectively evident during FVA in direct comparison to SVF when it was controlled for stimulus-response relations. The current data confirm the role of the left prefrontal-cingulate network in constrained word production. Hippocampal activity during spontaneous word production is a novel finding and seems to be dependent on the retrieval process (free vs. constrained) rather than the variety of stimulus-response relationships that is involved.

The neural correlates of ego-disturbances (passivity phenomena) and formal thought disorder in schizophrenia.

Ego-disturbances (passivity phenomena) and formal thought disorder are two hallmark symptoms of schizophrenia. Formal thought disorder has been highlighted already very early by Eugen Bleuler in his concept of basic symptoms (Grundsymptome). In contrast ego-disturbances (Ich-Störungen) or passivity phenomena have been declared as core symptoms of schizophrenia by Kurt Schneider in his concept of first-rank symptoms (Erstrangsymptome) that influenced the whole concept of schizophrenia until today (ICD10; DSM IV). We present new neuroimaging and cognitive neuropsychological results that help to explain what brain and cognitive functions may be involved in the emergence of these symptoms. Questions on cognitive and neural correlates of notions such as self-awareness, self-consciousness, introspective perspective or subjective experiences have re-emerged as topics of great interest in the scientific community. Employing new neuroscientific methods such as functional brain imaging, advances into thus far unexplored territory of mind-brain relationships have been made. These findings give new impulses for the search on the neural basis of psychopathological symptoms. We will review neuroscientific data and models on the pathogenesis of two of the core symptoms of schizophrenia, i.e. passivity phenomena and formal thought disorder.

Hippocampal dysfunction during free word association in male patients with schizophrenia.

In schizophrenia, speech production deficits in patients with positive formal thought disorder (FTD e.g. loosening of associations and derailment) have been attributed to impairments in the semantic network. The brain area implicated in the retrieval of associated (i.e. relational) concepts is the hippocampus, a key region in the psychopathology of schizophrenia. However, its role in schizophrenic speech production and FTD in particular is yet little understood. To investigate the neural correlates of associative verbal retrieval, twelve patients with schizophrenia with varying degrees of FTD and twelve matched healthy control subjects underwent a free verbal association (FVA), a semantic (SVF) and a phonological verbal fluency (PVF) task while brain activity was measured with fMRI. The tasks varied in the relational binding operations needed for linking the stimulus to the respective response. Compared to control subjects, patients revealed attenuated left hippocampal activity during both semantic word generation tasks (FVA, SVF). Contrasting verbal fluency with FVA, a failure in recruiting the anterior cingulate gyrus emerged in the patient group. A negative correlation was found between right middle temporal activity and the severity of FTD during FVA. The hippocampus seems to play a major role in word generation. In schizophrenia, attenuated hippocampal activity during semantic tasks strengthens the hypothesis of impaired relational memory processes, affecting thought and language.