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generation and for two-choice judgments involving mostly nouns indicates that the activations reflect the semantic requirements common across these diverse tasks rather than generation of verbs per se. Thus, left prefrontal activation occurs in a range of semantic tasks.

One limitation of these studies is that left prefrontal activation occurred in conditions that were always more difficult than the comparison condition, where difficulty is operation-alized as response time to a stimulus. It takes substantially longer to generate a verb to a presented noun than to read the noun, to decide whether a word is abstract or concrete in meaning than whether it is uppercase or lowercase in appearance (6), or to decide whether a word is living or nonliving in meaning than whether it contains a particular letter (7). Thus, semantic analysis and question difficulty were correlated (i.e., confounded) in all three studies making it impossible to determine whether the left prefrontal activation reflected semantic analysis per se or simply extended processing of words.

In an attempt to disambiguate these two potential bases of left prefrontal activations, one fMRI study (8) added a third condition with minimal semantic processing but even more extended processing than the semantic task. Thus, as before, activation was compared between a difficult semantic task (abstract/concrete classifications) and an easy nonsemantic task (uppercase/lowercase classifications). In a second scan, activation was compared between the same semantic task and a nonsemantic task in which participants had to decide whether the first and last letters of a word were ascending (“car”) or descending (“table”) alphabetically. Critically, the nonsemantic ascending/descending task was more difficult (as measured by time to respond) than the semantic abstract/concrete task. Left prefrontal activations, however, were almost identical in the two scans with greater activation for the semantic task than the less difficult (case) and more difficult (alphabetic) tasks. Another fMRI study compared two tasks that were matched in difficulty (response time): judging whether pairs of words were related in meaning or whether rows of asterisks had the same or different colors. Again, there was left prefrontal activation for the semantic task relative to the nonsemantic color task (9). Thus, left prefrontal activation reflects semantic processing rather than task difficulty. More precisely, left prefrontal activation may be correlated with the specific semantic difficulty of a task.

In all of the above studies, left prefrontal activations occurred for conditions in which participants made intentional or overt semantic analyses. Other studies have compared conditions in which no semantic analysis was required but where the stimuli in different conditions had greater or lesser (usually no) semantic content. In one such study, participants simply viewed words (that had meaning) or visually similar but meaningless stimuli such as pronounceable nonwords, unpronounceable letter strings, or false-font strings (10). In the absence of any semantic task, greater activation for the meaningful stimuli could only be due to incidental or covert analyses of meaning. Indeed, only the words yielded activation relative to a fixation baseline, and this activation was almost identical in location to that observed for the intentional generation of verbs. Similar findings are noted for silent viewing of words versus false-font strings, with the added finding that the duration of stimulus presentation can influence the magnitude of the left prefrontal response (for reasons not yet understood) (11).

In the passive viewing conditions of the above two studies, participants may have been performing some sort of voluntary semantic task when the stimuli allowed. This possibility was eliminated in another PET study in which participants had to detect letter features, specifically if a letter string contained a letter with an ascending feature (e.g., “b” and “d” but not “a” or “g”) (12). There was left prefrontal activation for feature detection in words relative to false fonts, to unpronounceable consonant strings, and to pronounceable nonwords. The activations relative to false fonts and consonant strings occurred in the left inferior frontal gyrus, the locus of the semantic activations described above. The activation relative to pronounceable nonwords occurred in the left middle frontal gyrus. It is unclear at present whether these anatomic distinctions reflect truly separate processes, measurement variability, or both.

All of the above studies employed visual presentation of verbal stimuli. The same left prefrontal and right cerebellar areas, however, are activated when participants generate verbs to visual or auditory nouns (5) or make semantic judgments for words or line drawings (13). Thus, the left prefrontal activations seem to reflect psychological processes that are involved in semantic analyses across many tasks, that operate across verbal, pictorial, visual, and auditory modalities, and that are engaged both intentionally and incidentally.

Left Prefrontal Cortex: Relations to Episodic Memory and Language. Tulving (14) noted that conditions yielding greater left prefrontal activations are often the same conditions that yield superior memory for words and other stimuli. It is well known that later memory for words is superior when encoded at study for meaning (semantic or deep encoding) than for appearance (perceptual or shallow encoding) (15). Indeed, the semantic encoding conditions that provoked left prefrontal activation also yielded superior later memory for words (68). Memory for words is also superior when participants generate words relative to when they merely read words (16), and this principle applies specifically to generating verbs versus reading nouns (14). Thus, the left prefrontal activations seem to reflect processes that are important for enhancing memory for materials encountered in particular episodes.

The fundamental linguistic nature of these left prefrontal processes is made evident in a study of epileptic patients in whom the lateralization of language dominance had been established definitively through invasive Wada evaluation (17). Seven such patients performed semantic (abstract/concrete) and nonsemantic (uppercase/lowercase) tasks. The four patients who were left-hemisphere dominant for language displayed the usual left prefrontal activation for the semantic relative to the nonsemantic task. The three patients who were right-hemisphere dominant for language, however, displayed right prefrontal activations. Thus, the lateralization of activation was in accord with that for language dominance in each of the seven patients.

These results are of interest for several reasons. First, they demonstrate the intimate relation between semantics and language. Second, they validate the accuracy of fMRI activation on an individual-by-individual basis, at least for such a major feature of brain organization as the laterality of language dominance. Wada testing remains the gold standard for establishing the laterality of language dominance, but it has a number of drawbacks. Because Wada testing is invasive, it can be associated with morbidity. It is often unpleasant and sometimes distressing for patients, which can result in some ambiguity in determining the basis of language performance deficits. It is expensive. With further development, fMRI may replace Wada testing as a less dangerous, more pleasant, and less expensive method that cannot only determine which hemisphere is dominant for language but also which part of the hemisphere is critical for language. Further, whereas Wada testing is only justified in cases of potential surgery, fMRI can be used to examine the role of hemispheric dominance in many disorders of language such as dyslexia or stuttering. In regard to psychological issues, these results suggest that the importance of left prefrontal processes in episodic memory may reside in the power of language to encode memories meaningfully.

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