Imaging the mind

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Local blood flow changes in association with proximal gastric vagotomy were studied with laser Doppler flowmetry in 10 patients. After the vagotomy a significant decrease in blood flow amounting to 57 +/- 21% (range, 18-87%; p less than 0.001) was observed within the dissected area along the lesser curvature. In three patients, the flowmeter recordings suggested localized areas with very poor perfusion. The blood flow was restored to preoperative control values within 3-4 weeks after the operation. It is suggested that the temporary poor blood perfusion along the lesser curvature may be an important factor in the genesis of postoperative ulcerations in the dissected area. We conclude that laser Doppler flowmetry seems to have great potential as a method to study localized blood flow changes in the stomach. Flowmeter recordings can be made both during operation and endoscopy.

Gastrointestinal (GI) peptides can increase or decrease blood flow in addition to their actions on digestive functions, such as GI motility, intestinal absorption, and gastric and pancreatic secretions. Their vasoactive potency (i.e., the dose required to produce vasoactivity) may differ from their potency to induce changes in digestive functions and, therefore, the respective potencies should be compared. The relative potency of some chemicals on GI motility and blood flow, and the relationship between these two variables, have been summarized (Chou 1989). Administration of a peptide often produces concomitant changes in a digestive function, local oxidative metabolism, and local blood flow. A change in the tissue activity and metabolism can cause changes in local blood flow, and a change in blood flow can influence tissue activity. One should determine which aspect is the cause and which is the result. Another issue to be considered is whether or not the digestive and vascular actions of a peptide are physiological. Physiologically, the GI peptides are released following a meal to regulate digestive functions and local blood flow. In order to be a physiological peptide, the postprandial tissue or blood concentrations must be sufficient to produce vasoactivity. This topic has been discussed previously by comparing the minimal local blood concentration required to produce vasodilation with that achieved following a meal (Chou and Kvietys 1981; Chou et al. 1984).

Quantitative measurement of cerebral physiology using respiratory-calibrated MRI

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessBrain Response After Trauma May Predict Recovery OutcomeAaron LevinAaron LevinPublished Online:17 Oct 2008https://doi.org/10.1176/pn.43.20.0023Varying changes in local blood flow in two areas of the brains of auto-crash survivors predicted later adaptation to their traumatic experience, according to a study "of recovery rather than pathology" in the August 15 Biological Psychiatry.The study scanned the brains of survivors within a few weeks of their accidents and before a diagnosis of posttraumatic stress disorder is possible. Positron emission tomography (PET) scans showed less blood flowing to the amygdala and more to the medial prefrontal cortex (mPFC) of subjects when listening to recountings of their trauma than when listening to neutral stories."There are specific brain correlates of normal, healthy recovery of exposed individuals, and those brain activities are located in the mPFC and the amygdala," said lead author Elizabeth Osuch, M.D., now an associate professor of psychiatry at the University of Western Ontario in London, Ontario, in an interview. The research was conducted when Osuch was at the Center for the Study of Traumatic Stress at the Uniformed Services University of the Health Sciences in Bethesda, Md."In people with long-term PTSD, we find hyperactive amygdala and hypoactive mPFC—the opposite of what we're finding in these recovering people."The research is another step in understanding the biological basis of trauma and recovery, said Osuch. The work was funded by the National Institute of Mental Health, and the authors said it is the first study addressing neurophysiological responses to traumatic reminders observed before a diagnosis of PTSD is possible.The researchers used PET scans to measure regional blood flow in the brains of 22 survivors of motor-vehicle collisions (MVC) and 12 nontraumatized control subjects. None had a history of head injury or major medical illness, but the accident victims had significantly higher Beck Depression Inventory scores than controls.Osuch's group had hoped to look at both resilience and recovery and at psychopathology. However, people with more severe PTSD and more severe avoidance symptoms did not volunteer to take part in the study, she said.After recruitment but before scanning, the survivors described their accidents in a "traumatic-reminder narrative." One of these was then selected as a standardized trauma narrative, played for the controls. Survivors also provided a neutral narrative of a favorite activity not related to the accident.Subjects were scanned within an average of 20 days following their accidents. Narratives were recorded and played back to the subjects during the scan. Survivors were evaluated (but not scanned) three months later as well.The session began with one resting scan, followed by pairs of the neutral and trauma scans, in that order.At rest, compared with healthy controls, the accident victims showed higher resting blood flow in a right medial prefrontal cortex (mPFC) area in the anterior cingulate sulcal area and lower flow in the right amygdala. During subsequent scans, accident victims listening to trauma narratives showed decreased flow in the right amygdala and left amygdala/perirhinal cortex, compared with when they heard the neutral narratives.Subjects were evaluated using the Impact of Events Scale-Revised (IES-R). On average, the accident survivors' IES-R score was above the threshold for clinical significance. However, at the three-month follow-up evaluation, only four of the 22 subjects had elevated IES-R scores. Only one met criteria for PTSD."Thus, most of the MVC subjects were 'resilient'—that is, they experienced a traumatic event, showed a transient stress response, and went on to recovery," wrote the authors. "[The results] suggest an adaptive process in recovering individuals that involves deactivation of the perirhinal cortex, perhaps as a means of terminating or preventing fear-potentiating associations."The clinical value of this information is still unclear, but the research may contribute to broader discussions of psychological injury and health, said Osuch."We live in a world where mental illness is very much stigmatized," she said. "We stigmatize pathology but don't understand the biological basis of the pathology. Neither do we understand or appreciate the biological aspects of resilience or health. This is one more thing to add to that understanding."An abstract of "Neurophysiological Responses to Traumatic Reminders in the Acute Aftermath of Serious Motor Vehicle Collisions Using [15O]-H2O Positron Emission Tomography" can be accessed at<www.journals.elsevierhealth.com/periodicals/bps/article/PIIS0006322308003028/abstract>.▪ ISSUES NewArchived

Functional variations in cerebral cortical activity are accompanied by local changes in blood flow, but the mechanisms underlying this physiological coupling are not well understood. Here we report that dopamine, a neurotransmitter normally associated with neuromodulatory actions, may directly affect local cortical blood flow. Using light and electron-microscopic immunocytochemistry, we show that dopaminergic axons innervate the intraparenchymal microvessels. We also provide evidence in an in vitro slice preparation that dopamine produces vasomotor responses in the cortical vasculature. These anatomical and physiological observations reveal a previously unknown source of regulation of the microvasculature by dopamine. The findings may be relevant to the mechanisms underlying changes in blood flow observed in circulatory and neuropsychiatric disorders.

Outcome from sinus vein thrombosis is very variable, with symptoms from headache to coma. Experimental findings suggest that an involvement of cortical veins is necessary to affect the cerebral microcirculation. Laser Doppler flowmetry was used to investigate the regional and temporal changes in local cortical blood flow after experimental occlusion and thrombosis of the superior sagittal sinus and tributary cortical veins in rats. Thrombosis was induced by slow injection of kaolin-cephalin suspension after frontal and caudal ligation of the sagittal sinus in rats. Local cerebral blood flow was measured by laser Doppler flowmetry and correlated with parenchymal damage found 24 hours after induction of thrombosis. Local cerebral blood flow 1 hour after sinus occlusion and induction of thrombosis had decreased to 60.92 +/- 29.05% (p < 0.01); however, there was a large variability among individual animals. Only five of 12 rats showed histological damage and intracerebral hemorrhages 24 hours after induction of thrombosis. A subgroup analysis revealed that parenchymal damage occurred in concurrence with reduced blood flow values after sinus ligation and injection of the thrombogenic material. Sinus thrombosis alone, without alteration of blood flow, did not cause tissue necrosis. The data support the contention that sinus vein thrombosis evolves gradually, with major symptoms occurring only if the thrombus expands from the sinus into bridging and cortical veins. Collateral venous outflow pathways are thereby occluded, and local blood flow may become reduced to and below the ischemic threshold.

Doppler transcraneal, BIS y entropía como medición indirecta del flujo cerebral durante la anestesia inhalatoria en pacientes pediátricos

Revealing Brain Activity and White Matter Structure Using Functional and Diffusion-Weighted Magnetic Resonance Imaging

The aim of this randomized controlled crossover study was to investigate the effect of a bout of unaccustomed eccentric exercise (ECC) followed by a consecutive bout of the same intensity on local muscle blood flow, amplitude, and frequency of the electromyographic (EMG) signal from the exercised tibialis anterior muscle. Sixteen healthy male participants (age, 25.7 (0.6) years; body mass index 24.8 (1) kg·m(-2) participated in this study. Two identical bouts of high-intensity ECC were performed on the tibialis anterior muscle 7 days apart. Control sessions involving no exercise were performed 4 weeks either before or after the exercise sessions. Changes in local total blood flow [ΔtHb], EMG root mean square, and median power frequency were recorded during isometric maximum voluntary contraction of ankle dorsiflexion. Measurements were performed before, immediately after, and the day after both ECCs (ECC1 and ECC2). The participants rested quietly in a chair in the control session. Eccentric exercise 1 led to a significant decrease in [ΔtHb] on the day after (p ≤ 0.05), whereas ECC2 did not. Median power frequency decreased significantly in ECC2 compared with ECC1 (p < 0.01). Root mean square was unchanged in all the instants. The present study showed that adaptation is depicted in the local muscle blood flow and the frequency contents of the EMG after an unaccustomed ECC inducing muscle soreness. These alterations provide a potential mechanism for a rapid adaptation, which decreases susceptibility of the muscle to develop further soreness in the subsequent ECC bout.

Long before the onset of clinical Alzheimer's disease non-fibrillar, soluble assembly states of amyloid-beta (Abeta) peptides are believed to cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Since many of the risk factors for Alzheimer's disease are vascular, impairment of cerebral blood flow by soluble Abeta has been proposed to be critical in triggering these early changes. However, it is not known if soluble Abeta can affect cerebrovascular function at the concentrations required to cause inhibition of synaptic plasticity mechanisms believed to underlie the early cognitive deficits of Alzheimer's disease. Here we developed a new method to simultaneously assess the ability of soluble Abeta to impair plasticity at synapses and to affect resting and activity-dependent local blood flow in the rat hippocampus in vivo. Intracerebroventricular injection of soluble synthetic Abeta(40) dimers rapidly inhibited plasticity of excitatory synaptic transmission at doses (10-42 pmol) comparable to natural Abeta, but failed to affect vascular function measured using laser-Doppler flowmetry (LDF). Like wild-type Abeta(40), the more vasculotropic Abeta produced by people with familial hemorrhagic stroke of the Dutch type (Abeta(40)E22Q), impaired hippocampal plasticity without causing a significant change in local blood flow. Furthermore, neither resting nor activation-evoked hippocampal perfusion was affected by soluble Abeta(42), even at a concentration that markedly (25%) reduced baseline synaptic transmission. These findings demonstrate that the putative synaptotoxic soluble Abeta species of early Alzheimer's disease cause synaptic dysfunction in the absence of detectible changes in local blood flow. This strongly indicates that early cognitive deficits can be caused by soluble Abeta independently of deleterious effects on cerebrovascular dynamics.

The local cerebral blood flow in cerebral cortical and subcortical regions of the rat brain was studied with the 14C-iodoantipyrine autoradiographic technique at rest and during strong non-noxious stimulation of the nose. Patterns of local blood flow changes evoked by stimulation with and without pretreatment of indomethacin, a potent cyclooxygenase inhibitor were determined. Stimulation produced a marked heterogeneous enhancement of CBF. Indomethacin did not prevent this effect although the absolute flow levels were considerably lower in indomethacin-treated animals. Indomethacin was especially effective in reducing the cerebral cortical blood flow response to stimulation whereas the subcortical response was much less affected.

Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-D-[(18)F]glucose without and with local blockade of NO and PG at rest and during one-legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-L-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1 and 4 cm away from the infusion of blockers. Local blockade during exercise at 25 and 40 watts significantly decreased blood flow in the infusion region and in the region 1 cm away from the site of infusion but not in the region 4 cm away. During exercise, muscle glucose uptake did not show any regional differences in response to blockade. These results show that NO and PG synergistically contribute to the local regulation of blood flow in skeletal muscle independently of muscle glucose uptake in healthy young men. Thus these vasodilators can play a role in regulating microvascular blood flow in localized regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.

Inflammation is a complex biological reaction to invasion of the host by a pathogen or harmful stimulus and is a normal response to maintain homeostasis after injury. However, unregulated or aberrant inflammatory responses are believed to be involved in the pathogenesis of a wide range of diseases, including Alzheimer’s disease, chronic depression, and autoimmune disorders such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Imaging the immune response and inflammation in preclinical models is important in the understanding of these disorders and for the development of novel therapeutics. Many processes associated with inflammation are amenable to imaging, including changes in local blood flow and cellular metabolism, presence of phagocytic cells, increased enzymatic activity, and the overexpression of certain cell surface markers that are characteristic of the immune response. Techniques such as optical fluorescence and bioluminescence imaging, magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), endoscopic imaging, and ultrasound play an important role in imaging inflammation. Visualization of drug delivery with imaging would be vital to ensure adequate exposure at the site of inflammation, particularly for targeted therapies that have been developed to reduce or eliminate toxicities from systemic exposure. Indeed, imaging plays a vital role in initial diagnosis and patient selection and for monitoring response to treatment over time. This chapter introduces inflammation and the immune system and describes numerous methods for imaging the inflammatory response, with specific applications in neuroinflammation, RA, and IBD.

Functional imaging has been used to study response to pain in fibromyalgia patients. Functional magnetic resonance imagery (fMRI) which tracks local changes in blood flow has a higher spatial and temporal resolution than other techniques such as positron emission tomography (PET) or single-photon emission tomography (SPECT). fMRI studies in fibromyalgia patients suggest that similar levels of subjective pain result in similar central nervous system (CNS) activation in both fibromyalgia patients and controls. For a similar stimulus, however, fibromyalgia patients have a greater subjective sensation of pain. This increased sensitivity is accompanied with a decreased activity in brain regions implicated in the descending pain inhibitory pathways. The hypothesis that increased sensitivity to pain is due to decreased activity of the descending inhibitory pathways is supported by results with milnacipran. Fibromyalgia patients treated with the serotonin and noradrenaline reuptake inhibitor, milnacipran, exhibited a reduction in pain sensitivity and a parallel increase in activity in brain regions implicated in the descending pain inhibitory pathways compared to placebo-treated patients.