Stopwatch training improves cognitive functions in patients with Parkinson's disease.

Parkinson's disease (PD) impairs various cognitive functions, including time perception. Dysfunctional time perception in PD is poorly understood, and no study has investigated the rehabilitation of time perception in patients with PD. We aimed to induce the recovery of time perception in PD patients and investigated the potential relationship between recovery and cognitive functions/domains other than time perception. Sixty patients with PD (27 females) and 20 healthy controls (10 females) were recruited. The participants underwent a feedback training protocol for 4 weeks to improve the accuracy of subjective spatial distance or time duration using a ruler or stopwatch, respectively. They participated in three tests at weekly intervals, each comprising 10 types of cognitive tasks and assessments. After duration feedback training for 1 month, performance on the Go/No-go task, Stroop task, and impulsivity assessment improved in patients with PD, while no effect was observed after distance feedback training. Additionally, the effect of training on duration production correlated with extended reaction time and improved accuracy in the Go/No-go and Stroop tasks. These findings suggest that time perception is functionally linked to inhibitory systems. If the feedback training protocol can modulate and maintain time perception, it may improve various cognitive/psychiatric functions in patients with PD. It may also be useful in the treatment of diseases other than PD that cause dysfunctions in temporal processing.

Cascade process mediated by left hippocampus and left superior frontal gyrus affects relationship between aging and cognitive dysfunction.

BACKGROUND: Cognitive function declines with age and has been shown to be associated with atrophy in some brain regions, including the prefrontal cortex. However, the details of the relationship between aging and cognitive dysfunction are not well understood. METHODS: Across a wide range of ages (24- to 85-years-old), this research measured the gray matter volume of structural magnetic resonance imaging data in 39 participants, while some brain regions were set as mediator variables to assess the cascade process between aging and cognitive dysfunction in a path analysis. RESULTS: Path analysis showed that age affected the left hippocampus, thereby directly affecting the left superior frontal gyrus. Furthermore, the gyrus directly affected higher order flexibility and maintenance abilities calculated as in the Wisconsin card sorting test, and the two abilities affected the assessment of general cognitive function. CONCLUSION: Our finding suggests that a cascade process mediated by the left hippocampus and left superior frontal gyrus is involved in the relationship between aging and cognitive dysfunction.

Olfactory deficits in individuals at risk for psychosis and patients with schizophrenia: relationship with socio-cognitive functions and symptom severity.

Odor identification deficits are well documented in patients with schizophrenia, but it remains unclear whether individuals at clinical high-risk for psychosis exhibit similar changes and whether their olfactory function is related to social/cognitive functions and symptomatology. In this study, we investigated odor detection sensitivity and identification ability in 32 individuals with at-risk mental state (ARMS), 59 schizophrenia patients, and 169 healthy controls using a T&T olfactometer. The ARMS and schizophrenia subjects were administered the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS) to assess their cognitive and social functions, and the Positive and Negative Syndrome Scale (PANSS) for clinical symptoms. Both the ARMS and schizophrenia subjects had lower odor identification ability when compared with healthy controls, while no significant difference was found in the odor detection sensitivity. The lower odor identification ability in the ARMS group correlated with the severity of negative symptoms and weakly correlated with lower performance on the BACS verbal fluency test. The olfactory measures of schizophrenia patients did not correlate with illness duration, medication, symptom severity, and social and cognitive functions. For the ARMS and schizophrenia groups, the olfactory measures did not correlate with the SOFAS and SCoRS scores. These findings suggest that high-risk subjects for psychosis already show odor identification deficits similar to those observed in schizophrenia patients, which probably reflect a biological trait related to vulnerability to psychosis.

Possible relation between olfaction and anxiety in healthy subjects.

AIMS: While olfaction is a sense closely associated with the limbic system and emotions, the relation between emotional status and olfactory functioning has not been well documented. This study aimed to examine the possible effect of anxiety on olfaction in healthy subjects. METHODS: We investigated the effect of state and trait anxiety on the detection and recognition thresholds for five different odors in 124 healthy subjects (62 men and 62 women, mean age = 27.2 years) using a T&T olfactometer. RESULTS: While the influences of age, socioeconomic status, IQ, and smoking history on olfaction were not significant, women had a lower recognition threshold for the odor of sweet fruit and a higher detection threshold for that of rotten food as compared with men. Both state and trait anxiety ratings were significantly associated with reduced olfactory ability, especially for identification of rose odor. CONCLUSIONS: These findings suggest that emotional status affects olfactory functioning in healthy subjects. Our findings may also partly explain the mild olfactory impairment reported in clinical conditions, such as anxiety disorders.

The right amygdala and migraine: Analyzing volume reduction and its relationship with symptom severity.

This study aimed to explore the relationship between gray matter volume changes and various clinical parameters in patients with migraine, focusing on symptom severity, quality of life, and states of depression and anxiety. Using a case-control design, we examined 33 patients with migraine, with or without aura, and 27 age-matched healthy subjects. We used magnetic resonance imaging to assess the volumes of 140 bilateral brain regions. Clinical evaluations included the Migraine Disability Assessment, the Migraine Specific Quality of Life Questionnaire, the Center for Epidemiologic Studies Depression scale, Spielberger's State and Trait Anxiety scales, and the Japanese version of the Montreal Cognitive Assessment. We compared the scores of these measures between migraine patients and healthy controls to examine the interplay between brain structure and clinical symptoms. Significant volumetric differences were observed in the pallidum and amygdala between migraine patients and healthy individuals. The reduction in the right amygdala volume correlated significantly with migraine severity as measured by the Migraine Disability Assessment. Path analysis revealed a model where Migraine Disability Assessment scores were influenced by Migraine Specific Quality of Life Questionnaire outcomes, which were further affected by depression, anxiety, and a low right pallidum volume. Our findings suggest that the chronicity and severity of migraine headaches specifically affect the right amygdala. Our path model suggests a complex relationship whereby migraine disability is strongly influenced by quality of life, which is, in turn, affected by psychological states, such as anxiety and depression.

Respiratory rhythm affects recalibration of body ownership.

Change in body perception requires recalibration of various sensory inputs. However, it is less known how information other than sensations relates to the recalibration of body perception. Here, we focused on the relationship between respiration and cognition and investigated whether respiratory rhythms are related to the recalibration of hand perception. We built a visual feedback environment, in which a mannequin hand moved in conjunction with its own respiratory rhythm, and participants performed an experiment under conditions in congruency/incongruency for spatial and temporal factors. The temporal and spatial congruency between own respiratory rhythm and the mannequin hand markedly facilitated the phenomenon of hand ownership sense transfer to the mannequin hand, while incongruency had little effect on the change in hand ownership. The finding suggests that an internal model in the brain allows respiratory rhythms to be involved in the adaptation of the body's neural representations.

Preoperative state anxiety predicts postoperative health-related quality of life: A prospective observational study on patients undergoing lung cancer surgery.

Objective: Improving quality of life (QOL) after surgery is very important. Recently, preoperative anxiety has been suggested to predict postoperative health-related (HR) QOL, however the accuracy of anxiety measurement remains problematic. We examined the relationship between preoperative anxiety level and postoperative HRQOL using qualitative and quantitative assessment of anxiety. Method: We used a detailed anxiety assessment to quantitatively investigate preoperative anxiety as a predictor of postoperative HRQOL in lung cancer patients. Fifty one patients who underwent surgery for lung cancer were included. They were assessed four times: on admission, on discharge, 1 month after surgery, and 3 months after surgery. Anxiety was measured separately as "state anxiety" and "trait anxiety" using the State-Trait Anxiety Inventory, and HRQOL was measured using the EuroQol 5 dimension 5-level. Results: The HRQOL decreased at discharge and gradually recovered over time, reaching the same level at 3 months after surgery as at admission. HRQOL score was lower at discharge than at pre-surgery and 3 months after the surgery (p < 0.0001 each), and the score at 1 month after the surgery was lower than at pre-surgery (p = 0.007). In addition, multiple regression analysis showed that HRQOL at discharge was associated with "state anxiety" rather than "trait anxiety" at admission (p = 0.004). Conclusion: This study identifies the types of anxiety that affect postoperative HRQOL. We suggest that postoperative HRQOL on discharge may be improved by interventions such as psychological or medication treatment for preoperative state anxiety if identified preoperative state anxiety can be managed appropriately.

Role of the amygdala-medial orbitofrontal relationship in odor recognition in the elderly.

INTRODUCTION: In patients with mild cognitive impairment, pathological changes begin in the amygdala (AMG) and hippocampus (HI), especially in the parahippocampal gyrus and entorhinal cortex (ENT). These areas play an important role in olfactory detection and recognition. It is important to understand how subtle signs of olfactory disability relate to the functions of the above-mentioned regions, as well as the orbitofrontal cortex (OFC). In this study, we evaluated brain activation using functional magnetic resonance imaging (fMRI), performed during the presentation of olfactory stimuli (classified as "normal odors" not inducing memory retrieval), and investigated the relationships of the blood oxygen level-dependent (BOLD) signal with olfactory detection and recognition abilities in healthy elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent fMRI during olfaction, and raw mean BOLD signals were extracted from regions of interest, including bilateral regions (AMG, HI, parahippocampus, and ENT) and orbitofrontal subregions (frontal inferior OFC, frontal medial OFC, frontal middle OFC, and frontal superior OFC). Multiple regression and path analyses were conducted to understand the roles of these areas in olfactory detection and recognition. RESULTS: Activation of the left AMG had the greatest impact on olfactory detection and recognition, while the ENT, parahippocampus, and HI acted as a support system for AMG activation. Less activation of the right frontal medial OFC was associated with good olfactory recognition. These findings improve our understanding of the roles of limbic and prefrontal regions in olfactory awareness and identification in elderly individuals. CONCLUSION: Functional decline of the ENT and parahippocampus crucially impacts olfactory recognition. However, AMG function may compensate for deficits through connections with frontal regions.

Slow breathing and emotions associated with odor-induced autobiographical memories.

An important feature of olfactory perception is its dependence on respiratory activity. By inspiration, olfactory information ascends directly to olfactory-related limbic structures. Therefore, every breath with odor molecules activates these limbic areas associated with emotional experience and memory retrieval. We tested whether odors associated with autobiographical memories can trigger pleasant emotional experiences and whether respiration changes during stimulation with these odors. During presentation of odors related to autobiographical memories and control odors, we measured minute ventilation, tidal volume, respiratory frequency, O2 consumption, and end tidal CO2 concentration. Findings showed that autobiographical memory retrieval was associated with increasing tidal volume and decreasing respiratory frequency more than during presentation of control odors. Subjective feelings such as emotional arousal during retrieval of the memory, arousal level of the memory itself, or pleasantness and familiarity toward the odor evoked by autobiographical memory were more specific emotional responses compared with those related to control odors. In addition, high trait anxiety subjects responded with a stronger feeling of being taken back in time and had high arousal levels with tidal volume increases. We discussed assumptions regarding how deep and slow breathing is related to pleasantness and comfortableness of an autobiographical memory.

Neuropsychological and radiological assessments of two cases with apparent idiopathic rapid eye movement sleep behaviour disorder.

We examined two male patients (64 and 70 years old) with rapid eye movement sleep behaviour disorder (RBD) using cognitive tests, myocardial (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, and dopamine positron emission tomography (PET) imaging. One patient had impaired social cognition and decision-making skills and reduced MIBG reuptake, and dopamine PET imaging indicated striatal terminal loss. The other patient had normal social cognition and reduced MIBG reuptake, but no abnormalities were detected by dopamine PET imaging. Both patients reported constipation. This study supports the hypothesis by Braak et al. [Mov Disord 2006;21:2042-2051] that impairment of the amygdala and striatum occurs at the same stage as α-synucleinopathy, and the findings suggest that autonomic dysfunctions such as reduced MIBG reuptake and constipation are the earliest symptoms of RBD. Detailed neuropsychological and radiological assessments of these 2 cases revealed that idiopathic RBD could develop in various clinical situations and include cognitive and autonomic changes. Further longitudinal studies with larger sample sizes will help understand the neuropsychology and pathophysiology of RBD.

New granule cells in the olfactory bulb are associated with high respiratory input in an enriched odor environment.

New neurons are constantly generated in the olfactory bulb and the dentate gyrus of the hippocampus. The number of new cells depends on sensory experiences; an enriched odor environment increases neurogenesis and neural survival. The aim of this study was to investigate whether enriched olfactory stimuli affect neurogenesis of mitral and granule cells of the olfactory bulb and dentate gyrus, and whether respiratory activity accompanied by olfactory stimuli is associated with new cells in these regions. To this end, respiratory activity during enriched odor stimuli was continuously measured in mice and new cells were stained with 5-bromo-2'-deoxyuridine, which selectively labels proliferating cells. An enriched olfactory environment significantly increased neurogenesis of mitral and granule cells in the olfactory bulb, but not in the dentate gyrus. Additionally, an increase of new granule cells under the enriched odor condition was correlated to sniffing frequency power, which had a significantly different pattern from the no-odor condition. A high respiratory frequency with frequent odor stimuli may be associated with activation of granule cells to form inhibitory neurons and this active state might increase granule cell neurogenesis.

Reading on a smartphone affects sigh generation, brain activity, and comprehension.

Electronic devices have become an indispensable part of our daily lives, while their negative aspects have been reported. One disadvantage is that reading comprehension is reduced when reading from an electronic device; the cause of this deficit in performance is unclear. In this study, we investigated the cause for comprehension decline when reading on a smartphone by simultaneously measuring respiration and brain activity during reading in 34 healthy individuals. We found that, compared to reading on a paper medium, reading on a smartphone elicits fewer sighs, promotes brain overactivity in the prefrontal cortex, and results in reduced comprehension. Furthermore, reading on a smartphone affected sigh frequency but not normal breathing, suggesting that normal breathing and sigh generation are mediated by pathways differentially influenced by the visual environment. A path analysis suggests that the interactive relationship between sigh inhibition and overactivity in the prefrontal cortex causes comprehension decline. These findings provide new insight into the respiration-mediated mechanisms of cognitive function.

Entorhinal cortex and parahippocampus volume reductions impact olfactory decline in aged subjects.

INTRODUCTION: Pathological abnormalities first appear in the medial temporal regions including entorhinal cortex and parahippocampus in patients with Alzheimer's disease. Previous studies showed that olfactory decline in elderly subjects was associated with volume reductions in the left hippocampus and left parahippocampus without cognitive impairment. The aim of this study is to investigate the link between olfaction and volume reductions in the medial temporal regions including the parahippocampus, entorhinal cortex, and hippocampal subfields. METHOD: 27 elderly subjects and 27 young controls were measured olfaction acuity, cognitive function, and structural magnetic resonance imaging. Image processing and gray matter volumetric segmentation were performed with FreeSurfer. Volume data were analyzed with SPSS Statistics software. RESULTS: Interesting results of this study were that volume reduction in the entorhinal cortex was not directly linked with declining olfactory ability. Volume reduction in the left entorhinal cortex was correlated with volume reduction in the left parahippocampus and dentate gyrus. However, left parahippocampus volume reduction had the greatest impact on olfactory decline, and the entorhinal cortex and dentate gyrus might additionally contribute to olfactory decline. CONCLUSION: Our results indicate that olfactory decline may be directly reflected in the medial temporal regions as reduced parahippocampus volumes, rather than as morphological changes in the entorhinal cortex and hippocampus. The parahippocampus may play an important role in the association between memory retrieval and olfactory identification.

Volume of the right supramarginal gyrus is associated with a maintenance of emotion recognition ability.

Emotion recognition is known to change with age, but associations between the change and brain atrophy are not well understood. In the current study atrophied brain regions associated with emotion recognition were investigated in elderly and younger participants. Group comparison showed no difference in emotion recognition score, while the score was associated with years of education, not age. We measured the gray matter volume of 18 regions of interest including the bilateral precuneus, supramarginal gyrus, orbital gyrus, straight gyrus, superior temporal sulcus, inferior frontal gyrus, insular cortex, amygdala, and hippocampus, which have been associated with social function and emotion recognition. Brain reductions were observed in elderly group except left inferior frontal gyrus, left straight gyrus, right orbital gyrus, right inferior frontal gyrus, and right supramarginal gyrus. Path analysis was performed using the following variables: age, years of education, emotion recognition score, and the 5 regions that were not different between the groups. The analysis revealed that years of education were associated with volumes of the right orbital gyrus, right inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the right supramarginal gyrus volume was associated with the emotion recognition score. These results suggest that the amount of education received contributes to maintain the right supramarginal gyrus volume, and indirectly affects emotion recognition ability.

Odors Associated With Autobiographical Memory Induce Visual Imagination of Emotional Scenes as Well as Orbitofrontal-Fusiform Activation.

Specific odors can induce memories of the past, especially those associated with autobiographical and episodic memory. Odors associated with autobiographical memories have been found to elicit stronger activation in the orbitofrontal cortex, hippocampus, and parahippocampus compared with odors not linked to personal memories. Here, we examined whether continuous odor stimuli associated with autobiographical memories could activate the above olfactory areas in older adults and speculated regarding whether this odor stimulation could have a protective effect against age-related cognitive decline. Specifically, we used functional magnetic resonance imaging to investigate the relationship between blood oxygen levels in olfactory regions and odor-induced subjective memory retrieval and emotions associated with autobiographical memory in older adults. In our group of healthy older adults, the tested odors induced autobiographical memories that were accompanied by increasing levels of retrieval and the feeling of being "brought back in time." The strength of the subjective feelings, including vividness of the memory and degree of comfort, impacted activation of the left fusiform gyrus and left posterior orbitofrontal cortex. Further, our path model suggested that the strength of memory retrieval and of the emotions induced by odor-evoked autobiographical memories directly influenced neural changes in the left fusiform gyrus, and impacted left posterior orbitofrontal cortex activation through the left fusiform response.

Respiratory response toward olfactory stimuli might be an index for odor-induced emotion and recognition.

Olfaction is a unique sensory modality. Odor molecules reach olfactory receptors by inspiration, and odor information projects directly to limbic structures not through the thalamus. Odor stimuli thus induce respiratory changes, and simultaneously induce emotion and memory recognition via stimulation of olfactory-related limbic structures. We review the relations between respiration and olfaction, and between brain rhythm and respiration from our studies in normal subjects and in patients with Parkinson's disease who had been reported to have olfactory impairment.

Heart Rate and Respiration Affect the Functional Connectivity of Default Mode Network in Resting-State Functional Magnetic Resonance Imaging.

A growing number of brain imaging studies show functional connectivity (FC) between regions during emotional and cognitive tasks in humans. However, emotions are accompanied by changes in physiological parameters such as heart rate and respiration. These changes may affect blood oxygen level-dependent signals, as well as connectivity between brain areas. This study aimed to clarify the effects of physiological noise on the connectivity between areas related to the default mode network using resting-state functional magnetic resonance imaging (rs-fMRI). Healthy adult volunteers (age range: 19-51 years, mean age: 26.9 ± 9.1 years, 8 males and 8 females) underwent rs-fMRI for 10 min using a clinical 3T scanner (MAGNETOM Trio A Tim System, Siemens) with simultaneously recorded respiration and cardiac output. Physiological noise signals were subsequently removed from the acquired fMRI data using the DRIFTER toolbox. Image processing and analysis of the FC between areas related to the default mode network were performed using DPARSF. Network-Based Statistic (NBS) analysis of the functional connectome of the DMN and DMN-related area was used to perform three groups of comparison: without physiological noise correction, with cardiac noise correction, and with cardiac and respiratory noise correction. NBS analysis identified 36 networks with significant differences in three conditions in FC matrices. Post hoc comparison showed no differences between the three conditions, indicating that all three had the same networks. Among the 36 networks, strength of FC of 8 networks was modified under physiological noise correction. Connectivity between left and right anterior medial frontal regions increased strength of connectivity. These areas are located on the medial cerebral hemisphere, close to the sagittal sinus and arteries in the cerebral hemispheres, suggesting that medial frontal areas may be sensitive to cardiac rhythm close to arteries. The other networks observed temporal regions and showed a decrease in their connectivity strength by removing physiological noise, indicating that physiological noise, especially respiration, may be sensitive to BOLD signal in the temporal regions during resting state. Temporal lobe was highly correlated with anxiety-related respiration changes (Masaoka and Homma, 2000), speech processing, and respiratory sensation. These factors may affect the rs-fMRI signaling sensitivity.

Hippocampus and Parahippocampus Volume Reduction Associated With Impaired Olfactory Abilities in Subjects Without Evidence of Cognitive Decline.

The aim of this study was to investigate the relationship between olfactory recognition and morphological changes in olfactory brain regions including the amygdala, hippocampus, rectus, parahippocampus, orbitofrontal cortex, and medial frontal cortex in 27 elderly subjects and 27 younger healthy controls. The specific aim of the study was to determine which brain areas are associated with the initial decline of olfaction in elderly subjects, which occurs before the onset of dementia. All subjects underwent magnetic resonance imaging to measure anatomical brain volume and cortical thickness, and subjects were assessed using tests of olfactory acuity and cognitive function measured with the Montreal Cognitive Assessment. Overall brain volume reductions were observed in elderly subjects compared with young healthy controls, but only reduction in the volume of the left hippocampus was associated with decreased olfactory ability. The parahippocampus of elderly subjects was not different from that of controls; the extent of the reduction of parahippocampus volume varied among individuals, and reduction in this region was associated with olfactory decline. Similarly, parahippocampus thinning was associated with decreased olfactory function. The path analysis showed direct and indirect effects of hippocampus and parahippocampus volume on olfactory ability and that volume reductions in these areas were not associated with cognitive function. Parahippocampus volume reduction and thinning exhibited individual variation; this may be the first appearance of pathological changes and may lead to dysfunction in the connection of olfactory memory to the neocortex. Parahippocampus change may reflect the first sign of olfactory impairment prior to pathological changes in the hippocampus, amygdala and orbitofrontal cortex.

Impaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?

Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution.

Association between olfactory sulcus morphology and olfactory functioning in schizophrenia and psychosis high-risk status.

Olfactory impairment has been reported in patients with schizophrenia and individuals with a high risk of psychosis, but its neural basis is largely unknown. We used magnetic resonance imaging to investigate the morphology of the olfactory sulcus (an indicator of olfactory system development) and its relation to olfactory function in 38 persons with an at-risk mental state (ARMS), 62 patients with schizophrenia, and 61 healthy controls. Odor detection and identification were examined with a T & T olfactometer. Compared with the controls, the olfactory sulcus was significantly shallower and odor identification was inferior among the ARMS and schizophrenia subjects. Across all subjects, but not within each group, the olfactory sulcus depth was significantly related to better identification of odors. Our results support the concept that olfactory sulcus morphology reflects the neurodevelopmental process of the olfactory system.