Koichi Ishizu

Positron emission tomography of cortical centers of tinnitus

Tinnitus is associated with a wide variety of disorders in the auditory system. Whether generated peripherally or centrally, tinnitus is believed to be associated with activity in specific cortical regions. The present study tested the hypothesis that these cortical centers subserve the generation, perception and processing of the tinnitus stimulus and that these processes are suppressed by lidocaine and masking. Positron emission tomography was used to map the tinnitus-specific central activity. By subtracting positron emission tomography images of regional cerebral blood flow distribution obtained during suppression of the tinnitus from positron emission tomography images obtained during the habitual tinnitus sensation, we were able to identify brain areas concerned with the cerebral representation of tinnitus. Increased neuronal activity caused by tinnitus occurred predominantly in the right hemisphere with significant foci in the middle frontal and middle temporal gyri, in addition to lateral and mesial posterior sites. The results are consistent with the hypothesis that the sensation of tinnitus is associated with activity in cortical regions functionally linked to subserve attention, emotion and memory. For the first time, the functional anatomy of conditions with and without the habitual tinnitus sensation was obtained and compared in the same subjects.

Cortical networks subserving the perception of tinnitus - A PET study

Subjective tinnitus is an auditory phantom perception that may arise from any aberrant signal within the auditory system. Further processing of this signal and the conscious perception of tinnitus takes place in the cerebral cortex. A few functional brain-imaging studies have been performed to elucidate the underlying cerebral mechanisms of this perception. These studies mostly concern rare types of tinnitus (e.g. tinnitus changeable by oral-facial movements), or compared tinnitus patients with healthy volunteers. These studies attributed variable activation of the primary auditory cortices, associative auditory cortices and the left hippocampus to the perception of tinnitus. Based on these heterogeneous results, no consensus on the underlying mechanisms has been reached. The aim of the present study was to obtain further details of the central perception and processing of the tinnitus signal. Positron emission tomography (PET) was used to map the tinnitus-specific central activity. By contrasting PET-images of suppressed tinnitus with PET-images of the habitual tinnitus sensation, we were able to identify a right prefrontal-temporal network associated with the perception of tinnitus. Besides the evidence of activation of associative auditory sensory regions, the results indicated that activation of cortical centres subserving attention and emotion may underlie the continuous irritability associated with severe tinnitus.

Stimulus-dependent central processing of auditory stimuli: A PET study

Positron emission tomography (PET) was used to investigate the neural systems involved in the central processing of different auditory stimuli. Noise, pure tone and pure-tone pulses, music and speech were presented monaurally. O-15-water PET scans were obtained in relation to these stimulations presented to five normal hearing and healthy subjects. All stimuli were related to a basic scan in silence. Processing of simple auditory stimuli, such as pure tones and noise, predominantly activate the left transverse temporal gyrus (Brodmann area [BA] 41), whereas sounds with discontinued acoustic patterns, such as pure-tone pulse trains, activated parts of the auditory association area in the superior temporal gyri (BA 42) in both hemispheres. Moreover, sounds with complex spectral, intensity, and temporal structures (words, speech, music) activated spatially even more extensive associative auditory areas in both hemispheres (BA 21, 22). PET has revealed a remarkable potential to investigate early central auditory processing, and has provided evidence of the coexistence of functionally linked, but individually active parallel and serial auditory networks.

Positron emission tomography of radioligand binding in porcine striatum in vivo: Haloperidol inhibition linked to endogenous ligand release

The ligands N‐methylspiperone and haloperidol both bind to D2‐like dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3‐N‐[11C]methylspiperone ([11C]NMSP) and haloperidol binding to striatal dopamine D2‐like receptors with positron emission tomography (PET) of pig brain. [11C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time–activity curves of the striatum and cerebellum from metabolite‐corrected arterial plasma [11C]NMSP and haloperidol concentrations. Two types of [11C]NMSP‐binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [11C]NMSP irreversibly, as dopamine D2‐like receptors, while the secondary sites bound [11C]NMSP reversibly, as do serotonin S2 receptors. Woolf‐Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm−3 in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm−3. Second‐order polynomial Eadie‐Hofstee‐Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6–7‐fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol. Synapse 38:87–101, 2000.

Cortical Centres Underlying Auditory Temporal Processing in Humans: A PET Study

We have used positron emission tomography (PET) to test a specific hypothesis of a neural system subserving auditory temporal processing (acoustical stimulus duration discrimination). Maps of the cerebral blood flow distribution during specific stimulations weobtained from five normally-hearing and otherwise healthy subjects. The auditory stimuli consisted of sounds of varying duration and of auditorily presented words in which the duration of the initial phoneme was manipulated. All stimuli alternated with conditions of silence in a subtraction paradigm. The blood flow distribution was mapped with O-15-labelled water. The results demonstrated that stimuli requiring recognizing, memorizing, or attending to specific target sounds during temporal processing generally resulted in significant activation of both frontal lobes and the parietal lobe in the right hemisphere. Based on these results, we hypothesise that a network consisting of anterior and posterior auditory attention and short-term memory sites subserves acoustical stimulus duration perception and analysis (auditory temporal processing).

Quantitative PET analysis of regional cerebral blood flow and glucose and oxygen metabolism in response to fenfluramine in living porcine brain

The serotonin agonist fenfluramine has been used widely in humans for studying neuronal activation. We carried out the present study in order to determine whether anesthetized pigs could be used for studying effects of fenfluramine on cerebral functions using positron emission tomography (PET). We obtained quantitative measures of regional cerebral blood flow (rCBF) and of glucose and oxygen utilization (rCMRglc and rCMR(O2)) during intravenous administration of fenfluramine, using [15O]water, [18F]FDG and [15O]oxygen, respectively. Fenfluramine (25 mg/h i.v.) caused a significant rise in rCBF and, to a lesser extent, in rCMR2(O2), but it failed to affect rCMRglc. The findings indicate that quantitative estimation of rCBF by repeated injection of [15O]water was more sensitive than either rCMRO2 or rCMRglc for detecting effects of fenfluramine on serotonin neurotransmission in living porcine brain.

[14C]Serotonin uptake and [O-methyl-11C]venlafaxine kinetics in porcine brain

As part of our program of developing PET tracers for neuroimaging of psychotropic compounds, venlafaxine, an antidepressant drug, was evaluated. First, we measured in vitro rates of serotonin uptake in synaptosomes prepared from selected regions of porcine brain. Then, we determined the pharmacokinetics of venlafaxine, [O-methyl-11C]-labeled for PET. Synaptosomal studies showed that the active uptake of [14C]5-HT differed markedly between brain regions, with highest rates in hypothalamus, raphé region, and thalamus, and lowest rates in cortex and cerebellum. PET studies showed that the unidirectional rate of uptake of [O-methyl-11C]venlafaxine from blood to brain was highest in the hypothalamus, raphé region, thalamus and basal ganglia and lowest in the cortex and cerebellum. Under normal physiological conditions, the capillary permeability-surface area (PS) product for [O-methyl-11C]venlafaxine could not be estimated, because of complete flow-limitation of the cerebral uptake. Nevertheless, a correlation occurred between the apparent partition volume of the radiotracer and the rate of active uptake of 5-HT in selected regions of the porcine brain. During hypercapnia, limitations of blood-brain transfer were observed, giving PS-products for water that were only ca. 50% higher than those of venlafaxine. Thus, under normal physiological conditions, the rate of uptake of venlafaxine from blood into brain is completely flow-limited.