Hideto Tsuchida

Relationship between limbic and cortical 5-HT neurotransmission and acquisition and reversal learning in a go/no-go task in rats

RationaleSpecific brain structures have been suggested to be involved in impulsive responding assessed by a variety of operant tasks. Central serotonin (5-HT) function has also been widely implicated in impulsivity; however, little research has addressed the regional aspect of 5-HT roles in different impulsive indices of task performance.ObjectiveWe analyzed the relationships between acquisition and reversal learning in a go/no-go task as different behavioral measures of impulsivity and focal concentrations of 5-HT and its metabolites in the brain.Materials and methodsRats administered with parachloroamphetamine (PCA) and vehicle were tested in both acquisition and reversal phases in a go/no-go visual discrimination task. Neurochemical analysis was performed to determine 5-HT concentrations in micropunched brain tissues.ResultsPCA administration induced regionally 5-HT depletion in the brain and impaired learning performance in both tests. For both tests, significant negative correlations between learning performance and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were observed in the medial prefrontal cortex (mPFC) and amygdala (Amyg). In contrast, significant negative correlations between learning performance and 5-HT and 5-HIAA concentrations were observed for the orbitofrontal cortex (OFC) exclusively in the reversal learning phase.ConclusionsThe present data indicate that 5-HT neurotransmission to the mPFC and Amyg is involved in inhibitory control over responses to discriminated stimuli associated with the go/no-go paradigm common to both tests. In contrast, 5-HT neurotransmission to the OFC is especially involved in additional processes associated with reversal learning.

Relationship between regional cerebral blood flow and verbal fluency in Alzheimer's disease

Abstract Category and letter verbal fluency tests are widely used for dementia detection and severity measure. Performances of these tasks have been regarded to be mainly associated with the left frontal lobe function. However, some recent studies suggest that there are different neuropsychological bases between these two tasks, and the brain region which contributes to these performances still remains unclear in Alzheimers disease (AD). To clarify the neural basis of verbal fluency in AD, we examined the relationship between performances of these tasks and regional cerebral blood flow (rCBF). Twenty‐five AD patients were administered verbal fluency tasks and single photon emission computed tomography (SPECT) scans. Thirteen cortical regions of interest were symmetrically defined in each hemisphere. Letter fluency scores were correlated significantly only with the left prefrontal (Brodmanns area (BA) 10–46) regional cerebral blood flow (rCBF). In contrast, category fluency scores were correlated most strongly with the left temporal rCBF and also with the left prefrontal (BA 10–46) rCBF. In conclusion, the present study suggests that left prefrontal (BA 10‐46) dysfunction contributes to decline in both letter and category fluency scores in AD, while typical posterior dysfunction of AD has a closer relationship with decline in category fluency scores.

Serotonergic mediation of the antidepressant-like effect of the green leaves odor in mice.

The green odor (GO) that emanates from green leaves has been observed to have many physiological actions in mammals and may be associated with a healing effect in humans. This study examined the effect of GO (we used a mixture of cis-3-hexenol and trans-2-hexenal) on behavior in the forced swim test (FST) of depression in mice. Exposure of GO showed the antidepressant-like effect in the FST, i.e., a significant decrease in immobility time and increase in swimming time, but no change in climbing time. The behavioral responses of GO-exposed animals to FST were similar to those observed for animals given citalopram, which is a selective serotonin reuptake inhibitor. In contrast, desipramine, which is a selective noradrenaline reuptake inhibitor, decreased immobility time and increased climbing time without affecting swimming time. To examine the involvement of the serotonergic system in mediating the antidepressant-like action of GO, we performed further FST examinations in which GO-exposed mice were treated with p-chlorophenylalanine (PCPA). Prior PCPA administration induced depletion of central 5-HT in the brain and completely diminished the GO effect on the behavioral responses seen during the FST. No changes in locomotor activity after GO inhalation were observed. These results indicate that acute exposure to GO has an antidepressant-like effect that may involve the serotonergic system.

Regional cerebral blood flow changes in a patient with delusional parasitosis before and after successful treatment with risperidone: A case report

The pathophysiology and appropriate pharmacological interventions for delusional parasitosis (DP) remain unknown. Here, we present a case of DP following brain infarction of the right temporoparietal region. Pharmacotherapy with risperidone resulted in a dramatic therapeutic response over a short period. In a sequential N-isopropyl-p-[(123)I]-iodoamphetamine single photon emission computed tomography ([(123)I]-IMP SPECT) study, post-treatment SPECT images revealed a marked increase of rCBF in the large areas including the bilateral frontal and left temporoparietal regions, the right parietal operculum and the bilateral basal ganglia, in contrast to pre-treatment SPECT images showing a global decrease of rCBF. Our clinical outcome suggests the efficacy and safety of risperidone for treatment of DP and that both dopaminergic and serotonergic dysfunction may play a role in DP. Our sequential SPECT findings suggest that psychiatric improvement of DP is associated with increased rCBF.

Donepezil-induced nightmares in mild cognitive impairment

Donepezil is a selective and long-acting acetylcholinesterase inhibitor that is currently approved in many countries for the treatment of mild-to-moderate Alzheimer’s disease (AD). Its safety and tolerability are well established, but sleep problems including nightmares have been identified as adverse events of donepezil in AD. 1 Recent studies also indicate the use of donepezil in mild cognitive impairment (MCI), based on evidence of a high rate of conversion from MCI to AD. 2 However, the efficacy and safety of donepezil in MCI remains ambiguous. Here, we report the case of a patient with MCI who experienced frequent frightening nightmares following donepezil treatment. The patient was a 79-year-old Japanese woman who had no history of sleep and psychiatric disorders. She was referred to our clinic in June 2002, because of difficulty in remembering the names of her friends. Her Mini-Mental State Examination (MMSE) score was 26/ 30 (calculation: − 2; delayed recall: − 2), MRI and 123 IIMP SPECT showed no abnormalities, and she was completely independent in her activities of daily living. She was diagnosed as having MCI, and her status remained unchanged for the next 16 months. From October 2003, daily morning administration of donepezil was initiated. After taking donepezil (5 mg/day) for a few days, she began to experience nightmares about ‘fierce animals and dead people pursuing her in a dark forest’. These nightmares caused her to wake in the middle of the night and she was very afraid of going back to sleep. She also became anxious and depressed because of the frequent nightmares. Co-use of a benzodiazepine (flunitrazepam, 1 mg/day) and a decrease of donepezil to 3 mg/day did not eliminate the nightmares, and so she stopped the treatment. Shortly after discontinuation of donepezil, the nightmares completely disappeared and they have not subsequently recurred. After this episode, no remarkable change in cognitive status was observed. From the end of 2004, her memory disturbance worsened. She began to ask the same questions repeatedly and her emotional balance became unstable. In February 2005, her MMSE score was 25/30 (calculation: − 2; delayed recall: − 3), and SPECT revealed a decrease in regional cerebral blood flow (rCBF) in the posterior cingulate and bilateral parietal cortex. She was diagnosed with probable AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association criteria. After diagnosis of AD, re-administration of donepezil at 5 mg/day did not cause nightmares. Informed consent for the study and the neuroimaging investigation was obtained from the patient and her family. This case was initially diagnosed as MCI based on evidence of mild memory impairment and the absence of both social dysfunction and imaging abnormalities. During the MCI stage, the patient experienced frequent nightmares following donepezil treatment, after which she stopped taking donepezil. About 2 years later, her diagnosis was changed from MCI to AD, because of deterioration of memory and social function and the appearance of decreased rCBF in the cingulate and parietal cortex. After the occurrence of AD, donepezil administration no longer caused nightmares. Activation of the cholinergic nervous system by donepezil increases REM sleep, REM density and the duration of the first REM period, and also reduces REM latency. 3 Previous studies have reported sleep problems, including nightmares, as adverse events associated with donepezil treatment in AD patients, 1

Effects of rat medial prefrontal cortex lesions on olfactory serial reversal and delayed alternation tasks

When reward reinforcement in a two-choice discrimination task is regularly changed from one stimulus to another immediately after one learning acquisition session, the learning efficiency of a rat increases as if the rat has come to recognize this regularity of reversal. To investigate how the rat medial prefrontal cortex (mPFC) is involved in such improvement, we examined the performance of mPFC-lesioned rats in a serial reversal task of olfactory discrimination. The performance of other mPFC-lesioned rats in a delayed alternation task was also analyzed using the same apparatus to evaluate the contribution of the mPFC to working memory. The mPFC-lesioned rats demonstrated selective difficulty in the second reversal session in the serial reversal task and also showed performance impairment in the delayed alternation task. These results suggest that the rat mPFC mediating working memory is involved in early progress in learning efficiency during experiences of multiple reversals, which may be relevant to cognitive operations in reversal learning beyond a one-time reversal of stimulus response associations.

Relationship between severity of obsessive-compulsive symptoms and schizotypy in obsessive-compulsive disorder.

Purpose Obsessive-compulsive disorder (OCD) patients exhibit a noninhibition response pattern very similar to that observed in schizotypy patients in cognitive tasks. It has been suggested that the reduced cognitive inhibition observed in both schizotypy and OCD may result in the frequent entry into awareness of unacceptable urges and intrusive thoughts. The aim of this study was to investigate the relationship between the severity of obsession or compulsion and schizotypy in OCD. Patients and methods Sixty subjects (25 males and 35 females) who were OCD outpatients in the University Hospital at the Kyoto Prefectural University of Medicine during the period 2008–2010 were enrolled in the study. Assessments of these patients were made using the Yale–Brown Obsessive Compulsive Scale (Y-BOCS), the Schizotypal Personality Questionnaire (SPQ), the Hamilton Depression Rating Scale (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). The Pearson correlation coefficients between Y-BOCS and SPQ scores were calculated. Furthermore, hierarchical multiple linear regression analyses were conducted to assess whether schizotypy predicted the severity of obsession and compulsion. Results By calculating the Pearson correlation coefficient, it was found that the Y-BOCS obsession score, not the Y-BOCS compulsion score, was correlated with the SPQ total score. Results of the hierarchical multiple linear regression analysis showed that SPQ total score was a significant predictor of the Y-BOCS obsession score, after accounting for control variables (ie, HAM-D and HAM-A). Conclusion Results of this study showed that the Y-BOCS obsession score, not the Y-BOCS compulsion score, was correlated with the SPQ total score. This finding suggests that OCD patients with an elevated SPQ total score experience a reduction of cognitive inhibition, resulting in the frequent entry into obsession. Future longitudinal studies are recommended to clarify the effect of schizotypy on the clinical course of OCD.

Cerebral blood flow changes in general paresis following penicillin treatment: A longitudinal single photon emission computed tomography study

Abstract Three cases of general paresis were successfully treated with high‐dose penicillin. In all cases, cerebrospinal fluid cell counts decreased to normal and mental status improved rapidly. Cerebrospinal fluid protein concentrations decreased and IQ scores and overall levels of functioning improved gradually over 1 year. Regional cerebral blood flow (CBF) changes were analyzed longitudinally for 1 year using single photon emission computed tomography (SPECT). Autoradiography method and region of interest (ROI) analyses were used for quantitative CBF assessment and 3D stereotactic surface projections (3D‐SSP) analyses were used for qualitative CBF pattern assessment. 3D‐SSP could not reveal remarkable CBF pattern changes through the courses. The ROI analyses showed remarkable CBF decreases in all brain regions 1 month after the treatment, which recovered to normal levels 1 year after the treatment. These results suggest that remarkable decreases of quantitative CBF counts reflect the disappearance of encephalitis, while their gradual recovery reflects the gradual improvement of cerebral functional activity. As Treponema pallidum infection affects whole brain and CBF changes globally, quantitative CBF assessment may be more efficient than qualitative CBF pattern analyses for the purpose of understanding the pathophysiology of general paresis.

Chronic high-dose nitrazepam dependence 123I-IMP SPECT and EEG studies

A patient who took 50–100 mg nitrazepam per day for 25 years is presented. 123I‐IMP SPECT (autoradiography method) and EEG were performed sequentially on the subject during and after the withdrawal syndrome. Severe hypoperfusion of the whole brain on SPECT and diffuse slow activity on EEG were demonstrated during the withdrawal syndrome and subsequently remarkably improved. However, the hypofrontal pattern on both early and delayed images in SPECT was unchanged. The changes observed on SPECT and EEG reflect the pathophysiology of dependence and withdrawal. Additionally, the hypofrontal pattern remained unchanged suggesting that organic brain damage can develop as a result of chronic high‐dose benzodiazepine abuse.