Cerebral Blood Flow In Hippocampus Research Articles

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study.

Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic‐like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo‐continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p = .031, family‐wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences.

Intense Fear Induces Low‐Frequency Oscillation of Cerebral Blood Flow, Arterial Pressure, and Sympathetic Nerve Activity in Conscious Rats

A traumatic event, such as disaster, causes intense fear, which potentially leads to an increase in occurrence of cerebrovascular diseases. Little information is available regarding why intense fear causes cerebrovascular diseases. The present study aimed to measure cerebral blood flow, arterial pressure, and sympathetic nerve activity during intense fear conditioning in conscious rats. Wistar rats were chronically instrumented with a probe made with glass fiber for measuring hippocampal cerebral blood flow. Electrodes for measurements of renal (RSNA) and lumbar sympathetic nerve activity (LSNA) were inserted, as well as for an electroencephalogram, electromyogram, and electrocardiogram. A catheter was inserted for measuring systemic arterial pressure. Standard fear‐conditioning trials, in which a tone was paired with a brief electrical shock (5 mA, 2 s), were performed in rats two times per day over 3 days. Oscillation of arterial pressure with an amplitude of 15.7 mmHg and frequency of 0.075 Hz was induced by exposing a tone without electrical shock in fear‐conditioned rats. Arterial pressure oscillation was associated with synchronized oscillation of hippocampal cerebral blood flow, RSNA, and LSNA. Coherence between arterial pressure and hippocampal cerebral blood flow, RSNA, and LSNA was significantly increased at low frequency (0–1 Hz) compared with naive rats. These data suggest that intense fear can trigger disorder of sympathetic regulation of arterial pressure, causing low‐frequency oscillation of arterial pressure and synchronized changes in cerebral blood flow. This may be one of the causes of cerebrovascular disease induced by intense fear.Support or Funding InformationJSPS GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hippocampal CA1 Neuronal and Sympathetic Nerve Activities in Response to Restraint Water‐Immersion Stress in Conscious Rats

The hippocampus has been suggested to play a significant role in adaptation to chronic stress. However, there has been lack of direct evidence for responses of hippocampal neuronal activity to chronic stress. The present study was aimed to record hippocampal CA1 neuronal and sympathetic nerve activities during chronic stress. Wistar rats were instrumented chronically with a combined probe made with multiple electrodes (100 micrometer stainless steel wires) for measurement of hippocampal CA1 neuronal activity and glass fiber for measurement of hippocampal cerebral blood flow (CBF), electrodes for measurements of renal (RSNA) and lumbar (LSNA) sympathetic nerve activity, and electroencephalogram, electromyogram, and electrocardiogram and with catheter for measurement of systemic arterial pressure (AP). Rats were exposed repeatedly to restraint water‐immersion stress (RWIS) for 90 min/day over 5 days. Hippocampal CA1 neuronal activity, RSNA, and LSNA were measured continuously and simultaneously before, during, and after RWIS. Hippocampal CA1 neuronal activity decreased immediately after onset of RWIS and the decreased level was maintained throughout the 90 min of RWIS on the first day of stress exposure. On day 5 of RWIS, hippocampal CA1 neuronal activity decreased immediately after onset of RWIS, however it gradually recovered to the control level during the RWIS period. Thus, hippocampal CA1 neurons gradually adapted to the repeated RWIS exposure while RSNA and LSNA increased immediately after the onset of RWIS and showed no adaptive response during repeated exposure to RWIS.Support or Funding InformationJSPS GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hippocampal cerebral blood flow depends on systemic endothelial function in individuals with mild cognitive impairment: The Train the Brain-Mind the vessel study

BackgroundDementia has been recently viewed as a predominantly vascular disorder. Indeed, reduced brain NO availability causes increased ß-amyloid deposition by several mechanisms, including hypoperfusion.PurposeTo investigate the relationship between cerebral blood flow in the hippocampal and parahippocampal regions (CBF-hipp and CBF-parahipp), crucial areas for memory and processing of non-verbal/spatial information, and systemic endothelial function in individuals with mild cognitive impairment (MCI), a subclinical condition predisposing to dementia.MethodsCBF-hipp and CBF-parahipp were evaluated by magnetic resonance imaging (arterial spin labeling, GE HDxt 1.5 T Signa Neuro-optimized System) and systemic endothelial function by flow-mediated dilation (FMD) in the brachial artery.ResultsComplete data about CBF and FMD at enrollment were available for 66 individuals with MCI and 32 without (non-MCI). The two groups were matched for age (75 ± 5 vs 74 ± 5 years, p = 0.22), sex (men 45 vs 50%, p = 0.18) and mean BP (96 ± 10 vs 97 ± 9 mmHg, p = 0.41). FMD was significantly lower in MCI than in non-MCI (2.93 ± 2.18 vs 3.74 ± 2.03%, p = 0.02); CBF-hipp (64.3 ± 9.43 vs 69.5 ± 7.03 ml/100 gr/min, p = 0.002) and CBF-parahipp (66.3 ± 8.02 vs 70.0 ± 8.12 ml/100 gr/min, p = 0.002) were significantly lower in MCI as well. Among MCI, FMD was significantly correlated with CBF-parahipp (r = 0.26, p = 0.03) and CBF-hipp (r = 0.32, p = 0.009). In multiple regression models, including age, sex, mean BP, BMI, brachial artery diameter as confounders, FMD remained an independent determinant of CBF-parahipp (beta = 0.93, r2 = 0.063, p = 0.04) and CBF-hipp (beta = 1.31, r2 = 0.089, p = 0.01). Nor CBF-parahipp (r = −0.13, p = 0.48) neither CBF-hipp (r = 0.05, p = 0.80) were correlated with FMD in non-MCI group.ConclusionsAn independent association between hippocampal and para-hippocampal CBF and systemic endothelial function is present in individuals with MCI.

Skeletal myofiber vascular endothelial growth factor is required for the exercise training-induced increase in dentate gyrus neuronal precursor cells.

Peripheral vascular endothelial growth factor (VEGF) is necessary for exercise to stimulate hippocampal neurogenesis. Here we report that skeletal myofiber VEGF directly or indirectly regulates exercise-signalled proliferation of neuronal precursor cells. Our results found skeletal myofiber VEGF to be necessary for maintaining blood flow through hippocampal regions independent of exercise training state. This study demonstrates that skeletal myofiber VEGF is required for the hippocampal VEGF response to acute exercise. These results help to establish the mechanisms by which exercise, through skeletal myofiber VEGF, affects the hippocampus. Exercise signals neurogenesis in the dentate gyrus of the hippocampus. This phenomenon requires vascular endothelial growth factor (VEGF) originating from outside the blood-brain barrier, but no cellular source has been identified. Thus, we hypothesized that VEGF produced by skeletal myofibers plays a role in regulating hippocampal neuronal precursor cell proliferation following exercise training. This was tested in adult conditional skeletal myofiber-specific VEGF gene-ablated mice (VEGFHSA-/- ) by providing VEGFHSA-/- and non-ablated (VEGFf/f ) littermates with running wheels for 14days. Following this training period, hippocampal cerebral blood flow (CBF) was measured by functional magnetic resonance imaging (fMRI), and neuronal precursor cells (BrdU+/Nestin+) were detected by immunofluorescence. The VEGFf/f trained group showed improvements in both speed and endurance capacity in acute treadmill running tests (P<0.05). The VEGFHSA-/- group did not. The number of proliferating neuronal precursor cells was increased with training in VEGFf/f (P<0.05) but not in VEGFHSA-/- mice. Endothelial cell (CD31+) number did not change in this region with exercise training or skeletal myofiber VEGF gene deletion. However, resting blood flow through the hippocampal region was lower in VEGFHSA-/- mice, both untrained and trained, than untrained VEGFf/f mice (P<0.05). An acute hypoxic challenge decreased CBF (P<0.05) in untrained VEGFf/f , untrained VEGFHSA-/- and trained VEGFHSA-/- mice, but not trained VEGFf/f mice. VEGFf/f , but not VEGFHSA-/- , mice were able to acutely run on a treadmill at an intensity sufficient to increase hippocampus VEGF levels. These data suggest that VEGF expressed by skeletal myofibers may directly or indirectly regulate both hippocampal blood flow and neurogenesis.

Cerebral Blood Flow and Amyloid-β Interact to Affect Memory Performance in Cognitively Normal Older Adults.

Cerebral blood flow (CBF) alterations and amyloid-β (Aβ) accumulation have been independently linked to cognitive deficits in older adults at risk for dementia. Less is known about how CBF and Aβ may interact to affect cognition in cognitively normal older adults. Therefore, we examined potential statistical interactions between CBF and Aβ status in regions typically affected in Alzheimer’s disease (AD) within a sample of older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Sixty-two cognitively normal participants (mean age = 72 years) underwent neuroimaging and memory testing. Arterial spin labeling magnetic resonance imaging was used to quantify CBF and florbetapir PET amyloid imaging was used to measure Aβ deposition. Aβ status (i.e., positivity versus negativity) was determined based on established cutoffs (Landau et al., 2013). The Rey Auditory Verbal Learning Test was used to assess memory. Linear regression models adjusted for age, education, and sex, demonstrated significant interactions between CBF and Aβ status on memory performance. Among Aβ positive older adults, there were significant negative associations between higher CBF in hippocampus, posterior cingulate, and precuneus and poorer memory performance. In contrast, among Aβ negative older adults, there were no significant associations between CBF and cognition. Our findings extend previous CBF studies of dementia risk by reporting interactions between Aβ status and CBF on memory performance in a sample of well-characterized, cognitively normal older adults. Results suggest that differential CBF-cognition associations can be identified in healthy, asymptomatic Aβ positive older adults relative to Aβ negative individuals. Associations between higherCBF and poorer memory among Aβ positive older adults may reflect a cellular and/or vascular compensatory response to pathologic processes whereby higher CBF is needed to maintain normal memory abilities. Findings indicate that CBF and its associations with cognition may have utility as a reliable marker of brain function early in the AD process when interventions are likely to be beneficial.

Hippocampal CA1 Neuronal and Sympathetic Nerve Activity in Response to Repeated Fear Conditioning in Rats

The aim of the present study was to assess the responses of hippocampal and sympathetic nerve activity (SNA) to fear conditioning in rats. Wistar rats were chronically instrumented with a combined probe comprising multiple electrodes (100‐μm stainless steel wires) for measurement of hippocampal CA1 neuronal activity, a glass fiber for measurement of hippocampal cerebral blood flow (CBF), electrodes for measurement of renal SNA (RSNA) and lumbar SNA (LSNA), and electroencephalogram, electromyogram, and electrocardiogram, and with a catheter for measurement of systemic arterial pressure (AP). Standard fear‐conditioning trials, in which a tone was paired with a brief electrical shock (5 mA, 1s), were given to rats twice per day over 3 days. Hippocampal CA1 neuronal activity and CBF in the CA1 region increased progressively over the 3‐day fear conditioning trial, as did AP and RSNA. By contrast, heart rate (HR) and LSNA did not change on day 2, but increased on day 3. These data suggest that the repeated fear conditioning trial causes long‐term potentiation of hippocampal CA1 neuronal activity in a progressive and additive manner. Further, this potentiation was correlated quantitatively with hippocampal CA1 CBF and RSNA, but not with LSNA or HR. Thus, CA1 activation induced by repeated fear conditioning may influence RSNA, LSNA, AP, and HR in a region‐specific manner. JSPS Grant.

Caloric restriction preserves memory and reduces anxiety of aging mice with early enhancement of neurovascular functions.

Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age. The neurovascular enhancements were associated with reduced mammalian target of rapamycin expression, elevated endothelial nitric oxide synthase signaling, and increased ketone bodies utilization. With age, CR decelerated the rate of decline in CBF. The preserved CBF in hippocampus and frontal cortex were highly correlated with preserved memory and learning, and reduced anxiety, of the aging mice treated with CR (18-20 months of age). Our results suggest that dietary intervention started in the early stage (e.g., young adults) may benefit cognitive and mental reserve in aging. Understanding nutritional effects on neurovascular functions may have profound implications in human brain aging and age-related neurodegenerative disorders.

Aerobic fitness is associated with greater hippocampal cerebral blood flow in children

The present study is the first to investigate whether cerebral blood flow in the hippocampus relates to aerobic fitness in children. In particular, we used arterial spin labeling (ASL) perfusion MRI to provide a quantitative measure of blood flow in the hippocampus in 73 7- to 9-year-old preadolescent children. Indeed, aerobic fitness was found to relate to greater perfusion in the hippocampus, independent of age, sex, and hippocampal volume. Such results suggest improved microcirculation and cerebral vasculature in preadolescent children with higher levels of aerobic fitness. Further, aerobic fitness may influence how the brain regulates its metabolic demands via blood flow in a region of the brain important for learning and memory. To add specificity to the relationship of fitness to the hippocampus, we demonstrate no significant association between aerobic fitness and cerebral blood flow in the brainstem. Our results reinforce the importance of aerobic fitness during a critical period of child development.

Increased hippocampal blood flow in sedentary older adults at genetic risk for Alzheimer's disease.

Resting cerebral blood flow (CBF) decreases with age; however regulatory increases in hippocampal CBF have been associated with genetic risk (Apolipoprotein E [APOE] ε4 carriers) for Alzheimer's disease (AD). Although physical activity exerts beneficial effects on CBF in healthy elderly, the effects of sedentary behaviors on CBF remain unknown. We measured resting hippocampal CBF (via arterial spin labeling magnetic resonance imaging) and sedentary time/physical activity (via accelerometry) on 33 cognitively healthy adults (ages 52-81), 9 of which were APOE ε4 carriers. Results indicate that the relationship between sedentary time and CBF in the left hippocampus differs by APOE status, whereby APOE ε4 carriers show higher CBF as a function of longer sedentary time (B = 10.8, SE = 3.17, β = 0.74, t = 3.41, p < 0.01) compared to noncarriers (B = 1.4, SE = 2.7, β = 0.096, t = 0.51, p = 0.61), possibly suggesting a CBF regulatory response to compensate for metabolic alterations in dementia risk. These preliminary data suggest that the relationship between CBF and sedentary time is different in APOE ε4 carriers and noncarriers and that sedentary time may act as a behavioral risk factor for CBF dysregulation in those at genetic risk for developing AD. More research is needed to further understand the role of sedentary behaviors and physical activity on CBF, especially in individuals at genetic risk of developing AD.

Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging

Physical exercise, particularly aerobic exercise, is documented as providing a low cost regimen to counter well-documented cognitive declines including memory, executive function, visuospatial skills, and processing speed in normally aging adults. Prior aging studies focused largely on the effects of medium to long term (>6 months) exercise training; however, the shorter term effects have not been studied. In the present study, we examined changes in brain blood flow, cognition, and fitness in 37 cognitively healthy sedentary adults (57–75 years of age) who were randomized into physical training or a wait-list control group. The physical training group received supervised aerobic exercise for 3 sessions per week 1 h each for 12 weeks. Participants' cognitive, cardiovascular fitness and resting cerebral blood flow (CBF) were assessed at baseline (T1), mid (T2), and post-training (T3). We found higher resting CBF in the anterior cingulate region in the physical training group as compared to the control group from T1 to T3. Cognitive gains were manifested in the exercise group's improved immediate and delayed memory performance from T1 to T3 which also showed a significant positive association with increases in both left and right hippocampal CBF identified earlier in the time course at T2. Additionally, the two cardiovascular parameters, VO2 max and rating of perceived exertion (RPE) showed gains, compared to the control group. These data suggest that even shorter term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.

Hippocampal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise

Current studies have demonstrated that exercise increases regional cerebral blood flow (rCBF), an index of neuronal activity. However, neuronal regulation of the increased rCBF in the brain parenchyma is poorly understood. We developed a running model with rats for monitoring hippocampal cerebral blood flow (Hip-CBF) and found that mild treadmill running increases Hip-CBF in a tetrodotoxin-dependent manner, suggesting that functional hyperemia, an increase in rCBF in response to neuronal activation, occurs in the running rat's hippocampus (Nishijima T and Soya H. Neurosci Res 54: 186-191, 2006). To further support our hypothesis, it was important to discover the neurogenic pathways behind the increase in Hip-CBF that occurred during running. Here, we examine the possible role of N-methyl-d-aspartate (NMDA) receptor/nitric oxide (NO) signaling and group I metabotropic glutamate receptors in mediating the Hip-CBF increase. Hip-CBF during running was measured by laser-Doppler flowmetry. Intrahippocampal drug administration was performed by microdialysis. Mild treadmill running (10 m/min) increased Hip-CBF, which was remarkably attenuated by either NMDA receptor antagonists (1 mM MK-801) or NO synthase inhibitors (2 mM N(G)-nitro-l-arginine methyl ester). However, group I metabotropic glutamate receptor antagonists {1 mM 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester + 1 mM 2-methyl-6-(phenylethynyl)pyridine hydrochloride} augmented the running-induced Hip-CBF increase. We also found that rCBF in the olfactory bulb was unchanged with running. These results strongly suggest that Hip-CBF during mild exercise is regulated locally under hippocampal neuronal activity, mediated mainly through NMDA receptor/NO signaling. Collectively, these results, together with our previous findings, support our hypothesis that mild exercise elicits neuronal activation, which then triggers functional hyperemia in the rat hippocampus.

Using network science to evaluate exercise-associated brain changes in older adults

Literature has shown that exercise is beneficial for cognitive function in older adults and that aerobic fitness is associated with increased hippocampal tissue and blood volumes. The current study used novel network science methods to shed light on the neurophysiological implications of exercise-induced changes in the hippocampus of older adults. Participants represented a volunteer subgroup of older adults that were part of either the exercise training (ET) or healthy aging educational control (HAC) treatment arms from the Seniors Health and Activity Research Program Pilot (SHARP-P) trial. Following the 4-month interventions, MRI measures of resting brain blood flow and connectivity were performed. The ET group's hippocampal cerebral blood flow (CBF) exhibited statistically significant increases compared to the HAC group. Novel whole-brain network connectivity analyses showed greater connectivity in the hippocampi of the ET participants compared to HAC. Furthermore, the hippocampus was consistently shown to be within the same network neighborhood (module) as the anterior cingulate cortex only within the ET group. Thus, within the ET group, the hippocampus and anterior cingulate were highly interconnected and localized to the same network neighborhood. This project shows the power of network science to investigate potential mechanisms for exercise-induced benefits to the brain in older adults. We show a link between neurological network features and CBF, and it is possible that this alteration of functional brain networks may lead to the known improvement in cognitive function among older adults following exercise.

Effects of alcohol (ethanol) on hippocampal CA1 neuronal activity and hippocampal cerebral blood flow in conscious rats

Effects of alcohol (ethanol) on hippocampal CA1 neuronal activity and hippocampal cerebral blood flow in conscious rats

RCBF to the hippocampal complex covaries with superior semantic memory retrieval

The study of medial-temporal amnesics has established that much of the brain's store of general knowledge can be retrieved without the hippocampus. Several brain imaging studies, however, have reported that the hippocampus is active during the performance of semantic memory tasks. Although this activity may reflect memory encoding, it is also possible that it is due to the process of retrieving the semantic representations of the stimuli. Here we show in two H 2 15O positron emission tomography studies that cerebral blood flow (CBF) to the hippocampus covaries with superior performance during the retrieval of general knowledge. Left hippocampal CBF was associated with faster word meaning retrieval and right hippocampal CBF with better picture naming. A follow-up experiment failed to show that faster responding in the word meaning task was associated with better episodic memory for the stimuli and so weakens the proposal that the hippocampal activity was strictly related to memory encoding. In both experiments CBF to the lateral temporal cortex covaried with hippocampal CBF in a way that suggests that the hippocampus provides complementary support to activation within the association cortex.

Evidence of functional hyperemia in the rat hippocampus during mild treadmill running

Exercise appears to improve hippocampal plasticity and cognitive function, leading us to postulate that exercise may activate hippocampal neurons, which in turn increase hippocampal cerebral blood flow (Hip-CBF). Recent studies using laser-Doppler flowmetry (LDF) have shown that Hip-CBF increases with behavior and locomotion, but it has not been examined whether these changes are due to neuronal activation. We aimed to examine whether functional hyperemia, an increase in cerebral blood flow in response to neuronal activation, can occur in the exercising rat hippocampus. We applied a treadmill running model of rats and LDF combined with microdialysis. Prolonged mild treadmill running (10 m/min) resulted in an increase in Hip-CBF of 26 ± 9% versus basal level. When tetrodotoxin was infused via microdialysis into the loci where Hip-CBF was monitored, the increased Hip-CBF with running was completely suppressed. These results provide evidence that functional hyperemia occurs in the rat hippocampus during mild treadmill running and suggest that our running animal model may be useful for examining the underlying mechanisms of exercise-induced hippocampal functional hyperemia.

Long-term glucocorticoid treatments decrease local cerebral blood flow in the rat hippocampus, in association with histological damage

The present study examined the influence of a long-term treatment with glucocorticoid on local cerebral blood flow of the hippocampus in rats, estimated with the hydrogen clearance method. Either a cholesterol (100 mg, as a control) or corticosterone (100 mg) bead was implanted subcutaneously in rats for a period of three months, beginning at 12 weeks of age. The effects of the treatments on the local circulation of the hippocampus were evaluated three to four months after the termination of the treatments. Hippocampal cerebral blood flow in corticosterone-treated rats was significantly lower ( P<0.05) than that in control rats, and fluctuated over a day in lower amplitude than the controls. Severe histological damage was observed in the CA1 and CA3 cell fields of the hippocampus in corticosterone-treated rats. These neuropathological changes were characterized by soma shrinkage and condensation, or nuclear pyknosis, as reported previously. We concluded that a long-term glucocorticoid exposure resulted in an impairment of the hippocampal functions, accompanied by neuronal damage similar to that found in aged hippocampus. The present results support the hypothesis that glucocorticoids accelerate age-related changes in the brain.

Laser-Doppler Flowmetry Measurements of Subcortical Blood Flow Changes after Fluid Percussion Brain Injury in Rats

Laser-Doppler flowmetry (LDF) was used to record subcortical cerebral blood flow in hippocampus and striatum immediately following parasaggital fluid percussion brain injuries of mild to moderate severity (2.58 +/- 0.09 atm, 10-11 msec duration) in spontaneously breathing anesthetized rats. At 5 min postinjury, mean blood flow decreased bilaterally by 20-30% in both brain structures, and remained significantly reduced during the remainder of the 60 min postinjury recording interval. Blood flow did not change in the sham-injured rats. Subsequent beam-walk, beam-balance, and rope-hang assessments revealed significant neurological impairments in the injured rats but not in the sham controls. The magnitude of the blood flow changes and the severity of the ensuing neurological impairment were significantly correlated. Histopathological assessments revealed hemorrhagic contusions within ipsilateral cortical regions, occasional neuronal necrosis within underlying thalamus and CA3 and CA4 sectors of the hippocampus, and neuronal cell loss in the hilus of the dentate gyrus. In a second series of experiments, radiolabeled microspheres were used to validate the LDF blood flow measurements. The microsphere measurements revealed that the preinjury baseline and postinjury right hippocampal blood flow changes were not significantly altered by the intrahippocampal presence of an LDF probe, verifying that the LDF probe was not by itself an unacceptably disruptive influence on local cerebrovascular reactivity. Moreover, when right hippocampal blood flow was simultaneously evaluated in injured rats by both techniques, the relative blood flow changes were significantly correlated. These results indicate that laser-Doppler flowmetry provides a potentially useful means to appreciate acute regional cerebrovascular changes relative to other measures of outcome after brain trauma.

Glutamate pharmacology and the treatment of schizophrenia

Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their functional importance in mental activity is considerable. Therefore, the involvement of this neurotransmitter in the pathology of schizophrenia is being studied. Biochemical evidence has suggested that glutamatergic transmission may be regionally reduced in schizophrenia, although this evidence has never been completely consistent nor fully replicable. More striking has been the behavioral effects in humans of the antiglutamatergic drugs phencyclidine (PCP) and its congener ketamine. By historical report, PCP produces a ‘schizophrenia-like’ psychosis in normal humans and aggravates the psychosis in schizophrenics. More recently, ketamine has been shown to produce a mild psychotomimetic effect in normal volunteers, which has some schizophrenia-like features. We have studied the effects of ketamine in schizophrenic patients. Here, ketamine intensified each patient's specific underlying psychosis, an effect not blocked by haloperidol. Moreover, ketamine selectively increased cerebral blood flow (CBF) in the anterior cingulate cortex and reduced CBF in hippocampus and lingual gyrus. These data may be pertinent to the subject's psychosis exacerbation, especially because both cingulate and hippocampus have been previously implicated in schizophrenic psychosis. In addition, ketamine produced a distinctive dynamic time-course of regional CBF changes in different anatomic regions, with immediate (5–10 min) changes in cingulate, but somewhat more delayed changes (20–40 min) in the thalamus and cerebellum. Our immediate early gene (IEG) time-course data with c-fos and zif 268 in rats following PCP suggest that a single dose of this antiglutamatergic compound can have an effect in some brain areas which lasts beyond 48 h, an effect which is distinct by IEG and by region. Together, these data suggest that glutamate-mediated neurotransmission has a strong influence in schizophrenia, although the specifics of this involvement have yet to be articulated.

Glutamate pharmacology and the treatment of schizophrenia: current status and future directions

Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their functional importance in mental activity is considerable. Therefore, the involvement of this neurotransmitter in the pathology of schizophrenia is being studied. Biochemical evidence has suggested that glutamatergic transmission may be regionally reduced in schizophrenia, although this evidence has never been completely consistent nor fully replicable. More striking has been the behavioral effects in humans of the antiglutamatergic drugs phencyclidine (PCP) and its congener ketamine. By historical report, PCP produces a 'schizophrenia-like' psychosis in normal humans and aggravates the psychosis in schizophrenics. More recently, ketamine has been shown to produce a mild psychotomimetic effect in normal volunteers, which has some schizophrenia-like features. We have studied the effects of ketamine in schizophrenic patients. Here, ketamine intensified each patient's specific underlying psychosis, an effect not blocked by haloperidol. Moreover, ketamine selectively increased cerebral blood flow (CBF) in the anterior cingulate cortex and reduced CBF in hippocampus and lingual gyrus. These data may be pertinent to the subject's psychosis exacerbation, especially because both cingulate and hippocampus have been previously implicated in schizophrenic psychosis. In addition, ketamine produced a distinctive dynamic time-course of regional CBF changes in different anatomic regions, with immediate (5-10 min) changes in cingulate, but somewhat more delayed changes (20-40 min) in the thalamus and cerebellum. Our immediate early gene (IEG) time-course data with c-fos and zif268 in rats following PCP suggest that a single dose of this antiglutamatergic compound can have an effect in some brain areas which lasts beyond 48 h, an effect which is distinct by IEG and by region. Together, these data suggest that glutamate-mediated neurotransmission has a strong influence in schizophrenia, although the specifics of this involvement have yet to be articulated.