Studies of semantic dementia and PET neuroimaging investigations suggest that the anterior temporal lobes (ATL) are a critical substrate for semantic representation. In stark contrast, classical neurological models of comprehension do not include ATL, and likewise functional MRI studies often fail to show activations in the ATL, reinforcing the classical view. Using a novel application of low-frequency, repetitive transcranial magnetic stimulation (rTMS) over the ATL, we demonstrate that the behavioral pattern of semantic dementia can be mirrored in neurologically intact participants: Specifically, we show that temporary disruption to neural processing in the ATL produces a selective semantic impairment leading to significant slowing in both picture naming and word comprehension but not to other equally demanding, nonsemantic cognitive tasks.repetitive transcranial magnetic stimulation ͉ semantic cognition ͉ temporal pole S emantic memory encompasses the meaning of all types of verbal and nonverbal stimuli including words, pictures, objects, and faces. In addition to underpinning comprehension, it also allows us to express knowledge in a wide variety of domains, both verbal (e.g., naming and verbal definitions) and nonverbal (e.g., drawing and object use). As such, it is integral to our everyday lives, and impairments of semantic memory are extremely debilitating. Key questions for neuroscience research, therefore, are which parts of the brain support semantic memory, and how do they function?Various neurological disorders cause impairments of semantic processing; however, the purest syndrome is semantic dementia (SD; the temporal lobe variant of frontotemporal dementia) (1). This neurodegenerative disease results in relatively focal atrophy and hypometabolism of the anterior temporal lobes (ATL) bilaterally (2, 3). SD is characterized by progressive impairment of verbal and nonverbal semantic tasks, with anomia as the first presenting symptom (4-6). Strikingly, other aspects of language and cognition remain largely intact. SD patients have increasing difficulty distinguishing concepts from their semantic neighbors, reflecting an increasing loss of ''semantic acuity'' (6, 7). As such, the patients have greater difficulty activating specific semantic information (e.g., ''zebras have stripes'') than more general properties (e.g., ''zebras are animals'') (6, 8). Likewise, their naming difficulties are graded by specificity (higher naming accuracy for basic-level concepts such as dog than specific ones, e.g., springer spaniel) (9) with errors reflecting more general semantic knowledge (e.g., dog 3 ''animal'').Careful and extensive assessment of SD patients indicates that bilateral anterior temporal lobe regions support the formation of amodal semantic representations. Accordingly, SD patients exhibit poor comprehension of items presented in every modality, including spoken and written words, pictures, environmental sounds, smells, and touch (4, 10, 11). The marked semantic deficit is also apparent in production task...

SummarySemantic cognition permits us to bring meaning to our verbal and nonverbal experiences and to generate context- and time-appropriate behavior [1–2]. It is core to language and nonverbal skilled behaviors and, when impaired after brain damage, it generates significant disability [3]. A fundamental neuroscience question is, therefore, how does the brain code and generate semantic cognition? Historical and some contemporary theories emphasize that conceptualization stems from the joint action of modality-specific association cortices (the “distributed” theory) [4, 5] reflecting our accumulated verbal, motor, and sensory experiences. Parallel studies of semantic dementia, rTMS in normal participants, and neuroimaging indicate that the anterior temporal lobe (ATL) plays a crucial and necessary role in conceptualization by merging experience into an amodal semantic representation [1, 2, 6–8]. Some contemporary computational models suggest that concepts reflect a hub-and-spoke combination of information—modality-specific association areas support sensory, verbal, and motor sources (the spokes) while anterior temporal lobes act as an amodal hub. We demonstrate novel and striking evidence in favor of this hypothesis by applying rTMS to normal participants: ATL stimulation generates a category-general impairment whereas IPL stimulation induces a category-specific deficit for man-made objects, reflecting the coding of praxis in this neural region.

The anterior temporal lobe (ATL) makes a critical contribution to semantic cognition. However, the functional connectivity of the ATL and the functional network underlying semantic cognition has not been elucidated. In addition, subregions of the ATL have distinct functional properties and thus the potential differential connectivity between these subregions requires investigation. We explored these aims using both resting-state and active semantic task data in humans in combination with a dual-echo gradient echo planar imaging (EPI) paradigm designed to ensure signal throughout the ATL. In the resting-state analysis, the ventral ATL (vATL) and anterior middle temporal gyrus (MTG) were shown to connect to areas responsible for multimodal semantic cognition, including bilateral ATL, inferior frontal gyrus, medial prefrontal cortex, angular gyrus, posterior MTG, and medial temporal lobes. In contrast, the anterior superior temporal gyrus (STG)/superior temporal sulcus was connected to a distinct set of auditory and language-related areas, including bilateral STG, precentral and postcentral gyri, supplementary motor area, supramarginal gyrus, posterior temporal cortex, and inferior and middle frontal gyri. Complementary analyses of functional connectivity during an active semantic task were performed using a psychophysiological interaction (PPI) analysis. The PPI analysis highlighted the same semantic regions suggesting a core semantic network active during rest and task states. This supports the necessity for semantic cognition in internal processes occurring during rest. The PPI analysis showed additional connectivity of the vATL to regions of occipital and frontal cortex. These areas strongly overlap with regions found to be sensitive to executively demanding, controlled semantic processing.

The key question of how the brain codes the meaning of words and pictures is the focus of vigorous debate. Is there a "semantic hub" in the temporal poles where these different inputs converge to form amodal conceptual representations? Alternatively, are there distinct neural circuits that underpin our comprehension of pictures and words? Understanding words might be primarily left-lateralised, linked to other language areas, while semantic representation of pictures may be more bilateral. To elucidate this debate, we used offline, low-frequency, repetitive transcranial magnetic stimulation (rTMS) to disrupt neural processing temporarily in the left or right temporal poles. During the induced refractory period, participants made judgements of semantic association for verbal and pictorial stimuli. The efficiency of semantic processing was reduced by rTMS, yet a perceptual task of comparable difficulty was unaffected. rTMS applied to the left or right temporal poles disrupted semantic processing for words and pictures to the same degree, while rTMS delivered at a control site had no impact. The results confirm that both temporal poles form a critical substrate within the neural network that supports conceptual knowledge, regardless of modality.

Numerous studies have established that inferior frontal cortex is active when hand actions are planned, imagined, remembered, imitated, and even observed. Furthermore, it has been proposed that these activations reflect a process of simulating the observed action to allow it to be understood and thus fully perceived. However, direct evidence for a perceptual role for left inferior frontal cortex is rare, and linguistic or motor contributions to the reported activations have not been ruled out. We used repetitive transcranial magnetic stimulation (rTMS) over inferior frontal gyrus during a perceptual weight-judgement task to test the hypothesis that this region contributes to action understanding. rTMS at this site impaired judgments of the weight of a box lifted by a person, but not judgements of the weight of a bouncing ball or of stimulus duration, and rTMS at control sites had no impact. This demonstrates that the integrity of left inferior frontal gyrus is necessary to make accurate perceptual judgments about other people's actions.