Clinical utility of resting-state functional connectivity magnetic resonance imaging for mood and cognitive disorders.

Although functional magnetic resonance imaging (fMRI) has long been used to assess task-related brain activity in neuropsychiatric disorders, it has not yet become a widely available clinical tool. Resting-state fMRI (rs-fMRI) has been the subject of recent attention in the fields of basic and clinical neuroimaging research. This method enables investigation of the functional organization of the brain and alterations of resting-state networks (RSNs) in patients with neuropsychiatric disorders. Rs-fMRI does not require participants to perform a demanding task, in contrast to task fMRI, which often requires participants to follow complex instructions. Rs-fMRI has a number of advantages over task fMRI for application with neuropsychiatric patients, for example, although applications of task fMR to participants for healthy are easy. However, it is difficult to apply these applications to patients with psychiatric and neurological disorders, because they may have difficulty in performing demanding cognitive task. Here, we review the basic methodology and analysis techniques relevant to clinical studies, and the clinical applications of the technique for examining neuropsychiatric disorders, focusing on mood disorders (major depressive disorder and bipolar disorder) and dementia (Alzheimer's disease and mild cognitive impairment).

Time course and spatial distribution of fMRI signal changes during single-pulse transcranial magnetic stimulation to the primary motor cortex.

Simultaneous transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) may advance the understanding of neurophysiological mechanisms of TMS. However, it remains unclear if TMS induces fMRI signal changes consistent with the standard hemodynamic response function (HRF) in both local and remote regions. To address this issue, we delivered single-pulse TMS to the left M1 during simultaneous recoding of electromyography and time-resolved fMRI in 36 healthy participants. First, we examined the time-course of fMRI signals during supra- and subthreshold single-pulse TMS in comparison with those during voluntary right hand movement and electrical stimulation to the right median nerve (MNS). All conditions yielded comparable time-courses of fMRI signals, showing that HRF would generally provide reasonable estimates for TMS-evoked activity in the motor areas. However, a clear undershoot following the signal peak was observed only during subthreshold TMS in the left M1, suggesting a small but meaningful difference between the locally and remotely TMS-evoked activities. Second, we compared the spatial distribution of activity across the conditions. Suprathreshold TMS-evoked activity overlapped not only with voluntary movement-related activity but also partially with MNS-induced activity, yielding overlapped areas of activity around the stimulated M1. The present study has provided the first experimental evidence that motor area activity during suprathreshold TMS likely includes activity for processing of muscle afferents. A method should be developed to control the effects of muscle afferents for fair interpretation of TMS-induced motor area activity during suprathreshold TMS to M1.

Hemispheric asymmetry of the arcuate fasciculus: a preliminary diffusion tensor tractography study in patients with unilateral language dominance defined by Wada test.

OBJECTIVE: Lateralization of language function is a prominent feature of human brain function, and its underlying structural asymmetry has been recently reported in normal right-handed subjects. By means of diffusion tensor tractography (DTT), we investigated the asymmetry of the language network, namely, the arcuate fasciculus in patients in whom the unilateral language dominance was defined by Wada test. METHODS: DTT was performed in 24 patients with a focal lesion or an epileptic focus outside the C-shaped segment of the arcuate fasciculus. The arcuate fasciculus was reconstructed by placing two regions-of-interest in the deep white matter lateral to the corona radiata. The pathway was then divided into one terminating in the temporal lobe (FT tract) and the other in the parietal lobe (FP tract). The relative number and volume of the FT and FP tracts in each hemisphere were submitted to repeated measure ANOVA separately, with the hemisphere as a within-subject factor and with the side of pathology as a between subject factor. RESULTS: The FT tract showed a significantly larger number and volume in the language dominant hemisphere than in the non-dominant hemisphere, while, for the FP tract, no significant hemispheric difference was observed in the relative number or volume. There was a tendency that the FT tract was less lateralized when the pathology was located in the dominant hemisphere than in the non-dominant hemisphere. CONCLUSION: Dominance of the FT tract in the language dominant hemisphere was demonstrated for the first time in a patient population and implicated a clinical utility of DTT for non-invasive evaluation of language lateralization. Our preliminary study might indicate reorganization of the language network in conjunction with pathology.

Diffusion tensor fiber tractography of the optic radiation: analysis with 6-, 12-, 40-, and 81-directional motion-probing gradients, a preliminary study.

BACKGROUND AND PURPOSE: Knowing the exact location of the optic radiation preoperatively is important for surgery of the temporal lobe. We hypothesized that a greater number of motion-probing gradients (MPGs) would provide better results of diffusion tensor (DT) fiber tractography of the optic radiation. To test this hypothesis, this study evaluated differences in DT fiber tractography of the optic radiation under different MPG settings. METHODS: DT images were obtained in 12 healthy volunteers (7 men, 5 women) with a mean age of 32 years (range, 22-45 years) by using a 3T MR imaging scanner with single-shot echo-planar imaging with parallel acquisition (reduction factor = 2). MPG was applied in 6, 12, 40, and 81 independent directions. The first region of interest (ROI) was placed in the occipital lobe, and the second ROI was placed in the lateral geniculate body. Fibers penetrating both ROIs were considered as the optic radiation. Anteroposterior distance between the tip of the Meyer loop and the lateral geniculate body on an axial section was defined as a loop index. Numbers of fibers and loop indices in both cerebral hemispheres were evaluated statistically. RESULTS: The optic radiation was well visualized in full length by DT fiber tractography in 20 of 24 hemispheres (83%). No significant differences were noted in number of fibers and loop indices among different MPG settings. CONCLUSION: DT fiber tractography can frequently depict almost the entire optic radiation. MPG number does not exert any significant effect on visualization of the optic radiation, and 6-directional MPG is thus sufficient for this purpose.

Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study.

Little is known about the neural correlates of tics and associated urges. In the present study, we aimed to explore the neural basis of tics in patients with Tourette syndrome by using event-related functional MRI (fMRI). Ten patients (6 women, 4 men; age: mean +/- SD = 31 +/- 11.2) were studied while spontaneously exhibiting a variety of motor and vocal tics. On the basis of synchronized video/audio recordings, fMRI activities were analysed 2 s before and at tic onset irrespective of the clinical phenomenology. We identified a brain network of paralimbic areas such as anterior cingulate and insular cortex, supplementary motor area (SMA) and parietal operculum (PO) predominantly activated before tic onset (P < 0.05, corrected for multiple comparisons). In contrast, at the beginning of tic action, significant fMRI activities were found in sensorimotor areas including superior parietal lobule bilaterally and cerebellum. The results of this study indicate that paralimbic and sensory association areas are critically implicated in tic generation, similar to movements triggered internally by unpleasant sensations, as has been shown for pain or itching.

Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study.

Although behavioral studies suggest that pain distress may alter the perception of somatic stimulation, neural correlates underlying such alteration remain to be clarified. The present study was aimed to test the hypothesis that expectation of pain might amplify brain responses to somatosensory stimulation in the anterior cingulate cortex (ACC) and the region including parietal operculum and posterior insula (PO/PI), both of which may play roles in regulating pain-dependent behavior. We compared brain responses with and subjective evaluation of physically identical nonpainful warm stimuli between two psychologically different contexts: one linked with pain expectation by presenting the nonpainful stimuli randomly intermixed with painful stimuli and the other without. By applying the event-related functional magnetic resonance imaging technique, brain responses to the stimuli were assessed with respect to signal changes and activated volume, setting regions of interest on activated clusters in ACC and bilateral PO/PI defined by painful stimuli. As a result, the uncertain expectation of painful stimulus enhanced transient brain responses to nonpainful stimulus in ACC and PO/PI. The enhanced responses were revealed as a higher intensity of signal change in ACC and larger volume of activated voxels in PO/PI. Behavioral measurements demonstrated that expectation of painful stimulus amplified perceived unpleasantness of innocuous stimulus. From these findings, it is suggested that ACC and PO/PI are involved in modulation of affective aspect of sensory perception by the uncertain expectation of painful stimulus.

Neural mechanisms underlying the processing of Chinese words: an fMRI study.

The present study employed functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms underlying orthographic, phonological and semantic processing of single character Chinese words. Twelve right-handed native Chinese speakers participated in the study. Three fundamental linguistic tasks including orthographic judgment, phonological matching and semantic association task were used. Our results demonstrated robust activation in the left posterior inferior temporal cortex (BA 37) for all three tasks. While the phonological matching task produced left-lateralized activation in the inferior frontal and parietal regions, semantic association task showed considerable bilateral activation in the inferior frontal and occipito-parietal regions. Direct comparison between phonological matching and semantic association task yielded semantic related activation in the anterior portion of the left inferior frontal gyrus (BA 47) and the right inferior frontal region (Broca's homology; BA 45). Behaviorally, there was no difference in response time between phonological matching and semantic association task. Our findings suggested that differential neural pathways were involved in the processing of meaning and sound of single-character Chinese words. The present study provided systemic information of the neural substrates underlying the processing of different components of Chinese language.

Internal capsule stroke in the common marmoset.

White matter (WM) impairment and motor deficit after stroke are directly related. However, WM injury mechanisms and their relation to motor disturbances are still poorly understood. In humans, the anterior choroidal artery (AChA) irrigates the internal capsule (IC), and stroke to this region can induce isolated motor impairment. The goal of this study was to analyze whether AChA occlusion can injure the IC in the marmoset monkey. The vascular distribution of the marmoset brain was examined by colored latex perfusion and revealed high resemblance to the human brain anatomy. Next, a new approach to electrocoagulate the AChA was developed and chronic experiments showed infarction compromising the IC on magnetic resonance imaging (MRI) scanning (day 4) and histology (day 11). Behavioral analysis was performed using a neurologic score previously developed and our own scoring method. Marmosets showed a decreased score that was still evident at day 10 after AChA electrocoagulation. We developed a new approach able to induce damage to the marmoset IC that may be useful for the detailed study of WM impairment and behavioral changes after stroke in the nonhuman primate.

Temporal lobe epilepsy in a genius of natural history: MRI volumetric study of postmortem brain.

Kumagusu Minakata (1867-1941), a Japanese genius devoted to natural history and folklore, is famous for his immense range of works, including his discovery of many new varieties of mycetozoa, or slime molds. His diary reveals that he was affected by epilepsy. In this study of his brain, we adopted a method of measuring the volume of the hippocampi by MRI of postmortem brain and found evidence of right hippocampal atrophy. This finding, together with the striking parallels between his behavior and the known behavioral syndrome in temporal lobe epilepsy (TLE), suggests that he was affected by TLE. The postmortem imaging analysis of brain, as performed in this study, offers a bridge between neuroscience and classic psychopathologic approaches to the creativity of geniuses.

Cerebral glucose metabolism in unilateral entorhinal cortex-lesioned rats: an animal PET study.

To evaluate the effect of entorhinal cortical lesion on cerebral cortical function, we studied cerebral glucose utilization (CMRGlc) using a high resolution PET scanner after quinolinic acid lesion of the unilateral entorhinal cortex in rats. [18F]Fluorodeoxyglucose PET was performed at 4 days and 4 weeks after surgery, and CMRGlc in the bilateral frontal, parietal and temporal regions were analyzed. At 4 days, the entorhinal lesion induced a 12-15% decrease in CMRGlc of frontal, parietal and temporal regions ipsilateral to the lesion. The hypometabolism continued at 4 weeks in the temporal region. These findings suggest that entorhinal lesion induces cerebral cortical hypometabolism, which implies a pathogenetic role of entorhinal area on the cortical hypometabolism in Alzheimer's disease.

Functional localization of pain perception in the human brain studied by PET.

To elucidate the functional localization and somatotopic organization of pain perception in the human cerebral cortex, we studied the regional cerebral blood flow using positron emission tomography during selective painful stimulation in six normal subjects. Response to a painful stimulus was elicited using a special CO2 laser, which selectively activates nociceptive receptors, to the hand and foot. Multiple brain areas, including bilateral secondary somatosensory cortices (SII) and insula, and the frontal lobe and thalamus contralateral to the stimulus side, were found to be involved in the response to painful stimulation. While our data indicate that the bilateral SII play an important role in pain perception, they also indicate that there is no pain-related somatotopic organization in the human SII or insula.

The effect of sequential lesioning in the basal forebrain on cerebral cortical glucose metabolism in rats. An animal positron emission tomography study.

We studied the effect of the cortical projection from the basal forebrain on the cerebral cortical metabolism using positron emission tomography (PET) with [(18)F] fluorodeoxyglucose. Unilateral damage of the nucleus basalis magnocellularis (NBM) did not cause a permanent reduction of cortical metabolism: recovery was observed 4 weeks after the operation. Destruction of the contralateral side after recovery from unilateral damage produced persistent bilateral suppression of glucose metabolism, with partial recovery. We speculate that recovery from the unilateral NBM lesions is partly ascribable to the cholinergic projection from the contralateral NBM, and partly due to non-cholinergic systems, and conclude that bilateral damage might be responsible for persistent cortical glucose metabolism suppression.

Cortical control of voluntary blinking: a transcranial magnetic stimulation study.

OBJECTIVE: To investigate cortical regions related to voluntary blinking. METHODS: Transcranial magnetic stimulation (TMS) was applied to the facial motor cortex (M1) and the midline frontal region (Fz) in 10 healthy subjects with eyes opened and closed. Motor-evoked potentials were recorded from the orbicularis oculi (OOC), orbicularis oris (OOR), abductor digiti minimi and tibialis anterior using surface and needle electromyography electrodes. Facial M waves and blink reflex were measured using supramaximal electrical stimulation of the facial and supraorbital nerves. RESULTS: TMS at Fz elicited 3 waves in OOC with no response in other tested muscles except for the early wave in OOR. Facial M1 stimulation produced only early and late waves. Because of their latencies, shapes, and relationship to coil position and stimulation intensity, early and late waves appeared to be analogous to the facial M wave and R1 component of the blink reflex. The intermediate wave at 6-8 ms latency was elicited in OOC by Fz stimulation with eyes closed. CONCLUSIONS: Since its latency matches the central conduction time of other cranial muscles and it has characteristic of muscle activation-related facilitation, the intermediate wave is presumably related to cortical stimulation. This result provides evidence that the cortical center for the upper facial movements, including blinking, is not principally located in the facial M1, but rather in the mesial frontal region.

Waveform changes of compound muscle action potential (CMAP) with muscle length.

Changes in finger positions influence the waveform of CMAP recorded from the muscle that moves that finger. The present study suggested that the muscle length, dependent on the finger position, was a main factor affecting the waveform. On shortening the muscle length, the amplitude of CMAP increased with concomitant reduction in the duration, and on lengthening, the amplitude decreased with concomitant increase in the duration. These changes are considered due to changes in propagation velocities of muscle fibers dependent on the muscle length. In nerve conduction studies, it is important to carefully monitor the finger position to distinguish the waveform changes with muscle length from those due to nerve lesions.

[A case of familial juvenile dystonia-parkinsonism: 18F-6-fluorodopa and 18F-fluoro-2-deoxyglucose PET study].

A 27-year-old Japanese woman was admitted to Kyoto University Hospital because of gait disturbance since age 25. Her elder sister had been suffering from childhood-onset dystonia-parkinsonism with diurnal fluctuation which initially responded well to levodopa therapy, but later larger dose of levodopa was needed because of severe treatment-related fluctuation of the clinical symptoms. Physical examination revealed left foot dystonia, mild parkinsonism with kinesie paradoxale and dyskinesia of lower limbs. Symptoms were relieved by sleep and worsened by walking. Laboratory data including serum ceruloplasmin, serum and urinary amino acid analysis, and hexosaminidase and beta-glucosidase activity in leukocytes were all normal. Homovanillic acid (HVA) in cerebrospinal fluid was normal (68 ng/ml) at 8 pm but markedly decreased (7 ng/ml) at 4 pm. Cranial MRI was normal. 18F-6-fluorodopa PET demonstrated decreased dopa uptake in the bilateral striatum, especially in the putamen. 18F-fluoro-2-deoxyglucose PET showed decreased regional glucose metabolism in the bilateral putamen. Levodopa therapy rendered equivocal effects while trihexyphenydil was effective. This case indicated that some cases of dopa-unresponsive dystonia with parkinsonism might be a clinical variant of juvenile parkinsonism. 18F-6-fluorodopa PET is useful in evaluating juvenile dystonia-parkinsonism, though it may not predict levodopa effectiveness. 18F-fluoro-2-deoxyglucose PET study will be helpful in predicting the effect of levodopa therapy, because decreased regional glucose metabolism in the putamen probably indicates poor response to levodopa. Further study including dopaminergic receptor imaging study is needed to clarify the physiological mechanism of co-existing dystonia and parkinsonism in patients with juvenile parkinsonism and related disorders.

Movement and afferent representations in human motor areas: a simultaneous neuroimaging and transcranial magnetic/peripheral nerve-stimulation study.

Neuroimaging combined with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) is an emerging technique that can examine motor-system functionality through evoked activity. However, because sensory afferents from twitching muscles are widely represented in motor areas the amount of evoked activity directly resulting from TMS remains unclear. We delivered suprathreshold TMS to left M1 or gave electrical right median nerve stimulation (MNS) in 18 healthy volunteers while simultaneously conducting functional magnetic resonance imaging and monitoring with electromyography (EMG). We examined in detail the localization of TMS-, muscle afferent- and superficial afferent-induced activity in M1 subdivisions. Muscle afferent- and TMS-evoked activity occurred mainly in rostral M1, while superficial afferents generated a slightly different activation distribution. In 12 participants who yielded quantifiable EMG, differences in brain activity ascribed to differences in movement-size were adjusted using integrated information from the EMGs. Sensory components only explained 10-20% of the suprathreshold TMS-induced activity, indicating that locally and remotely evoked activity in motor areas mostly resulted from the recruitment of neural and synaptic activity. The present study appears to justify the use of fMRI combined with suprathreshold TMS to M1 for evoked motor network imaging.

Cognitive slowing in Parkinson disease is accompanied by hypofunctioning of the striatum.

OBJECTIVE: To investigate whether cognitive slowing in Parkinson disease (PD) reflects disruption of the basal ganglia or dysfunction of the frontal lobe by excluding an influence of abnormal brain activity due to motor deficits. METHODS: We measured neuronal activity during a verbal mental-operation task with H(2)(15)O PET. This task enabled us to evaluate brain activity change associated with an increase in the cognitive speed without an influence on motor deficits. RESULTS: As the speed of the verbal mental-operation task increased, healthy controls exhibited proportional increase in activities in the anterior striatum and medial premotor cortex, suggesting the involvement of the corticobasal ganglia circuit in normal performance of the task. By contrast, patients with PD lacked an increase in the striatal activity, whereas the medial premotor cortex showed a proportional increase. CONCLUSIONS: Although the present study chose a liberal threshold and needs subsequent confirmation, the findings suggest that striatal disruption resulting in abnormal processing in the corticobasal ganglia circuit may contribute to cognitive slowing in Parkinson disease, as is the case in motor slowing.

Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome.

OBJECTIVE: To identify brain regions generating tics in patients with Tourette syndrome using sleep as a baseline. METHODS: We used [15O]H2O PET to study nine patients with Tourette syndrome and nine matched control subjects. For patients, conditions included tic release states and sleep stage 2; and for control subjects, rest states and sleep stage 2. RESULTS: Our study showed robust activation of cerebellum, insula, thalamus, and putamen during tic release. CONCLUSION: The network of structures involved in tics includes the activated regions and motor cortex. The prominent involvement of cerebellum and insula suggest their involvement in tic initiation and execution.