Identification of sulfonylpyrimidines as novel selective aldosterone synthase (CYP11B2) inhibitors.

4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro.

[Cortical Midline Structures: "Self" and "Pain"].

Emerging evidence indicates that cortical midline structures (CMS) (which consist of the orbitomedial prefrontal cortex (OMPFC), dorsomedial prefrontal cortex (DMPFC), anterior cingulate cortex (ACC), and precuneus/posterior cingulate cortex (pC/PCC)) have a critical role in generating a model of the self. These regions also serve as hub regions for the default mode network (DMN) or salience network (SN). Furthermore, regions of the CMS overlap with pain-related regions such as the so-called "pain matrix," suggesting that pain has unique attributes compared to other sensations like vision. Previous studies have reported that disturbances of the CMS relate to chronic pain, as well as neurological and psychiatric diseases. The considerable overlap between regions involved in pain and those involved in self-cognition may provide important insights not only into the pathology of chronic pain and cognitive aspects of pain, but also for understanding self-representation in the brain.

4-Anilino-pyrimidine, novel aldosterone synthase (CYP11B2) inhibitors bearing pyrimidine structures.

2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range.

A novel aldosterone synthase inhibitor ameliorates mortality in pressure-overload mice with heart failure.

It has been elucidated that mineralocorticoid receptor antagonists reduce mortality in patients with congestive heart failure and post-acute myocardial infarction. A direct inhibition of aldosterone synthase (CYP11B2) is also expected to have therapeutic benefits equal in quality to mineralocorticoid receptor antagonists in terms of reducing mineralocorticoid receptor signaling. Therefore, we have screened our chemical libraries and identified a novel and potent aldosterone synthase inhibitor, 2,2,2-trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-y}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol (compound 1), by lead optimization. Pharmacological properties of compound 1 were examined in in vitro cell-based assays and an in vivo mouse model of pressure-overload hypertrophy by transverse aortic constriction (TAC). Compound 1 showed potent CYP11B2 inhibition against human and mouse enzymes (IC50; 0.003µM and 0.096µM, respectively) in a cell-based assay. The oral administration of 0.06% compound 1 in the food mixture of a mouse TAC model significantly reduced the plasma aldosterone level and ameliorated mortality rate. This study is the first to demonstrate that a CYP11B2 inhibitor improved survival rates of heart failure induced by pressure-overload in mice. The treatment of 0.06% compound 1 did not elevate plasma potassium level in this model, although further evaluation of hyperkalemia is needed. These results suggest that compound 1 can be developed as a promising oral CYP11B2 inhibitor for pharmaceutical applications. Compound 1 could also be a useful compound for clarifying the role of aldosterone in cardiac hypertrophy.

Internally-represented space and its mirror-reversed image of the visuospatial representation: A possible association.

The cognitive capacity for number representation is thought to be a functional isomorphism of space representation. Numbers are represented in a left-to-right-oriented mental number line and hemispatial neglect patients consistently demonstrate rightward midline shift of visuospace, the internal space and number representation. However, patients with pathologic pain in one limb showed a negative correlation between midline shift of the visuospace and number representation. The purpose of the present study is to ascertain whether such dissociation in accessing space and number representation is observed in another neuropathic pain condition, and then to propose a theoretical model regarding an intimate relationship between visuospace and internal space representations. Using patients with deafferentation pain caused by a nerve lesion in a limb, we investigated whether number representation is closely linked to space representation by evaluating visual subjective body-midline judgments in dark and light conditions (egocentric- and allocentric-spaces, respectively). We also used a number-interval-bisection task to analyze this question. All of the patients perceived allocentric-space accurately. Respective patients showed perceptual shifts in egocentric-space and number representation, however they did not demonstrate any trend of the shifted-direction. Direct comparison revealed that number representation is negatively correlated with not allocentric-space but egocentric-space: a leftward midline-shift of egocentric-space was linked with a rightward midline-shift of number bisection, and vice-versa. Internally-represented space demonstrated a mirror-reversed image of the visuospatial representation, similar to our previous finding. To explain the inverted representation, we can propose a theoretical model that spacing between mentally-aligned numbers in a left-to-right sequential line is anisometric.

Spinal cord stimulation ameliorates neuropathic pain-related sleep disorders: a case series.

OBJECTIVE: Although sleep disorder is one of the most serious comorbidities of refractory chronic pain, it is usually assessed only from the patients' subjective point of view. Therefore, we aimed to objectively evaluate the sleep efficiency of patients with chronic pain. METHODS: Using an actigraph, a highly sensitive accelerometer, we assessed the sleep efficiency of six patients with chronic pain before and after the introduction of spinal cord stimulation (SCS). RESULTS: While pain improved in only five out of six patients after SCS, sleep efficiency improved in all cases. Interestingly, in one case, sleep efficiency improved even though pain intensity remained unchanged. CONCLUSION: With the use of an actigraph, improvements in sleep of patients with chronic pain undergoing SCS were demonstrated. One case showing improvement in sleep despite pain palliation may suggest that SCS might have independently affected the sleep system, although further studies are necessary.

Dissociation in accessing space and number representations in pathologic pain patients.

Space is represented by integrating egocentric and allocentric reference frames; however, little is known about the role of these independent reference frames in number representation. Using patients with unilateral pathologic pain in one limb, we investigated whether number representation is closely linked to space representation by evaluating visual subjective body-midline judgments in dark and light conditions (egocentric and allocentric space, respectively). To evaluate the number representation, pairs of numbers were read aloud to the participant, who was then asked to state the midpoint number that they intuitively perceived to be at the middle of each interval. All of the patients perceived allocentric space accurately in the light condition. However, each of the patients showed perceptual shifts in egocentric space and number representation in the dark as compared with control subjects. Direct comparison showed a consistent relationship between number representation and egocentric space. We suggest that numbers are represented spatially by integrating these independent reference frames.

fMRI evidence of improved visual function in patients with progressive retinitis pigmentosa by eye-movement training.

To evaluate changes in the visual processing of patients with progressive retinitis pigmentosa (RP) who acquired improved reading capability by eye-movement training (EMT), we performed functional magnetic resonance imaging (fMRI) before and after EMT. Six patients with bilateral concentric contraction caused by pigmentary degeneration of the retina and 6 normal volunteers were recruited. Patients were given EMT for 5 min every day for 8-10 months. fMRI data were acquired on a 3.0-Tesla scanner while subjects were performing reading tasks. In separate experiments (before fMRI scanning), visual performances for readings were measured by the number of letters read correctly in 5 min. Before EMT, activation areas of the primary visual cortex of patients were 48.8% of those of the controls. The number of letters read correctly in 5 min was 36.6% of those by the normal volunteers. After EMT, the activation areas of patients were not changed or slightly decreased; however, reading performance increased in 5 of 6 patients, which was 46.6% of that of the normal volunteers (p< 0.05). After EMT, increased activity was observed in the frontal eye fields (FEFs) of all patients; however, increases in the activity of the parietal eye fields (PEFs) were observed only in patients who showed greater improvement in reading capability. The improvement in reading ability of the patients after EMT is regarded as an effect of the increased activity of FEF and PEF, which play important roles in attention and working memory as well as the regulation of eye movements.

Network-dependent modulation of brain activity during sleep.

Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy model to brain activity obtained by functional magnetic resonance imaging from sleeping healthy subjects. We found that the brain activity of individual brain regions and functional interactions between pairs of regions significantly increased in the default-mode network during SWS and decreased during REM sleep. In contrast, the network activity of the fronto-parietal and sensory-motor networks showed the opposite pattern. Furthermore, in the three networks, the amount of the activity changes throughout REM sleep was negatively correlated with that throughout SWS. The present findings suggest that the brain activity is dynamically modulated even in a sleep stage and that the pattern of modulation depends on the type of the large-scale brain networks.

Efficiency of a "small-world" brain network depends on consciousness level: a resting-state FMRI study.

It has been revealed that spontaneous coherent brain activity during rest, measured by functional magnetic resonance imaging (fMRI), self-organizes a "small-world" network by which the human brain could sustain higher communication efficiency across global brain regions with lower energy consumption. However, the state-dependent dynamics of the network, especially the dependency on the conscious state, remain poorly understood. In this study, we conducted simultaneous electroencephalographic recording with resting-state fMRI to explore whether functional network organization reflects differences in the conscious state between an awake state and stage 1 sleep. We then evaluated whole-brain functional network properties with fine spatial resolution (3781 regions of interest) using graph theoretical analysis. We found that the efficiency of the functional network evaluated by path length decreased not only at the global level, but also in several specific regions depending on the conscious state. Furthermore, almost two-thirds of nodes that showed a significant decrease in nodal efficiency during stage 1 sleep were categorized as the default-mode network. These results suggest that brain functional network organizations are dynamically optimized for a higher level of information integration in the fully conscious awake state, and that the default-mode network plays a pivotal role in information integration for maintaining conscious awareness.

[Pharmacological treatment strategy and mirror visual feedback treatment for neuropathic pain].

Neuropathic pain is a debilitating condition, and pharmacotherapy is the most established treatment strategy. A variety of pharmacotherapies is used for neuropathic pain management: however, pharmacotherapies with evidence for analgesic potency are less common. Several pharmacotherapeutic treatment guidelines for neuropathic pain treatment recommend the first- to third-line drugs on the basis of evidence-based medicine; however, neuropathic pain is often resistant to pharmacotherapies. We have treated pharmacotherapy-resistant neuropathic pain with neurorehabilitation techniques such as mirror visual feedback (MVF) treatment. Further to our clinical experience using MVF, we discuss the cerebral mechanism associated with neuropathic pain in this study.

Distinct role of spatial frequency in dissociative reading of ideograms and phonograms: an fMRI study.

It has been proposed that distinct neural circuits are activated by reading Japanese ideograms (Kanji) and phonograms (Kana). By measuring high-density event-related potentials, we recently reported that spatial frequency (SF) information is responsible for the dissociation between Kanji and Kana reading. In particular, we found close links between Kana and low SF (LSF) information and between Kanji and high SF (HSF) information. However, it remains unclear which brain regions contribute to this dissociation. To determine this, we performed functional magnetic resonance imaging while presenting unfiltered or spatially filtered Kanji and Kana word stimuli to healthy native Japanese subjects. Fourier analysis revealed that Kanji and Kana stimuli were characterized by HSF and LSF information, respectively. When presented with either type of unfiltered stimulus (Kanji or Kana), the bilateral inferior temporal (IT, BA 37) regions were activated compared to the resting condition. Kana but not Kanji reading also activated the bilateral inferior parietal lobules (IPL, BA 40). When we compared Kanji and Kana reading directly, the left IT region was significantly activated by Kanji reading, while significant activation of the left IPL was observed during Kana reading. In response to filtered HSF stimuli, the Kanji reading minus Kana reading comparison revealed significant activation of the left IT region but not the left IPL. Conversely, significant activation of the left IPL but not the left IT region occurred in the Kana reading minus Kanji reading comparison for filtered LSF stimuli. These results suggest that Kanji and Kana engage a relatively overlapping network, within which the left IT is more involved in Kanji processing, while the left IPL contributes more to Kana processing. The preferential engagements of these brain regions could reflect the close links between Kana and LSF information, and between Kanji and HSF information. Therefore, this study provides further evidence that SF contributes to the dissociation between Kanji and Kana reading.

Complex Regional Pain Syndrome Revived by Epileptic Seizure Then Disappeared Soon during Treatment with Regional Intravenous Nerve Blockade: A Case Report.

We present a case of complex regional pain syndrome (CRPS), in which symptoms, including burning pain and severe allodynia, were alleviated by using a regional intravenous nerve blockade (Bier block) combined with physiotherapy, but reappeared following an epileptic seizure. Symptoms disappeared again following control of epileptic discharges, as revealed by single-photon emission computed tomography (SPECT) and electroencephalography (EEG) results. Although systemic toxicity of a local anesthetic applied by Bier block was suspected as a cause of the first seizure, the patient did not present any other toxic symptoms, and seizures repeatedly occurred after Bier block cessation; the patient was then diagnosed as having temporal symptomatic epilepsy. This case suggests that symptoms of CRPS may be sustained by abnormal brain conditions, and our findings contribute to the understanding of how the central nervous system participates in maintaining pain and allodynia associated with CRPS.

Oral Local Anesthesia Successfully Ameliorated Neuropathic Pain in an Upper Limb Suggesting Pain Alleviation through Neural Plasticity within the Central Nervous System: A Case Report.

Neural blockades are considered an alternative to pharmacotherapy for neuropathic pain although these blockades elicit limited effects. We encountered a patient with postbrachial plexus avulsion injury pain, which was refractory to conventional treatments but disappeared temporarily with the administration of the local anesthetic lidocaine around the left mandibular molar tooth during dental treatments. This analgesic effect on neuropathic pain by oral local anesthesia was reproducible. Under conditions of neuropathic pain, cerebral somatotopic reorganization in the sensorimotor cortices of the brain has been observed. Either expansion or shrinkage of the somatotopic representation of a deafferentated body part correlates with the degree of neuropathic pain. In our case, administration of an oral local anesthetic shrank the somatotopic representation of the mouth, which is next to the upper limb representation and thereby expanded the upper limb representation in a normal manner. Consequently, oral local anesthesia improved the pain in the upper limb. This case suggests that pain alleviation through neural plasticity within the brain is related to neural blockade.

Activation in left primary visual cortex representing parafoveal visual field during reading Japanese texts.

Activation in the left primary visual cortex (V1) representing the parafoveal field during text reading has been interpreted as attentional modulation in the process of deciding saccadic target for reading ahead. Kanji words serve the main cue to decide the goal of saccades in Japanese. We aimed to determine the exact location of this modulation in the V1 and to determine whether the area of the modulation changes according to the location where the next Kanji word appears or it is fixed on a certain region in V1. Using functional magnetic resonance imaging, we determined the area in V1 representing each eccentricity on the horizontal meridian of the visual field for each participant. Then we investigated brain activation while they were reading two sets of Japanese texts that scrolled leftward as the participants. In set 1, the distance between the heads of adjacent Kanji words was about 3°. In set 2, the distance was about 5°. From the results of these experiments, we obtained activation amplitude of the area corresponding to each eccentricity. We recorded eye movements simultaneously with the acquisition of fMRI data. The maximum peak of the activation was found in the region representing about 4.5° of eccentricity on the horizontal meridian in the left V1 for each participant. The activation pattern did not essentially differ between the two text conditions, although the location of the saccades made for reading next section of the text corresponds to the head of the next Kanji word. The activation modulation during reading Japanese texts occurs in the parafoveal V1 of the left hemisphere. The attentional modulation did not change with the distance to the next goal of saccade but was fixed on the area representing about 4.5° of eccentricity.

Brain imaging of mechanically induced muscle versus cutaneous pain.

This study aimed to investigate the differences in the brain responses between muscle versus skin pain, both of which were caused by tonic mechanical stimuli. Using local anesthesia (LA), we induced muscle pain without any accompanying cutaneous sensation. Subjects underwent functional magnetic resonance imaging while tonic pressure was applied to the right calf under the following four conditions: (1) non-painful pressure without LA (causing mechanoreceptive skin and muscle stimulation); (2) painful pressure without LA (causing nociceptive skin stimulation and mechanoreceptive skin and muscle stimulation); (3) non-painful pressure with LA (causing mechanoreceptive muscle stimulation); (4) painful pressure with LA (causing nociceptive and mechanoreceptive muscle stimulation). Although there was no brain region specifically activated by nociceptive muscle stimuli, activation in the following regions was observed specifically during nociceptive muscle stimuli: anterior midcingulate cortex, anterior and posterior insular cortex, lentiform nucleus, thalamus, pre-supplementary motor area, dorsolateral prefrontal cortex, and inferior parietal lobule. This indicates that there is no region specific for muscle pain but activation pattern or network specific for muscle pain. Furthermore, secondary somatosensory cortex (S2) was found to be responsive to cutaneous pain, not muscle pain, because S2 was specifically activated by nociceptive cutaneous stimuli.

Connectivity pattern changes in default-mode network with deep non-REM and REM sleep.

Recent studies have compared default-mode network (DMN) connectivity in different arousal levels to investigate the relationship between consciousness and DMN. The comparison between the DMN in rapid eye movement (REM) sleep with that in non-REM (NREM) sleep is useful for revealing the relationship between arousal level and DMN, because the arousal level is at its lowest during deep NREM, while during REM sleep it is as high as wakefulness. Functional magnetic resonance imaging (fMRI) and polysomnogram data were acquired from participants in REM, deep NREM, and light NREM sleep, and the DMN was compared using functional connectivity analysis. Our analysis revealed that functional connectivity among the DMN core regions - the posterior cingulate cortex, rostral anterior cingulate cortex, and inferior parietal lobule - remained consistent across sleep states. In contrast, connectivity involving the DMN subsystems of REM sleep differs from that of NREM sleep, and the change well accounts for the characteristics of REM sleep. Our results suggest that both the DMN core region and subsystems may not relate to the maintenance of arousal. The DMN core network and subsystems may respectively serve to integrate brain regions and perform function specific to each level of arousal.

[Phantom limb pain originates from dysfunction of the primary motor cortex].

Accumulated knowledge indicates that phantom limb pain is a phenomenon of the central nervous system that is related to plastic changes at several levels of the nervous systems. Especially, reports using patients with neuropathic pain clearly indicate the sensorimotor cortex as underlying mechanisms of phantom limb and its pain. Here, we focus the notion that limb amputation or deafferentation results in plasticity of connections between the brain and the body, and that the cortical motor representation of the missing or deafferented limb seemingly disappears. Meanwhile, the sensory representation of the limb does not disappear and thereby patients feel phantom limbs. We propose that dissociation between motor and sensory representations in the primary motor cortex induces pathologic pain and reconcile of sensorimotor integration of the limb would alleviate pain, on the basis of our neurorehabilitation approaches and artificial neuromodulation strategies.

Task-dependent V1 responses in human retinitis pigmentosa.

PURPOSE: During measurement with functional MRI (fMRI) during passive viewing, subjects with macular degeneration (MD) have a large unresponsive lesion projection zone (LPZ) in V1. fMRI responses can be evoked from the LPZ when subjects engage in a stimulus-related task. The authors report fMRI measurements on a different class of subjects, those with retinitis pigmentosa (RP), who have intact foveal vision but peripheral visual field loss. METHODS: The authors measured three RP subjects and two control subjects. fMRI was performed while the subjects viewed drifting contrast pattern stimuli. The subjects passively viewed the stimuli or performed a stimulus-related task. RESULTS: During passive viewing, the BOLD response in the posterior calcarine cortex of all RP subjects was in phase with the stimulus. A bordering, anterior LPZ could be identified by responses that were in opposite phase to the stimulus. When the RP subjects made stimulus-related judgments, however, the LPZ responses changed: the responses modulated in phase with the stimulus and task. In control subjects, the responses in a simulated V1 LPZ were unchanged between the passive and the stimulus-related judgment conditions. CONCLUSIONS: Task-dependent LPZ responses are present in RP subjects, similar to responses measured in MD subjects. The results are consistent with the hypothesis that deleting the retinal input to the LPZ unmasks preexisting extrastriate feedback signals that are present across V1. The authors discuss the implications of this hypothesis for visual therapy designed to replace the missing V1 LPZ inputs and to restore vision.