Neural capacity limits during unconscious semantic processing.

A growing body of neuroimaging data suggests that direct measurements of brain activity can reveal subliminal effects that remain invisible with behavior measures alone. We examined whether sentence comprehension processes could be triggered by a sequence of masked words. On each trial, participants viewed a rapid sequence of masked or unmasked words, including a subject noun, three adverbs and followed by a visible target verb. To probe the capacity limits of unconscious processing, we measured event-related potentials associated with the semantic congruency between the noun and the verb, while varying the subject position in each sentence. Unmasked sentences produced significant behavioral effects of congruency, paralleled by robust N400 effects, independently of subject-verb distance. By contrast, masked sentences produced no behavioral effect and elicited N400 effects only when subjects and verbs were separated by 0 or 1 word. The present results suggest that semantic integration of multiple words can occur unconsciously only if the distance between the words to be integrated does not exceed two words. Although the possibility remains that even longer sequence of invisible words may produce similar neural effects in different experimental settings, our ERP data show that only conscious perception gives access to a buffer that enables robust sentence-level processing independently of temporal distance.

Mirror visual feedback can induce motor learning in patients with callosal disconnection.

Mirror therapy using mirror visual feedback (MVF) has been applied to the stroke rehabilitation of hemiparesis. One possible mechanism of mirror therapy is the functional interhemispheric connectivity between sensorimotor areas via corpus callosum. To test this hypothesis, we investigated the MVF-induced motor learning in 2 patients with callosal disconnection. Callosal connection in patients was evaluated by clinical measures and the interhemispheric inhibition (IHI) using transcranial magnetic stimulation. Both patients suffered from somatosensory cognitive disconnection, and one showed the loss of IHI. Motor training with MVF significantly improved the motor behavior of both patients. Extending our previous study, the results of callosal patients suggested that the visual feedback through a mirror might play the crucial important role for the improvement of motor performance, rather than interhemispheric interaction via corpus callosum.

Altered prefrontal function with aging: insights into age-associated performance decline.

We examined the effects of aging on visuo-spatial attention. Participants performed a bi-field visual selective attention task consisting of infrequent target and task-irrelevant novel stimuli randomly embedded among repeated standards in either attended or unattended visual fields. Blood oxygenation level dependent (BOLD) responses to the different classes of stimuli were measured using functional magnetic resonance imaging. The older group had slower reaction times to targets, and committed more false alarms but had comparable detection accuracy to young controls. Attended target and novel stimuli activated comparable widely distributed attention networks, including anterior and posterior association cortex, in both groups. The older group had reduced spatial extent of activation in several regions, including prefrontal, basal ganglia, and visual processing areas. In particular, the anterior cingulate and superior frontal gyrus showed more restricted activation in older compared with young adults across all attentional conditions and stimulus categories. The spatial extent of activations correlated with task performance in both age groups, but the regional pattern of association between hemodynamic responses and behavior differed between the groups. Whereas the young subjects relied on posterior regions, the older subjects engaged frontal areas. The results indicate that aging alters the functioning of neural networks subserving visual attention, and that these changes are related to cognitive performance.

Transient functional suppression and facilitation of Japanese ideogram writing induced by repetitive transcranial magnetic stimulation of posterior inferior temporal cortex.

The Japanese writing system is unique in that it is composed of two different orthographies: kanji (morphograms) and kana (syllabograms). The retrieval of the visual orthographic representations of Japanese kanji is crucial to the process of writing in Japanese. We used low-frequency repetitive transcranial magnetic stimulation (rTMS) to clarify the functional relevance of the left and right posterior inferior temporal cortex (PITC) to this process in native Japanese speakers. The experimental paradigms included the mental recall of kanji, kana-to-kanji transcription, semantic judgment, oral reading, and copying of kana and kanji. The first two tasks require the visualization of the kanji image of the word. We applied 0.9 Hz rTMS (600 total pulses) over individually determined left or right PITC to suppress cortical activity and measured subsequent task performance. In the mental recall of kanji and kana-to-kanji transcription, rTMS over the left PITC prolonged reaction times (RTs), whereas rTMS over the right PITC reduced RTs. In the other tasks, which do not involve the mental visualization of kanji, rTMS over the left or right PITC had no effect on performance. These results suggest that the left PITC is crucial for the retrieval of the visual graphic representation of kanji. Furthermore, the right PITC may work to suppress the dominant left PITC in the neural network for kanji writing, which involves visual word recognition.

Cortical mechanisms of unilateral voluntary motor inhibition in humans.

While motor control is very often a goal-oriented event, little is known about the mechanisms underlying the termination of motor performance. To investigate what type of cortical activation underlies the muscle relaxation required to terminate the act, we performed single- and double-pulse transcranial magnetic stimulation (TMS) studies during voluntary muscle relaxation in nine normal volunteers. Subjects maintained a weak isometric contraction of the right first dorsal interosseous muscle (FDI), and either increased the level of contraction (Contraction), terminated the contraction (Relaxation), or maintained it (No-go) depending on a visual cue. Motor evoked potentials (MEP) and the silent period (SP) were recorded from the FDI during motor activity. To measure intra-cortical inhibition (ICI), we also performed double-pulse TMS, applying subthreshold conditioning stimuli at interstimulus intervals of 2 ms. When single-pulse TMS was given just prior to muscle relaxation (-21 to -70 ms), the MEP was reduced while the SP was unchanged. Intra-cortical inhibition was smaller just prior to the muscle relaxation. Unilateral voluntary muscle relaxation may not be associated with activation of the intracortical inhibitory system, but rather with the possible excitation of the corticospinal system, which can inhibit motoneurons disynaptically. These findings suggest that multiple inhibitory mechanisms act in diverse ways to achieve motor inhibition.

Second somatosensory area (SII) plays a significant role in selective somatosensory attention.

In order to explore human cortical areas involved in active attention toward a somatosensory modality, somatosensory evoked cortical magnetic fields were recorded in ten healthy adults with a 122-channel whole-head magnetometer while the subjects performed the selective attention task. Two kinds of stimulus modality, somatosensory and auditory, were presented independently in the same session. For the somatosensory modality, a randomized sequence of strong (P=0.45) and weak (P=0.05) electric stimuli was delivered to the right median nerve at the wrist. For the auditory modality, a randomized sequence of 900-Hz (P=0.45) and 950-Hz (P=0.05) tones was delivered to both ears. Subjects were requested to pay attention to the specified stimulus modality (either somatosensory or auditory) and to count the number of rare stimuli of the attended modality (weak stimuli in the somatosensory or 950-Hz tone in the auditory modality). A total of 12 sessions were performed for each subject, among which the order of attended modality was changed alternately and counterbalanced among subjects. In the data analysis, somatosensory evoked fields for frequent stimuli (strong electric stimuli) were compared between the two conditions; attend somatosensory condition (ATS) and attend auditory condition (non-attend somatosensory condition; NATS). In six out of the ten subjects, somatosensory evoked fields showed attention-related change. The magnitude of the estimated generator source in SII, but not in SI, significantly increased from NATS to ATS while keeping the same locations. Moreover, a simulation study using the estimated sources in SII in NATS supported the enhancement of the activity in the SII rather than participation of additional sources in the selective attention task. These results suggest that the SII plays a main role in selective somatosensory attention.

Cortical potentials related to assessment of pain intensity with visual analogue scale (VAS).

OBJECTIVES: To elucidate brain mechanisms underlying the psychophysical processes to measure pain intensity, pain-related somatosensory evoked potentials (pain SEPs) following painful CO(2) laser stimulation were studied while employing a task to measure intensity of pain on a visual analogue scale (VAS). METHODS: In 12 healthy subjects, 3 kinds of CO(2) laser stimuli, different in intensity as determined by irradiation duration of 40, 60 and 80ms, were randomly delivered to the left hand dorsum at an irregular interval of 4-6s. The subject was requested to assess the intensity of each pain stimulus and point to the VAS scale by moving a pointer held with the right hand according to the subjective feeling of pain sensation (pain intensity assessment (PIA) condition). For the control condition, the subject moved the pointer to the midpoint of the VAS line irrespective of the pain intensity (control motor task condition). Electroencephalograms were recorded from 21 scalp electrodes, referenced to the linked earlobes, and were averaged time-locked to the stimulus onset for each stimulus duration as well as for each task condition. RESULTS: The VAS scores were 2.8+/-0.5/10 for the stimulus of 40ms duration, 4.8+/-0.8/10 for 60ms and 6.1+/-0.9/10 for 80ms, and showed a highly significant positive correlation with the stimulus duration. Following the early components of pain SEPs which were affected by stimulus duration but not modulated by task conditions, a surface-positive peak at latency of 612-642ms was identified exclusively under the PIA condition regardless of the stimulus intensity and was called 'intensity assessment-related potential (IAP)'. The IAP was maximal at the midline parietal area and symmetrically distributed over the scalp. Neither latency nor amplitude of the IAP was significantly different among the 3 different stimulus intensities. CONCLUSIONS: IAP is an event-related potential (ERP) associated with assessment of pain intensity but not influenced by pain intensity itself. From its scalp distribution, it can be assumed that the assessment of pain intensity involves multiple areas in both hemispheres.

Nausea as a complication of low-frequency repetitive transcranial magnetic stimulation of the posterior fossa.

BACKGROUND: Transcranial magnetic stimulation (TMS) can non-invasively investigate the function of human brain. However, it can induce a focal pain at the stimulated site on the scalp or seizures when applied with high frequency (>1 Hz). Here we report an induction of nausea as a complication of low-frequency repetitive TMS (rTMS) of the cerebellum. SUBJECTS AND METHODS: Eight right-handed normal volunteers underwent low-frequency (0.9 Hz) rTMS of the right cerebellum. The stimulus intensity was set at 90% of the resting motor threshold determined by TMS to motor cortex. RESULTS: Nausea lasted as long as 10 min after the end of rTMS without apparent neurological deficit in two subjects. This symptom was replicated when the same protocol was applied on a different day in the same subjects. CONCLUSIONS: Low-frequency rTMS of cerebellum is still a safe procedure, but the experimenters should keep in mind the possibility of inducing nausea.

Transcranial magnetic stimulation (TMS) of the sensorimotor cortex and medial frontal cortex modifies human pain perception.

OBJECTIVE: Although recent neuroimaging studies have shown that painful stimuli can produce activity in multiple cortical areas, the question remains as to the role of each area in particular aspects of human pain perception. To solve this problem we used transcranial magnetic stimulation (TMS) as an 'interference approach' tool to test the consequence on pain perception of disrupting activity in several areas of cortex known to be activated by painful input. METHODS: Weak CO(2) laser stimuli at an intensity around the threshold for pain were given to the dorsum of the left hand in 9 normal subjects. At variable delays (50, 150, 250, 350 ms) after the onset of the laser stimulus, pairs of TMS pulses (dTMS: interpulse interval of 50 ms, and stimulus intensity of 120% resting motor threshold) were applied in separate blocks of trials over either the right sensorimotor cortex (SMI), midline occipital cortex (OCC), second somatosensory cortex (SII), or medial frontal cortex (MFC). Subjects were instructed to judge whether or not the stimulus was painful and to point to the stimulated spot on a drawing of subject's hand. RESULTS: Subjects judged that the stimulus was painful on more trials than control when dTMS was delivered over SMI at 150-200 ms after the laser stimulus; the opposite occurred when dTMS was delivered over MFC at 50-100 ms. dTMS over the SII or OCC failed to alter the pain threshold. CONCLUSIONS: These results suggest that TMS to SMI can facilitate whereas stimulation over MFC suppresses central processing of pain perception. Since there was no effect of dTMS at any of the scalp sites on the localization task, the cortical locus for point localization of pain may be different from that for perception of pain intensity or may involve a more complex mechanism than the latter. SIGNIFICANCE: This is the first report that TMS of SMI facilitates while that of MFC suppresses the central processing of pain perception. This raises the possibility of using TMS as a therapeutic device to control pain.

Low-frequency rTMS over lateral premotor cortex induces lasting changes in regional activation and functional coupling of cortical motor areas.

OBJECTIVE: To study the effect of 0.9 Hz repetitive transcranial magnetic stimulation (rTMS) of the lateral premotor cortex on neuronal activity in cortical motor areas during simple motor tasks. METHODS: In 8 subjects, electroencephalogram (EEG) and electromyogram (EMG) were simultaneously recorded during voluntary contractions of the thumb before and after a 15 min train of 0.9 Hz rTMS over the left lateral premotor cortex at stimulus intensity of 90% of active motor threshold. After-effects on cortical motor activity were assessed by measuring the task-related EEG power and inter-regional coherence changes, and the EEG-EMG coherence (EMGCoh). RESULTS: Low-frequency rTMS over the premotor cortex gave rise to (i) a reduction of the task-related power decrease in the alpha and beta bands, (ii) a selective increase in the task-related coherence change among cortical motor areas in the upper alpha band, and (iii) a decrease in the cortico-muscular coherence. These effects lasted about 15 min after the end of rTMS intervention. CONCLUSIONS: The attenuated task-related power changes and decreased EMGCoh point to a lasting suppression of voluntary activation of cortical motor areas after rTMS. The present data provide an evidence for a transient reorganization of movement-related neuronal activity in the cortical motor areas after 0.9 Hz rTMS over the premotor cortex. SIGNIFICANCE: Low-frequency rTMS changes the regional activation and functional coupling of cortical motor areas as demonstrated by EEG analysis.

Short-term high-frequency transcutaneous electrical nerve stimulation decreases human motor cortex excitability.

Several previous studies have shown that periods of changed sensory input can have after effects on the excitability of the corticospinal system. Here we test whether the parameters of peripheral stimulation conventionally used to treat pain with transcutaneous electrical nerve stimulation (TENS: 90 Hz) also have modulatory effects on the motor system. We measured the amplitude of motor evoked potentials (MEPs) elicited by the focal transcranial magnetic stimulation in the right abductor pollicis brevis and first dorsal interosseous muscles before and after 30 min TENS over the right thenar eminence. In addition, we evaluated tactile and 2-point discrimination thresholds at the same site. TENS transiently reduced MEPs and increased sensory thresholds. This suggests that short-term TENS might have an inhibitory effect on both the sensory and motor systems.

Eating tools in hand activate the brain systems for eating action: a transcranial magnetic stimulation study.

There is increasing neuroimaging evidence suggesting that visually presented tools automatically activate the human sensorimotor system coding learned motor actions relevant to the visual stimuli. Such crossmodal activation may reflect a general functional property of the human motor memory and thus can be operating in other, non-limb effector organs, such as the orofacial system involved in eating. In the present study, we predicted that somatosensory signals produced by eating tools in hand covertly activate the neuromuscular systems involved in eating action. In Experiments 1 and 2, we measured motor evoked response (MEP) of the masseter muscle in normal humans to examine the possible impact of tools in hand (chopsticks and scissors) on the neuromuscular systems during the observation of food stimuli. We found that eating tools (chopsticks) enhanced the masseter MEPs more greatly than other tools (scissors) during the visual recognition of food, although this covert change in motor excitability was not detectable at the behavioral level. In Experiment 3, we further observed that chopsticks overall increased MEPs more greatly than scissors and this tool-driven increase of MEPs was greater when participants viewed food stimuli than when they viewed non-food stimuli. A joint analysis of the three experiments confirmed a significant impact of eating tools on the masseter MEPs during food recognition. Taken together, these results suggest that eating tools in hand exert a category-specific impact on the neuromuscular system for eating.

Castleman's disease accompanied by hypolipidemic cerebral hemorrhage and nephrosclerosis.

A 56-year-old Japanese man developed a cerebral hemorrhage and was diagnosed with plasma cell-type multicentric Castleman's disease (MCD) based on the findings of an inguinal lymph node biopsy in addition to clinical findings, including hypergammaglobulinemia, anemia and elevation of the levels of CRP and serum IL-6. Although a renal biopsy showed nephrosclerosis, the levels of serum lipids and apolipoprotein were low. Following the initiation of treatment with anti-interleukin-6 receptor antibodies, the hypergammaglobulinemia, anemia, CRP level and serum lipid profile improved. However, inflammation due to overproduction of IL-6 persisted, and atherosclerotic vascular events occurred as critical complications, even though the serum levels of lipids were very low.

Task-sensitivity of unconscious word processing in spatial neglect.

Neuropsychological studies of spatial neglect have shown that ignored visual stimuli can produce measurable behavioral changes without eliciting subjective perceptual experience. However, such non-conscious, implicit cognitive processing may not be fully automatic but rather could be influenced by the patients' voluntary behavioral control. Using a hemifield priming paradigm with two different task instructions, we studied spatial neglect patients to assess whether non-conscious processing of ignored words is modulated by behavioral task requirements. In each trial, participants named or categorized a centrally presented target following a masked prime flashed to the left or right hemifield. By delivering equally invisible stimuli to both hemifields, this design allowed rigorous testing of the impact of task instructions on non-conscious processing in neglect patients and control participants. We observed that neglect patients showed slightly different patterns of masked priming from those obtained in healthy and right-hemisphere control patients. Importantly, however, all these three groups showed strong sensitivity to task contexts during the unconscious processing of masked words. The present results provide neuropsychological evidence that robust task-sensitive neural pathways are covertly operating on weak and normally imperceptible visual stimuli even when visuospatial attention is severely compromised.

Symmetrical hemispheric priming in spatial neglect: a hyperactive left-hemisphere phenomenon?

Hemispheric rivalry models of spatial neglect suggest that the left hemisphere becomes hyperactive following right-hemisphere lesions since the two hemispheres normally exert an inhibitory influence on each other via callosal connections. Using a masked hemifield priming paradigm, we investigated whether the putative change in hemispheric balance involves other, higher-order abstract representational systems in spatial neglect. Participants consisted of 12 neglect patients with right-hemisphere damage and three groups of control participants, i.e., 12 young healthy controls, 10 age-matched healthy controls and 10 right-hemisphere patients without spatial neglect. In each trial, participants made semantic categorization about a centrally presented target word which was preceded by a masked prime flashed either to the left or right visual field. All three control groups exhibited strong left-hemisphere advantage in inhibitory syllabic priming, consistent with the known left-hemisphere dominance in lexical inhibition during reading. By contrast, neglect patients exhibited a symmetrical pattern of priming between the left and right visual fields. These results suggest that (1) the neglected hemifield can rapidly extract abstract information even from weak and normally non-perceptible visual stimuli, but that (2) the normal left hemispheric dominance in reading is absent in neglect patients probably because of the generalized hyperactivity of the left hemisphere. Our results demonstrate a covert behavioral change in spatial neglect which may reflect the altered inter-hemispheric balance in the bilateral word recognition system encompassing lexico-semantic memory.

Hemispheric asymmetry emerges at distinct parts of the occipitotemporal cortex for objects, logograms and phonograms: a functional MRI study.

Behavioral and neuropsychological studies have suggested that the right hemisphere has a special advantage in the visual recognition of logograms. While this long-standing 'right hemisphere hypothesis' has never been investigated systematically by previous neuroimaging studies, a candidate neural substrate of such asymmetry might be found within the occipitotemporal cortex that is known to exhibit lateralized response to a certain class of stimuli, such as letters and faces. The present study examined the hemispheric specialization of brain activation during naming of objects, logograms and phonograms using functional magnetic resonance imaging. The three types of stimuli overall produced left-predominant activation of the perisylvian and inferior parietal regions relative to the resting baseline. This inter-hemispheric difference was significant irrespective of the stimuli type. In the occipitotemporal cortex, six subregions showing lateralized response were identified. That is, the three stimuli commonly produced left-lateralized response in the posterior fusiform and superior temporal gyri and right-lateralized response in the extrastriate cortex. Only logograms and objects produced a distinct cluster showing right-lateralized activation in the medial anterior fusiform gyrus associated with semantic knowledge, whereas only phonograms produced a left-lateralized activation in the posterior middle temporal cortex close to the site associated with visual perception of alphabetical letters. These findings suggest that while these stimuli similarly recruit the left perisylvian language area as a common neural component for naming, processing of objects and logograms becomes left-lateralized only in the downstream of the occipitotemporal cortex. By contrast, visual processing of phonograms is specialized to the left hemisphere in earlier stages of the area. The present data provide further evidence suggesting that both the left-right and anterior-posterior axes of the occipitotemporal cortex are differentially tuned according to the specific features of visual stimuli.

Implicit and explicit processing of kanji and kana words and non-words studied with fMRI.

Using functional magnetic resonance imaging (fMRI), we investigated the implicit language processing of kanji and kana words (i.e., hiragana transcriptions of normally written kanji words) and non-words. Twelve right-handed native Japanese speakers performed size judgments for character stimuli (implicit language task for linguistic stimuli), size judgments for scrambled-character stimuli (implicit language task for non-linguistic stimuli), and lexical decisions (explicit language task). The size judgments for scrambled-kanji stimuli and scrambled-kana stimuli produced activations on the bilateral lingual gyri (BA 18), the bilateral occipitotemporal regions (BA 19/37), and the bilateral superior and inferior parietal cortices (BA 7/40). Interestingly, besides these areas, activations of the left inferior frontal region (Broca's area, BA 44/45) and the left posterior inferior temporal cortex (PITC, BA 37), which have been considered as language areas, were additionally activated during size judgment for kanji character stimuli. Size judgment for kana character stimuli also activated Broca's area, the left PITC, and the left supramarginal gyrus (SMG, BA 40). The activations of these language areas were replicated in the lexical decisions for both kanji and kana. These findings suggest that language processing of both kanji and kana scripts is obligatory to literate Japanese subjects. Moreover, comparison between the scrambled kanji and the scrambled kana showed no activation in the language areas, while greater activation in the bilateral fusiform gyri (left-side predominant) was found in kanji vs. kana comparison during the size judgment and the lexical decision. Kana minus kanji activated the left SMG during the size judgment, and Broca's area and the left middle/superior temporal junction during the lexical decision. These results probably reflect that in implicit or explicit reading of kanji words and kana words (i.e., hiragana transcriptions of kanji words), although using largely overlapping cortical regions, there are still some differences. Kanji reading may involve more heavily visual orthographic retrieval and lexical-semantic system through the ventral route, while kana transcriptions of kanji words require phonological recoding to gain semantic access through the dorsal route.

Modulation of the visual word retrieval system in writing: a functional MRI study on the Japanese orthographies.

We used functional magnetic resonance imaging (fMRI) to examine whether the act of writing involves different neuropsychological mechanisms between the two script systems of the Japanese language: kanji (ideogram) and kana (phonogram). The main experiments employed a 2 x 2 factorial design that comprised writing-to-dictation and visual mental recall for kanji and kana. For both scripts, the actual writing produced a widespread fronto-parietal activation in the left hemisphere. Especially, writing of kanji activated the left posteroinferior temporal cortex (lPITC), whereas that of kana also yielded a trend of activation in the same area. Mental recall for both scripts activated similarly the left parietotemporal regions including the lPITC. The writing versus mental recall comparison revealed greater activations in the left sensorimotor areas and right cerebellum. The kanji versus kana comparison showed increased responses in the left prefrontal and anterior cingulate areas. Especially, the lPITC showed a significant task-by-script interaction. Two additional control tasks, repetition (REP) and semantic judgment (SJ), activated the bilateral perisylvian areas, but enhanced the lPITC response only weakly. These results suggest that writing of the ideographic and phonographic scripts, although using the largely same cortical regions, each modulates the visual word-retrieval system according to their graphic features. Furthermore, comparisons with two additional tasks indicate that the activity of the lPITC increases especially in expressive language operations regardless of sensory modalities of the input stimulus.