Near-Infrared Time-Resolved Spectroscopy Shows Anterior Prefrontal Blood Volume Reduction in Schizophrenia but Not in Major Depressive Disorder.

Previous studies using various brain imaging methods have reported prefrontal blood flow disturbances in psychiatric disorders, including schizophrenia and major depressive disorder. In both disorders, alterations of the resting blood flow, in addition to that of the activation in response to task load, have been shown, but the results are not consistent. The present study aimed to examine the anterior prefrontal hemoglobin concentration at the resting state in schizophrenia and depression using near-infrared time-resolved spectroscopy (NIR-TRS), which estimates the optical absorption coefficients and calculates the absolute concentrations of oxygenated (oxy-Hb), deoxygenated (deoxy-Hb), and total (total-Hb; sum of oxy-Hb and deoxy-Hb) hemoglobin. Their ratios to systemic blood hemoglobin concentration (blood-Hb) were also assessed. In agreement with our previous data, total-Hb and total-Hb/blood-Hb in schizophrenia were significantly lower. The present study further revealed that both oxy-Hb/blood-Hb and deoxy-Hb/blood-Hb in schizophrenia were reduced. In depression, total-Hb, total-Hb/blood-Hb, oxy-Hb, and oxy-Hb/blood-Hb were higher than in schizophrenia and were not different from the control. The oxygen saturation (oxy-Hb/total-Hb), in addition to the optical pathlengths, did not show group differences. Lowered oxy-Hb/blood-Hb and deoxy-Hb/blood-Hb together with unchanged oxygen saturation may indicate that the prefrontal blood volume is reduced in schizophrenia. The present findings suggest that NIR-TRS is useful in analyzing the hemodynamic aspects of prefrontal dysfunction in schizophrenia and differentiating schizophrenia from depression.

Decay behavior and optical parameter identification for spatial-frequency domain imaging by the radiative transport equation.

The decay behavior of specific intensity is studied for spatial-frequency domain imaging (SFDI). It is shown using the radiative transport equation that the decay is given by a superposition of different decay modes, and the decay rates of these modes are determined by spatial frequencies and Case's eigenvalues. This explains why SFDI can focus on shallow regions. The fact that light with nonzero spatial frequency rapidly decays makes it possible to exclusively extract optical properties of the top layer of a layered medium. We determine optical properties of the top layer of a solid phantom. This measurement is verified with different layered media of numerical phantoms.

Atrial electromechanical interval may predict cardioembolic stroke in apparently low risk elderly patients with paroxysmal atrial fibrillation.

BACKGROUND: A considerable number of patients with atrial fibrillation (AF) develop cardioembolic stroke (CE) despite low CHADS2 score. We examined the possibility that use of the atrial electromechanical interval (AEMI) improves prediction of CE in patients with paroxysmal AF (PAF), particularly those with low CHADS2 score. METHODS: We consecutively enrolled 108 patients with nonvalvular PAF and 52 healthy subjects as controls. The PAF patients were divided into 2 groups depending on presence (n = 36) or absence (n = 72) of the history of CE. Left atrial (LA) volume index (LAVI), peak myocardial velocity during late diastole (a'), and AEMI as time from onset of P-wave to onset of lateral a' were measured. RESULTS: Patients with PAF had significantly larger LAVI, longer AEMI, and lower lateral a' than those in controls. Area under the curves for LAVI, lateral a', and AEMI for identifying patients with PAF were 0.70, 0.69, and 0.88, respectively. Multivariate logistic regression analysis indicated that age, use of antiarrhythmic drugs, and AEMI, but not LAVI or a', were independently associated with history of CE in patients with PAF. PAF patients were categorized into low risk by CHADS2 score (i.e. CHADS2 score = 0 or 1, n = 60), those with prolonged AEMI (>82 msec) had significantly higher rates of CE than those with ≤ 82 msec (48% vs. 15%, P < 0.05). CONCLUSION: As compared with echocardiographic parameters of LA size and LA function, AEMI appears to be more useful for identifying PAF patients. AEMI may enable to detect high risk PAF patients, especially those categorized into low risk by CHADS2 score.

Influence of subjective happiness on the prefrontal brain activity: an fNIRS study.

Focusing on the relationship between subjective happiness (SH) and emotional changes, we examined influences of SH on emotion-related prefrontal activity using multichannel NIRS. The International Affective Picture System (IAPS) was used to evoke emotional changes. Subjects were a total of 18 right-handed healthy students. Frequency of picture-induced increases in oxygenated haemoglobin (oxy-Hb) was evaluated. Subjects with a high SH score had a higher frequency of increased oxy-Hb in the left prefrontal cortex (PFC) while viewing pleasant pictures, whereas they showed a lower frequency in the right PFC while viewing unpleasant pictures. It is well known that the left PFC and right PFC are engaged in different ways in the emotional processes. Although further investigations are required, the present results indicate that the SH level influences the right-left differences in emotion-related prefrontal activity.

Diversity of neural-hemodynamic relationships associated with differences in cortical processing during bilateral somatosensory activation in rats.

The neural-hemodynamic relationships may vary depending on cortical processing patterns. To investigate how cortical hemodynamics reflects neural activity involving different cortical processing patterns, we delivered electrical stimulation pulses to rat hindpaws, unilaterally or bilaterally, and simultaneously measured electrophysiological (local field potential, LFP < 100 Hz; multiunit activity, MUA>300 Hz) and optical intrinsic signals associated with changes in cerebral blood volume (CBV). Unilateral stimulation evoked neural and optical signals in bilateral primary somatosensory cortices. Ipsilateral optical responses indicating an increased CBV exhibited a peak magnitude of ~30% and mediocaudal shifts relative to contralateral responses. Correlation analyses revealed different scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships. Bilateral stimulation at varying time intervals evoked hemodynamic responses that were strongly suppressed at 40-ms intervals. This suppression quantitatively reflected suppressed LFP responses to contralateral testing stimulation and not linear summation, with slowly fluctuating LFP responses to ipsilateral conditioning stimulation. Consequently, in the overall responses to bilateral stimulation, CBV-related responses were more linearly correlated with MUA than with LFPs. When extracting high-frequency components (>30 Hz) from LFPs, we found similar scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships, resulting in significant linear relationships among these components, MUA, and cortical hemodynamics in overall responses to bilateral stimulation. The dependence of LFP-MUA-hemodynamic relationships on cortical processing patterns and the LFP temporal/spectral structure is important for interpreting hemodynamic signals in complex functional paradigms driving diverse cortical processing.

Paradox of schizophrenia genetics: is a paradigm shift occurring?

BACKGROUND: Genetic research of schizophrenia (SCZ) based on the nuclear genome model (NGM) has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM) but not in the NGM. METHODS: We deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011) were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed. RESULTS: 19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date. CONCLUSION: The central paradox of SCZ genetics and the results of association studies to date argue against the NGM, and in its place the MGM is emerging as a viable option to account for genomic and pathophysiological research findings involving SCZ.

Neural mechanisms underlying rule selection based on response evaluation: a near-infrared spectroscopy study.

The ability of humans to use rules for organizing action demands a high level of executive control. Situational complexity mediates rule selection, from the adoption of a given rule to the selection of complex rules to achieve an appropriate response. Several rules have been proposed to be superordinate to human behavior in a cognitive hierarchy and mediated by different brain regions. In the present study, using a novel rule-selection task based on pre-response evaluations that require several cognitive operations, we examined whether the task is mediated by a specific region of the prefrontal cortex using near-infrared spectroscopy. We showed that the selection of rules, including prior evaluation of a stimulus, activates broader areas of the prefrontal and premotor regions than response selection based on a given rule. The results are discussed in terms of hierarchical cognitive models, the functional specialization of multiple-cognitive operations in the prefrontal cortex, and their contribution to a novel cognitive task.

Blood oxygenation level-dependent functional magnetic resonance imaging of bilateral but asymmetrical responses to gustatory stimulation in the rat insular cortex.

Evidence has suggested asymmetrical processing of taste in the human insular cortex, but this phenomenon has not been demonstrated in the rodent brain. Functional magnetic resonance imaging (fMRI) is a powerful tool for studying the functional organization of the brain. In this study, we established a blood oxygenation level-dependent (BOLD) fMRI method at 7 T to investigate the responses to gustatory stimulation in the insular cortex of anesthetized rats (220-310 g, n=15). BOLD signals were observed in the insular cortex in response to 0.5 M sucrose solution as the tastant but not observed in response to distilled water as the control. The reproducibility of the BOLD signals in response to the tastant was confirmed between fMRI runs in the same animal and across animals. The signals were mainly located between 2.3 mm and 0.0 mm anterior to the bregma in the insular cortex. Interestingly, the signals were observed in the insular cortex of both hemispheres, but they were asymmetrical: the anterior and posterior regions to the intersection of the middle cerebral artery and the rhinal fissure as the landmark of the gustatory cortex were dominant in the left and right hemispheres of the insular cortex, respectively. These results suggest that activity in both hemispheres of the insular cortex should be considered to analyze taste processing. We think that BOLD fMRI of taste function in rodents will improve our understanding of taste information processing.

Near-infrared spectroscopic study on the effects of chewing on short-term memory.

Using near-infrared spectroscopy, we examined whether chewing gum improves performance in a short-term memory task - immediate recall of random eight-digit numbers - by assessing cerebral hemodynamic response in the prefrontal cortex. We found that the oxyhemoglobin concentration during and after chewing gum was higher than that before chewing; further, the concentration increased during the task, and this increase was reduced with chewing, although non-significantly. Chewing did not improve task performance. Therefore, chewing-induced hemodynamic responses were unrelated to the performance in short-term memory tasks.

In situ estimation of optical properties of rat and monkey brains using femtosecond time-resolved measurements.

An accurate knowledge of tissue optical properties (absorption coefficients, µa, and reduced scattering coefficients, µs') is critical for precise modeling of light propagation in biological tissue, essential for developing diagnostic and therapeutic optical techniques that utilize diffusive photons. A great number of studies have explored the optical properties of various tissue, and these values are not known in detail due to difficulties in the experimental determination and significant variations in tissue constitution. Especially, in situ estimates of the optical properties of brain tissue, a common measurement target in optical imaging, is a challenge because of its layer structure (where the thin gray matter covers the white matter). Here, we report an approach to in situ estimates of the µa and µs' of the gray and white matter in living rat and monkey brains by using femtosecond time-resolved measurements and Monte Carlo simulation. The results demonstrate that the µa of the gray matter is larger than that of the white matter, while there was no significant difference in the µs' between the gray and white matter. The optical properties of the rat brain were very similar to those of the monkey brain except for the µa of the gray matter here.

Co-activation of the secondary somatosensory and auditory cortices facilitates frequency discrimination of vibrotactile stimuli.

The contribution of the auditory cortex to tactile information processing was studied by measuring somatosensory evoked magnetic fields (SEFs). Three kinds of vibrotactile stimuli with frequencies of 180, 280 and 380 Hz were randomly delivered on the right index finger with a probability of 40, 20 and 40%, respectively. Twenty normal subjects participated in four kinds of tasks: a control condition to ignore these stimuli, a simple task to discriminate the 280-Hz stimulus from the other two stimuli (discrimination task for the vibrotactile stimuli, Ts task), a feedback task modified from the Ts task by adding acoustic feedback of the vibratory frequency at 1300 ms poststimulus (tactile discrimination with auditory clues, TA), and an easy version of the TA task (TA-easy) to discriminate the 280-Hz stimulus (20% target) from the 180- or 380-Hz stimuli (80% nontarget). The Ts and TA tasks required accurate perception of the vibrotactile frequencies to discriminate among the three kinds of stimuli. Under such a task demand, the post hoc auditory feedback in the TA task was expected to induce acoustic imagery for the tactile sensation. The SEFs for the nontarget stimuli were analyzed. A middle-latency component (M150/200) was specifically evoked by the three discrimination tasks. In the Ts and TA-easy tasks, the M150/200 source indicated inferior parietal cortical activities (SII area). In the TA task, 11 subjects showed activity in both the SII area and the superior temporal auditory region and increased accuracy of discrimination compared with the Ts task, in contrast with other subjects who showed activity only in the SII area and small changes in task accuracy between the Ts and TA tasks. Asynchronous auditory feedback for the vibrotactile sensation induced the auditory cortex activity in the SEFs in relation to the progress in tactile discrimination, which suggested an induction of acoustic imagery to complement the tactile information processing.

Functional near-infrared spectroscopy: current status and future prospects.

Near-infrared spectroscopy (NIRS), which was originally designed for clinical monitoring of tissue oxygenation, has been developing into a useful tool for neuroimaging studies (functional near-infrared spectroscopy). This technique, which is completely noninvasive, does not require strict motion restriction and can be used in a daily life environment. It is expected that NIRS will provide a new direction for cognitive neuroscience research, more so than other neuroimaging techniques, although several problems with NIRS remain to be explored. This review demonstrates the strengths and the advantages of NIRS, clarifies the problems, and identifies the limitations of NIRS measurements. Finally, its future prospects are described.

Resting hypofrontality in schizophrenia: A study using near-infrared time-resolved spectroscopy.

Hypofrontality has been a major finding obtained from functional neuroimaging studies on schizophrenia, although there have also been contradictory results that have questioned the reality of hypofrontality. In our previous study, we confirmed the existence of activation hypofrontality by using a 2-channel continuous-wave-type (CW-type) near-infrared spectroscopy (NIRS) instrument. In this study, we employed a single-channel time-resolved spectroscopy (TRS) instrument, which can quantify hemoglobin (Hb) concentrations based on the photon diffusion theory, to investigate resting hypofrontality. A pair of incident and detecting light guides was placed on either side of the forehead at approximately Fp2-F8 or Fp1-F7 alternately in 14 male schizophrenic patients and 16 age-matched male control subjects to measure Hb concentrations at rest. The patients were also measured with a 2-channel CW-type NIRS instrument during the performance of a random number generation (RNG) task. A reduced total hemoglobin concentration (t-Hb) less than 60 microM (the mean value of the control subjects-1.5 SD) was observed bilaterally in 4 patients and only in the left side in 3 patients. Activation hypofrontality was more manifest in these patients than in the remaining 7 patients despite the same task performance. This decreased t-Hb was related to the duration of illness, and it was not observed in patients whose duration of illness was less than 10 years. These results indicate that resting hypofrontality is a chronically developed feature of schizophrenia. This does not necessarily represent frontal dysfunction, but may reflect anatomical and/or functional changes in frontal microcirculation.

Cerebral hemodynamics during the induction of antenatal periventricular leukomalacia by hemorrhagic hypotension in chronically instrumented fetal sheep.

OBJECTIVE: Our purpose was to determine the characteristics of cerebral ischemia during the induction of antenatal periventricular leukomalacia by hemorrhagic hypotension in premature fetal sheep. STUDY DESIGN: The hemorrhage group received an acute withdrawal of 40% of the fetoplacental blood volume (n = 7), whereas an isovolemic exchange transfusion was performed in the control group (n = 7). Changes in the total hemoglobin, oxy-hemoglobin, and deoxy-hemoglobin levels in the cerebral tissue were assessed with the use of near-infrared spectroscopy and compared statistically. RESULTS: Of 7 fetuses in the hemorrhage group, 5 exhibited periventricular leukomalacia but none in the control group (P < .05). In the hemorrhage group, both brain total-hemoglobin and deoxy-hemoglobin decreased seriously after insult, and the decreased levels persisted even after recovery of systemic blood pressure, whereas such drastic changes were not observed in the control group, suggesting the occurrence of reperfusion failure in the fetal brain in the hemorrhage group. CONCLUSION: The no-reflow phenomenon and successive reperfusion injuries after cerebral ischemia could be closely involved in the induction of antenatal periventricular leukomalacia in this experimental condition.

Overview of diffuse optical tomography and its clinical applications.

Near-infrared diffuse optical tomography (DOT), one of the most sophisticated optical imaging techniques for observations through biological tissue, allows 3-D quantitative imaging of optical properties, which include functional and anatomical information. With DOT, it is expected to be possible to overcome the limitations of conventional near-infrared spectroscopy (NIRS) as well as offering the potential for diagnostic optical imaging. However, DOT has been under development for more than 30 years, and the difficulties in development are attributed to the fact that light is strongly scattered and that diffusive photons are used for the image reconstruction. The DOT algorithm is based on the techniques of inverse problems. The radiative transfer equation accurately describes photon propagation in biological tissue, while, because of its high computation load, the diffusion equation (DE) is often used as the forward model. However, the DE is invalid in low-scattering and/or highly absorbing regions and in the vicinity of light sources. The inverse problem is inherently ill-posed and highly undetermined. Here, we first summarize NIRS and then describe various approaches in the efforts to develop accurate and efficient DOT algorithms and present some examples of clinical applications. Finally, we discuss the future prospects of DOT.

Spatial distributions of hemoglobin signals from superficial layers in the forehead during a verbal-fluency task.

Functional near-infrared spectroscopy (fNIRS) signals originate in hemoglobin changes in both the superficial layer of the head and the brain. Under the assumption that the changes in the blood flow in the scalp are spatially homogeneous in the region of interest, a variety of methods for reducing the superficial signals has been proposed. To clarify the spatial distributions of the superficial signals, the superficial signals from the forehead during a verbal-fluency task were investigated by using ten source­detector pairs separated by 5 mm, whereas fNIRS signals were also detected from two source­detector pairs separated by 30 mm. The fNIRS signals strongly correlated with the superficial signals at some channels on the forehead. Hierarchical cluster analysis was performed on the temporal cross-correlation coefficients for two channels of both the NIRS signals, and the analysis results demonstrate spatially heterogeneous distributions and network structures of the superficial signals from within the forehead. The results also show that the assumption stated above is invalid for homogeneous superficial signals from any region of interest of 15-mm diameter or larger on the forehead. They also suggest that the spatially heterogeneous distributions may be attributable to vascular networks, including supraorbital, supratrochlear, and superficial temporal vessels.

Right ventrolateral prefrontal cortex involvement in the integration of emotional processing: Parametric mediation analysis of fMRI.

Emotion plays an important role in goal-directed behavior. Although numerous neuroimaging studies have been conducted, the neural mechanisms behind emotion generation and regulation are still elusive. This is partly explained by large individual variations in emotional responses in addition to the fact that emotion is a complex process. The present functional magnetic resonance imaging study aimed firstly to specify valence-dependent brain activation, and secondly to clarify the interactions between the regions underlying emotional processing. We measured brain activation in 12 healthy adults while passively viewing affective pictures. The individual valence ratings were negatively correlated with activation in the frontal, parietal, occipital lobes, and in the subcortical regions including the amygdalae. The parametric mediation analysis performed on these regions showed that the right ventrolateral prefrontal cortex (Brodmann area 47) was main mediator of the valence ratings with other regions. Interestingly, there was no mediator region for the ventrolateral prefrontal cortex. These results indicated the possibility that the right ventrolateral prefrontal cortex mainly participated in the integration of visually induced emotional processes in the valence dimension.

Characterization of a time-resolved non-contact scanning diffuse optical imaging system exploiting fast-gated single-photon avalanche diode detection.

We present a system for non-contact time-resolved diffuse reflectance imaging, based on small source-detector distance and high dynamic range measurements utilizing a fast-gated single-photon avalanche diode. The system is suitable for imaging of diffusive media without any contact with the sample and with a spatial resolution of about 1 cm at 1 cm depth. In order to objectively assess its performances, we adopted two standardized protocols developed for time-domain brain imagers. The related tests included the recording of the instrument response function of the setup and the responsivity of its detection system. Moreover, by using liquid turbid phantoms with absorbing inclusions, depth-dependent contrast and contrast-to-noise ratio as well as lateral spatial resolution were measured. To illustrate the potentialities of the novel approach, the characteristics of the non-contact system are discussed and compared to those of a fiber-based brain imager.

Roadmap on neurophotonics.

Mechanistic understanding of how the brain gives rise to complex behavioral and cognitive functions is one of science's grand challenges. The technical challenges that we face as we attempt to gain a systems-level understanding of the brain are manifold. The brain's structural complexity requires us to push the limit of imaging resolution and depth, while being able to cover large areas, resulting in enormous data acquisition and processing needs. Furthermore, it is necessary to detect functional activities and 'map' them onto the structural features. The functional activity occurs at multiple levels, using electrical and chemical signals. Certain electrical signals are only decipherable with sub-millisecond timescale resolution, while other modes of signals occur in minutes to hours. For these reasons, there is a wide consensus that new tools are necessary to undertake this daunting task. Optical techniques, due to their versatile and scalable nature, have great potentials to answer these challenges. Optical microscopy can now image beyond the diffraction limit, record multiple types of brain activity, and trace structural features across large areas of tissue. Genetically encoded molecular tools opened doors to controlling and detecting neural activity using light in specific cell types within the intact brain. Novel sample preparation methods that reduce light scattering have been developed, allowing whole brain imaging in rodent models. Adaptive optical methods have the potential to resolve images from deep brain regions. In this roadmap article, we showcase a few major advances in this area, survey the current challenges, and identify potential future needs that may be used as a guideline for the next steps to be taken.

Attention induces reciprocal activity in the human somatosensory cortex enhancing relevant- and suppressing irrelevant inputs from fingers.

OBJECTIVE: We studied whether attention regulates information processing in the human primary somatosensory cortex (SI) by selective enhancement of relevant- and suppression of irrelevant information. METHODS: Under successive and simultaneous electric stimuli to both the right index and middle fingers, tactile stimuli were randomly (20%) presented on one of the two fingers in separate two runs exchanging the finger. Subjects were requested to discriminate the tactile stimuli in an attention task to induce attention to one finger and to ignore the stimuli in a control task to avoid such an attention focus. Somatosensory evoked magnetic fields were measured only for the two-finger electric stimulation and an early component (M50) was analyzed. RESULTS: In spite of the two-finger simultaneous stimulation, attention to either the index or middle finger lowered or heightened the M50-sourse location, respectively. The attention task did not increase the M50 amplitude. CONCLUSIONS: Attention to a finger enhanced selectively the representation of the finger in the SI cortex. However, this SI activity did not increase the M50 amplitude, suggesting that the attention suppressed another finger region receiving the unattended inputs. SIGNIFICANCE: Attention regulates the SI activity by selectively enhancing the task-relevant information and by filtering out other noise inputs.