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Abstract: Many studies of creative cognition with a neuroimaging component now exist; what do they say about where and how creativity arises in the brain? We reviewed 45 brain-imaging studies of creative cognition. We found little clear evidence of overlap in their results. Nearly as many different tests were used as there were studies; this test diversity makes it impossible to interpret the different findings across studies with any confidence. Our conclusion is that creativity research would benefit from psychometrically informed revision, and the addition of neuroimaging methods designed to provide greater spatial localization of function. Without such revision in the behavioral measures and study designs, it is hard to see the benefit of imaging. We set out eight suggestions in a manifesto for taking creativity research forward. [ABSTRACT FROM AUTHOR]

Objective – To study the post-surgical metabolic and structural cerebral changes in patients with glioblastoma multiforme (GBM). Materials and methods – We examined ten patients prospectively with newly diagnosed GBM. All patients were primarily treated with surgery, followed by chemotherapy (carmustine, cisplatine and etoposide) and radiotherapy. Positron emission tomography (PET) was used to measure tumor- and cerebral metabolism. CT or MRI was used to estimate tumor volume by measurements of tumor area. Results – Tumor metabolism was not increased during chemotherapy ( P = 0.71), but increased during radiotherapy ( P = 0.01). CT/MRI showed similar results with no increase in tumor area during chemotherapy ( P = 0.33) but increase during radiotherapy ( P = 0.002). During the entire study, tumor metabolism and area increased evenly ( P = 0.01). Conclusions – Our study did not show a gain of PET compared with structural imaging in the prospective evaluation of GBM. We found a difference in metabolic increase and tumor growth between the two treatment regimens, although this finding has limited relevance due to the design of the study. [ABSTRACT FROM AUTHOR]

Abstract: ERP waveforms evoked by target-right and target-left stimuli in a directed-attention, dichotic-listening paradigm were examined using cross-correlation analysis. We analyzed data from two experiments involving linguistic processing. They involved listening for (1) a phonemic feature, and (2) a series of morpho-syntactic anomalies. The maximum correlation between target-right and target-left waveforms was achieved when the target-right waveform was delayed relative to the target-left waveform (the τ shift), reflecting the shorter latency of the target-right waveform. We interpret the direction of displacement as equivalent to a “right-ear advantage” in the dichotic listening paradigm. In both tasks, τ shifts were not uniformly distributed across the parietal electrode array. They were greatest on the extreme left side of the head and systematically declined as the electrode site moved rightward, indicating a temporal gradient in the relative latencies of the two waveforms. Results are interpreted in relation to both structural and attentional aspects of dichotic listening. [Copyright &y& Elsevier]

This review outlines recent findings from human neuroimaging concerning the role of a highly interconnected network of brain areas including orbital and medial prefrontal cortex, amygdala, striatum and dopaminergic mid-brain in reward processing. Distinct reward-related functions can be attributed to different components of this network. Orbitofrontal cortex is involved in coding stimulus reward value and in concert with the amygdala and ventral striatum is implicated in representing predicted future reward. Such representations can be used to guide action selection for reward, a process that depends, at least in part, on orbital and medial prefrontal cortex as well as dorsal striatum. [Copyright &y& Elsevier]

Brain imaging experiments identify plausible circuits involved in the genesis of the cardinal symptoms of Parkinson''s disease. Akinesia is linked to hypoactivation of the supplementary motor area secondary to insufficient thalamocortical facilitation. Overactivation in other areas such as the lateral premotor and parietal cortex probably represents a compensatory mechanism. Bradykinesia is associated with abnormal functioning within intrinsic basal ganglia circuitry for scaling movements to appropriate magnitude. Parkinson''s disease tremor is localized to pontine- and mesencephalic-cerebellar-thalamic circuits, with abnormalities of both dopamine and serotonin neurotransmission. There is a need to understand the anatomic intersections where information is shared across these circuits. [Copyright &y& Elsevier]

Local hemodynamics of the cerebral cortex is the basis of modern functional imaging techniques, such as fMRIand PET. Despite the importance of local regulation of the blood flow, capillary level quantification of cerebral blood flow has been limited by the spatial resolution of functional imaging techniques and the depth penetration of conventional optical microscopy. Two-photon laser scanning microscopic imaging technique has the necessary spatial resolution and can image capillaries in the depth of the cortex. We have loaded the serum with fluorescein isothiocyanate dextran and quantified the flow of red blood cells (RBCs) in capillaries in layers 2/3 of the mouse somatosensory cortex in vivo. Basal capillary flux was quantified as approximately 28.9±13.6 RBCs/s (n=50, mean±S.D.) under ketamine–xylazine anesthesia and 26.7±16.0 RBCs/s (n=31) under urethane anesthesia. Focal interictal (epileptiform) activity was induced by local infusion of bicuculline methochloride in the cortex. We have observed that capillary blood flow increased as the cortical local field events developed into epileptiform in the vicinity of GABA receptor blockade (<300μm from the administration site). Local blood flow in the interictal focus increased significantly (42.5±18.5RBCs/s, n=52) relative to the control conditions or to blood flow measured in capillaries at distant (>1mm from the focus) sites from the epileptic focus (27.8±12.9 RBCs/s, n=30). These results show that hyper-synchronized neural activity is associated with increased capillary perfusion in a localized cortical area. This volume is significantly smaller than the currently available resolution of the fMRI signal. [Copyright &y& Elsevier]

We used magnetoencephalography to study effects of sleep on cortical responses to noxious stimuli and to clarify the mechanisms underlying pain perception. For a noxious stimulus, painful intra-epidermal electrical stimulation, which selectively activates A-δ fibers, was applied to the dorsum of the left hand. While awake, subjects were asked to count the number of stimuli silently (Attention) or ignore the stimuli (Control). During sleep, magnetic fields recorded in stage 1 sleep and stage 2 sleep were analyzed. One main component at a latency around 140–160 ms was identified in the awake condition. Multiple source analysis indicated that this main component was generated by activities in the contralateral primary somatosensory cortex (SI), bilateral secondary somatosensory cortex (SII) and insular cortex. The medial temporal area (MT) and cingulate cortex were activated later than the main component. Cortical responses in the contralateral SI, ipsilateral SII and MT, bilateral insula and cingulate cortex were significantly enhanced in Attention as compared with Control. The main component 1 M as well as later magnetic fields were markedly attenuated during sleep, suggesting that all these cortical areas are involved in pain cognition. [Copyright &y& Elsevier]

Abstract: In contrast to the cerebroarterial system, the cerebrovenous system is not well examined and only partly understood. The cerebrovenous system represents a complex three-dimensional structure that is often asymmetric and considerably represent more variable pattern than the arterial anatomy. Particular emphasis is devoted to the venous return to extracranial drainage routes. As the state-of-the-art-imaging methods are playing a greater role in visualizing the intracranial venous system at present, its clinically pertinent anatomy and physiology has gain increasing interest, even so only few data are available. For this reason, experimental research on specific biophysical (fluid dynamic, rheologic factors) and hemodynamic (venous pressure, cerebral venous blood flow) parameters of the cerebral venous system is more on the focus; especially as these parameters are different to the cerebral arterial system. Particular emphasis is devoted to the venous return to extracranial drainage routes. From the present point of view, it seems that the cerebrovenous system may be one of the most important factors that guarantee normal brain function. In the light of this increasing interest in the cerebral venous system, the authors have summarized the current knowledge of the physiology of the cerebrovenous system and discuss it is in the light of its clinical relevance. [Copyright &y& Elsevier]

Abstract: Motor overflow refers to the involuntary movements which may accompany the production of voluntary movements. While overflow is not usually seen in the normal population, it does present in children and the elderly, as well as those suffering certain neurological dysfunctions. Advancements in methodology over the last decade have allowed for more convincing conclusions regarding the cortical origins of motor overflow. However, despite significant research, the exact mechanism underlying the production of motor overflow is still unclear. This review presents a more comprehensive conceptualization of the theories of motor overflow, which have often been only vaguely defined. Further, the major findings are explored in an attempt to differentiate the competing theories of motor overflow production. This exploration is done in the context of a range of neurological and psychiatric disorders, in order to elucidate the possible underlying mechanisms of overflow. [Copyright &y& Elsevier]

The aim of the present study was to investigate the functional organization of the auditory cortex for pure tones of 1, 2, 4, 6, 8 and 12 kHz. Ten subjects were tested with a whole-head magnetometer (151 channels). The location, latency and amplitude of the generators of the N1m (the main component of the response, peaking approximately at 100 ms) were explored simultaneously in the right and left hemispheres under monaural stimulation. Our results revealed that tonotopy is a rather complex functional organization of the auditory cortex. From 1 to 12 kHz, tonotopic maps were found for contralateral as well as for ipsilateral stimulation: N1m generators were found to be tonotopically organized mainly in an anterior–posterior direction in both hemispheres, whatever the stimulated ear, but also in an inferior–superior direction in the right hemisphere. Furthermore, latencies were longer in the left than in the right hemisphere. Two different representations of spectral distribution were found in the right auditory cortex: one for ipsilateral and one for contralateral stimulation. [Copyright &y& Elsevier]

Bipolar affective disorder (BD) is a severe mental illness, characterized by episodes of mania and depression. With the development of Magnetic Resonance Imaging (MRI), neuroimaging methods are now allowing investigation of the neurocircuitry involved in this disorder. This in turn has aided further neuropathological exploration of the brain. Structural MRI and Magnetic Resonance Spectroscopy studies suggest that brain abnormalities in BD are mostly regional, as global measures (cerebral, white and gray matter and ventricular volumes) do not seem to be affected in the majority of patients. The prefrontal and anterior cingulate cortices, and amygdalae are consistently implicated in BD, whilst the evidence for hippocampal involvement is less convincing. Functional studies have found that the activity of the dorsal prefrontal cortex and the anterior cingulate are closely associated with mood symptoms. Activity in the ventral and orbital prefrontal cortex appears reduced both during episodes and in remission. In contrast, amygdala activity shows a persistent increase. We suggest that abnormal interaction between the amygdala and the ventral/orbitofrontal cortex may be a central feature of the pathophysiology of BD. [Copyright &y& Elsevier]

The auditory steady state response (aSSR) is an oscillatory electrical potential recorded from the scalp induced by amplitude-modulated (AM) or click/tone burst stimuli. Its clinical utility has been limited by uncertainty regarding the specific areas of the brain involved in its generation. To identify the generators of the aSSR, 15O-water PET imaging was used to locate the regions of the brain activated by a steady 1 kHz pure tone, the same tone amplitude modulated (AM) at 40 Hz and the specific regions of the brain responsive to the AM component of the stimulus relative to the continuous tone. The continuous tone produced four clusters of activation. The boundaries of these activated clusters extended to include regions in left primary auditory cortex, right non-primary auditory cortex, left thalamus, and left cingulate. The AM tone produced three clusters of activation. The boundaries of these activated clusters extended to include primary auditory cortex bilaterally, left medial geniculate and right middle frontal gyrus. Two regions were specifically responsive to the AM component of the stimulus. These activated clusters extended to include the right anterior cingulate near frontal cortex and right auditory cortex. We conclude that cortical sites, including areas outside primary auditory cortex, are involved in generating the aSSR. There was an unexpected difference between morning and afternoon session scans that may reflect a pre- versus post-prandial state. These results support the hypothesis that a distributed resonating circuit mediates the generation of the aSSR. [Copyright &y& Elsevier]

Childhood is a time filled with wondrous changes, as brain plasticity permits experiences to shape the immature brain to meet the demands of the environment. Change occurs at various levels—from neuroanatomy, including within a given region and its connectivity to other regions, to the function of neurotransmitter systems and their reactivity to pharmacological agents in the short- and long-term. The nature and degree to which drug exposure influences the final adult topography is influenced greatly by the maturational phase of these critical factors. Moreover, evidence is slowly emerging that suggests that the long-term effects of drug exposure are delayed and expressed once the vulnerable system reaches maturation (i.e., typically during adulthood). This phenomenon is known as neuronal imprinting and occurs when the effects of drug exposure outlast the drug itself. Thus, understanding the persistent effects critically depends on the window of observation. Embracing this concept should influence how we conduct preclinical assessments of developmental drug exposure, and ultimately how we conduct clinical assessments of drug efficacy, effectiveness, and safety for the treatment of childhood psychiatric disorders. In this article, we present a model to provide a heuristic framework for making predictions about imprinted effects of childhood drug exposure. We then review epidemiological data on attention deficit hyperactivity disorder (ADHD) and childhood depression, prescription practices, and what is known regarding the long-term consequences of drug exposure in these populations. We conclude with a discussion of the current status of preclinical studies on juvenile stimulant exposure. [Copyright &y& Elsevier]

Prior studies have shown that tactile perception recruits activity not only in somatosensory but also in visual cortical areas. The present study used functional magnetic resonance imaging to investigate the distribution of neural activity during tactile perception of 2D form. In a macrospatial form task, raised letters (uppercase T and V) were presented upside-down. In a microspatial form task, a bar, either with or without a gap, was presented. Stimuli were applied to the immobilized right index fingerpad. Six neurologically normal volunteers were studied in a block design paradigm, with alternating blocks of rest and covert discrimination between the two alternatives for a task. Each task was studied in a separate run. Contrasting macrospatial form discrimination against rest revealed activity in an extensive, bilateral network of cortical and subcortical regions, including areas of somatosensory cortex and the intraparietal sulcus (IPS), occipito-temporal cortex, dorsal and ventral premotor cortex, medial superior frontal cortex, lateral inferior frontal cortex, thalamus and cerebellar hemispheres. Contrasting (microspatial) gap detection against rest showed activity in a similar network, with the notable exception of the occipito-temporal cortical regions. A direct contrast between the two tasks yielded greater activity for the macrospatial than microspatial task in these occipito-temporal regions bilaterally, and also in foci near the right IPS and in the right cerebellar hemisphere. The occipito-temporal cortical activations were in the lateral occipital complex, a part of the ventral visual pathway active during visual form perception. Thus, macrospatial form perception preferentially recruits this region of extrastriate visual cortex, compared to microspatial form perception. [Copyright &y& Elsevier]

Two- or 100-Hz electrical acupoint stimulation (EAS) can induce analgesia via distinct central mechanisms. It has long been known that the extent of EAS analgesia showed tremendous difference among subjects. Functional MRI (fMRI) studies were performed to allocate the possible mechanisms underlying the frequency specificity as well as individual variability of EAS analgesia. In either frequencies, the averaged fMRI activation levels of bilateral secondary somatosensory area and insula, contralateral anterior cingulate cortex and thalamus were positively correlated with the EAS-induced analgesic effect across the subjects. In 2-Hz EAS group, positive correlations were observed in contralateral primary motor area, supplementary motor area, and ipsilateral superior temporal gyrus, while negative correlations were found in bilateral hippocampus. In 100-Hz EAS group, positive correlations were observed in contralateral inferior parietal lobule, ipsilateral anterior cingulate cortex, nucleus accumbens, and pons, while negative correlation was detected in contralateral amygdala. These results suggest that functional activities of certain brain areas might be correlated with the effect of EAS-induced analgesia, in a frequency-dependent dynamic. EAS-induced analgesia with low and high frequencies seems to be mediated by different, though overlapped, brain networks. The differential activations/de-activations in brain networks across subjects may provide a neurobiological explanation for the mechanisms of the induction and the individual variability of analgesic effect induced by EAS, or that of manual acupuncture as well. [Copyright &y& Elsevier]

In the literature on bilingualism, cognate relatedness has been shown to interact with proficiency in the foreign language such that cognate items are a measure of higher mastery than non-cognate ones. Systematic variation of these items in an activation study thus allows inter-subject control of different proficiency levels in the same bilingual subject. A positron emission tomography (PET) experiment was conducted with 11 Belgian subjects who were native speakers of Flemish/Dutch and had good proficiency in French. The experimental task consisted of internally naming pictures of objects in French and Dutch. For each language, there were two conditions. In one condition, the picture names were cognate across both languages, i.e. the translation equivalents shared phonological/orthographic similarity. In a second condition, picture names were non-cognate items without phonological/orthographic similarity in the French-Dutch translation equivalents. The items in both subsets were matched for visual complexity, object familiarity and familiarity of the French word. The results of our PET experiment on bilingual production showed hardly any difference between L2 cognates, L1 cognates and L1 non-cognates. The few significant differences of activation between L1 and L2 were almost exclusively due to increased activation for French non-cognate items in left inferior frontal and temporo-parietal areas. Thus, non-cognate foreign language naming recruited additional brain regions compared to native language non-cognate and native as well as foreign language cognate items. In our study, these areas of additional activation in L2 non-cognates were restricted to left hemispheric inferior frontal and temporal structures in or at the periphery of the known language areas. In conclusion, the bilingual production study presented here supports an important role of proficiency in activation differences between L1 and L2. The results suggest a relation between activation in left BA 20, BA 44 and BA 47 and effortful lexical retrieval. Our results are not in line with the hypothesis of entirely distinct neural substrates for the different languages of a bilingual individual. [Copyright &y& Elsevier]

Recent data demonstrate that the cerebellum contributes to the internal representation of action. This representation is used not only to generate motor actions, but also to understand and learn the actions and skills of others by imitation. The cerebellar networks appear to be indispensable for acquiring complex behaviors and procedures. The cerebellar role in the acquisition of procedural competencies is particularly evident in spatial information processing. The cerebellum allows acquiring by observation competencies in exploration behaviors as efficient as the competencies acquired by actually performing the same task. The specificity of the cerebellar role in the acquisition phases of learning by observation is demonstrated by the complete absence of spatial learning when the observational training is performed in presence of a cerebellar lesion. This datum is further corroborated by the evidence that, once acquired, spatial procedures can be efficiently performed even in the presence of cerebellar damage, in agreement with the neuroimaging findings of low cerebellar activation after prolonged practice. The finding that the cerebellum is involved in procedural acquisition and in observational learning allowed us to dissect a complex behavior into single behavioral units forming a complete procedural sequence, demonstrating that such behavioral units do exist and can be independently acquired. [Copyright &y& Elsevier]

The renaissance of glucose–insulin–potassium infusion (GIK) as a treatment of acute myocardial infarction both in diabetic and nondiabetic subjects has raised new interests to clarify the effects and mechanisms of insulin on myocardium. Although the action of insulin on substrate metabolism is quite well studied in heart, the cardiovascular effects were until recent years poorly known. Insulin induces skeletal muscle vasodilation mainly via the endothelium-dependent mechanism and appears to have an important role in normal vascular function. There is increasing amount of evidence that insulin acts as a vasodilatory hormone also in coronary arteries. Insulin enhances myocardial blood flow and decreases coronary vascular resistance in a dose-dependent manner in healthy subjects. Moreover, insulin is able to increase myocardial blood flow also in subjects who are characterized by coronary dysfunction such as subjects with obesity, type 1 diabetes and coronary artery disease. However, vasodilatory effect of insulin may be blunted in these patients. Since already very small increase in myocardial blood flow can reduce significantly myocardial ischemia, these vasodilatory actions of insulin in coronary arteries might partly contribute to beneficial effects of GIK therapy. On the other hand, in contrast to these acute beneficial effect of insulin, epidemiological studies have indentified chronic hyperinsulinemia, a common feature in subjects with insulin resistance to glucose uptake, as an independent risk factor for coronary artery disease. The present article review the physiological and pathophysiological role of insulin in cardiac vasculature and its clinical importance during myocardial ischemia and development of coronary artery disease. [Copyright &y& Elsevier]

Tinnitus is most often initiated by modality specific otopathologic disturbances affecting peripheral and central auditory pathways. However, there is growing evidence indicating that the anatomical location generating tinnitus occurs at sites different from the initial pathology. Support for this notion is found in individuals where tinnitus can be triggered or modulated by inputs from other sensory modalities or sensorimotor systems (somatosensory, somatomotor, visual-motor). The use of functional imaging methods combined with psychophysics, detailed physical examinations and questionnaire-based assessments has reinforced and validated these observations. Available data suggest that tinnitus-related crossmodal interactions are more common than previously anticipated. This communication reviews these advancements and suggests that a relatively broad multimodal network of neurons is involved in generating and sustaining the tinnitus perception in some forms of the disorder. Also implicated as part of the tinnitus experience are interactions within large-scale neural networks subserving attention, cognition, and emotion. Incorporating this knowledge into contemporary psychophysiological models will help facilitate the conceptualization of this phantom perception in a more comprehensive manner. [Copyright &y& Elsevier]

In vivo microdialysis offers a unique approach to monitor biochemical events related to brain function and metabolism, and has been used extensively in many systems to measure the release of endogenous transmitters and other neuroactive substances during normal and pathological conditions. The characterization of neurotransmitters’ changes induced by salicylate in the inferior colliculus (IC) and the auditory cortex (AC) may provide insight into the action of salicylate on the auditory system and, through this, provide a better understanding of neurological mechanism of salicylate-induced tinnitus. In the present study, the effect of salicylate on 5-HT system in IC and AC has been monitored by microdialysis in salicylate-induced tinnitus animal models. Glucose and lactate levels in IC and AC were significantly increased after application of salicylate (350 mg/kg, i.p.), indicating a salicylate-related increase in regional neuronal activity. The 5-HT level increased to a maximum of 268±27% basal level in IC 2 h after application and of 277±24% basal level in AC around 3 h after application. These data suggest that the increases of 5-HT levels in IC and AC may be involved in the tinnitus generation. [Copyright &y& Elsevier]

The CB1 cannabinoid receptor is expressed in the brain at levels sufficient to serve as potential target for in vivo imaging using positron emission tomography (PET) or single photon emission computed tomography methodology. To date, the most promising radioligands for the in vivo imaging of this receptor have structures based on that of the cannabinoid antagonist, SR141716A. Rodent data obtained using these in vivo radiotracers has demonstrated that both the behavioral and neurochemical effects of cannabinoids occur at very low levels of receptor occupancy. More recently, an agonist radiotracer based on the structure of aminoalkylindole cannabinoids has also been examined for in vivo labeling of CB1 receptors. Although rodent studies have indicated that in vivo imaging of CB1 receptors is feasible, at the present time this receptor has still to be successful imaged in a human PET study. [Copyright &y& Elsevier]

Noninvasive in vivo molecular imaging has developed over the past decade and involves nuclear (Positron emission tomography (PET), gamma camera), magnetic resonance, and in vivo optical imaging systems. Most current in vivo molecular imaging strategies are “indirect” and involve the coupling of a “reporter gene” with a complimentary “reporter probe”. Imaging the level of probe accumulation provides indirect information related to the level of reporter gene expression. Reporter gene constructs are driven by upstream promoter/enhancer elements; they can be constitutive leading to continuous transcription and used to identify the site of transduction and to monitor the level and duration of gene (vector) activity. Alternatively, they can be inducible leading to controlled gene expression, or they can function as a sensor element to monitor the level of endogenous promoters and transcription factors. Several examples of imaging endogenous biological processes in animals using reporter constructs, radiolabelled probes and PET imaging are reviewed (p53-dependent gene expression and T-cell receptor-dependent activation of T-lymphocytes). Issues related to the translation of non-invasive molecular imaging technology into the clinic are discussed. [Copyright &y& Elsevier]

Alzheimer’s disease (AD) is the most common form of degenerative dementia and is characterized by progressive impairment in cognitive function during mid- to late-adult life. Brains from AD patients show several distinct neuropathological features, including extracellular β-amyloid-containing plaques, intracellular neurofibrillary tangles composed of abnormally phosphorylated τ, and degeneration of cholinergic neurons of the basal forebrain. In this review, we will present evidence implicating involvement of the basal forebrain cholinergic system in AD pathogenesis and its accompanying cognitive deficits. We will initially discuss recent results indicating a link between cholinergic mechanisms and the pathogenic events that characterize AD, notably amyloid-β peptides. Following this, animal models of dementia will be discussed in light of the relationship between basal forebrain cholinergic hypofunction and cognitive impairments in AD. Finally, past, present, and future treatment strategies aimed at alleviating the cognitive symptomatology of AD by improving basal forebrain cholinergic function will be addressed. [Copyright &y& Elsevier]

Previous neuroimaging studies generally demonstrate a growth in the cortical response with an increase in sound level. However, the details of the shape and topographic location of such growth remain largely unknown. One limiting methodological factor has been the relatively sparse sampling of sound intensities. Additionally, most studies have either analysed the entire auditory cortex without differentiating primary and non-primary regions or have limited their analyses to Heschl’s gyrus (HG). Here, we characterise the pattern of responses to a 300-Hz tone presented in 6-dB steps from 42 to 96 dB sound pressure level as a function of its sound level, within three anatomically defined auditory areas; the primary area, on HG, and two non-primary areas, consisting of a small area lateral to the axis of HG (the anterior lateral area, ALA) and the posterior part of auditory cortex (the planum temporale, PT). Extent and magnitude of auditory activation increased non-linearly with sound level. In HG, the extent and magnitude were more sensitive to increasing level than in ALA and PT. Thus, HG appears to have a larger involvement in sound-level processing than does ALA or PT. [ABSTRACT FROM AUTHOR]

Using a single-blind placebo-controlled design, we mapped lidocaine related changes in neural activity, measured by regional cerebral blood flow (rCBF) with 15O-H2O positron emission tomography. Intravenous lidocaine produced both increases and decreases in the loudness of tinnitus. The change in tinnitus loudness was associated with a statistically significant change in neural activity in the right temporal lobe in auditory association cortex. Decreases in tinnitus loudness resulted in larger changes in rCBF than increases. The unilateral activation pattern associated with tinnitus, in contrast with the bilateral activation produced by a real sound, suggests that tinnitus originates in the central auditory system rather than the cochlea. In addition, generalized lidocaine effects were found in the basal ganglia, thalamus, and a region spanning the Rolandic fissure. [ABSTRACT FROM AUTHOR]

Cerebral processing of first pain, associated with Aδ-fibers, has been studied intensively, but the cerebral processing associated with unmyelinated C-fibers, relating to second pain, remains to be investigated. This is the first study to clarify the primary cortical processing of second pain by magnetoencephalography, through the selective activation of C-fibers, by the stimulation of a tiny area of skin with a CO2 laser. In the hemisphere contralateral to the side stimulated, a one-source generator in the upper bank of the Sylvian fissure (secondary somatosensory cortex, SII) or two-source generators in SII and the hand area of the primary somatosensory cortex (SI) were the optimal configurations for the first component 1M. The onset and peak latency of the two sources in SI and SII were not significantly different. In the hemisphere ipsilateral to the stimulation, only one source was estimated in SII, and its peak latency was significantly (approximately 18 ms on average) longer than that of the SII source in the contralateral hemisphere.From our findings we suggest that parallel activation of SI and SII contralateral to the stimulation represents the first step in the cortical processing of C-fiber-related activities, probably related to second pain. [Copyright &y& Elsevier]

We studied the auditory evoked magnetic fields (AEFs) in response to pure tones especially at very high frequencies (from 4000 Hz to 40 000 Hz). This is the first systematic study of AEFs using tones above 5000 Hz, the upper audible range of humans, and ultrasound. We performed two experiments. In the first, AEFs were recorded in 12 subjects from both hemispheres under binaural listening conditions. Six types of auditory stimulus (pure tones of five different frequencies: 4000 Hz, 8000 Hz, 10 000 Hz, 12 000 Hz, 14 000 Hz, and a click sound as the target stimulus) were used. In the second experiment, we used 1000 Hz, 15 000 Hz, and two ultrasounds with frequencies of 20 000 Hz and 40 000 Hz. The subjects could detect all stimuli in the first experiment but not the ultrasounds in the second experiment.We analyzed N1m, the main response with approximately 100 ms in peak latency, and made the following findings. (1) N1m responses to the tones up to 12 000 Hz were clearly recorded from at least one hemisphere in all 12 subjects. N1m for 14 000 Hz was identified in at least one hemisphere in 10 subjects, and in both hemispheres in six subjects. No significant response could be identified to ultrasounds over 20 000 Hz. (2) The amplitude of the N1m to the tones above 8000 Hz was significantly smaller than that to 4000 Hz in both hemispheres. There was a tendency for the peak latency of the N1m to be longer for the tones with higher frequencies, but no significant change was found. (3) The equivalent current dipole (ECD) of the N1m was located in the auditory cortex. There was a tendency for the ECD for the tones with higher frequencies to lie in more medial and posterior areas, but no significant change was found. (4) As for the interhemispheric difference, the N1m amplitude for all frequency tones was significantly larger and the ECDs were estimated to be located more anterior and medial in the right hemisphere than the left. The priority of the right hemisphere, that is the larger amplitude, for very high frequency tones was confirmed. (5) The orientation of the ECD in the left hemisphere became significantly more vertical the higher the tones. This result was consistent with previous studies which revealed the sensitivity of the frequency difference in the left hemisphere.From these findings we suggest that tonotopy in the auditory cortex exists up to the upper limit of audible range within the small area, where the directly air-conducted ultrasounds are not reflected. [Copyright &y& Elsevier]

Neurotransmitter receptor systems have been the focus of intensive pharmacological research for more than 20 years for basic and applied scientific reasons, but only recently has there been a better understanding of their key features. One of these systems includes the type A receptor for the γ-aminobutyric acid (GABA), which forms an integral anion channel from a pentameric subunit assembly and mediates most of the fast inhibitory neurotransmission in the adult vertebrate central nervous system. Up to now, depending on the definition, 16–19 mammalian subunits have been cloned and localized on different genes. Their assembly into proteins in a poorly defined stoichiometry forms the basis of functional and pharmacological GABAA receptor diversity, i.e. the receptor subtypes. The latter has been well documented in autoradiographic studies using ligands that label some of the receptors’ various binding sites, corroborated by recombinant expression studies using the same tools. Significantly less heterogeneity has been found at the physiological level in native receptors, where the subunit combinations have been difficult to dissect.This review focuses on the characteristics, use and usefulness of various ligands and their binding sites to probe GABAA receptor properties and to gain insight into the biological function from fish to man and into evolutionary conserved GABAA receptor heterogeneity. We also summarize the properties of the novel mouse models created for the study of various brain functions and review the state-of-the-art imaging of brain GABAA receptors in various human neuropsychiatric conditions.The data indicate that the present ligands are only partly satisfactory tools and further ligands with subtype-selective properties are needed for imaging purposes and for confirming the behavioral and functional results of the studies presently carried out in gene-targeted mice with other species, including man. [Copyright &y& Elsevier]

Language is constituted by discrete building blocks, sounds and words, which can be concatenated according to serial order principles. The neurobiological organization of these building blocks, in particular words, has been illuminated by recent metabolic and neurophysiological imaging studies. When humans process words of different kinds, various sets of cortical areas have been found to become active differentially. The old concept of two language centers processing all words alike must therefore be replaced by a model according to which words are organized as discrete distributed neuron ensembles that differ in their cortical topographies. The meaning of a word, more precisely, aspects of its reference, may be crucial for determining which set of cortical areas becomes involved in its processing. Whereas the serial order of sounds constituting a word may be established by serially aligned sets of neurons called synfire chains, different mechanisms are necessary for establishing word order in sentences. The serial order of words may be organized by higher-order neuronal sets, called sequence detectors here, which are being activated by sequential excitation of neuronal sets representing words. Sets of sequence detectors are proposed to process aspects of the syntactic information contained in a sentence. Other syntactic rules can be related to general features of the dynamics of cortical activation and deactivation. These postulates about the brain mechanisms of language, which are rooted in principles known from neuroanatomy and neurophysiology, may provide a framework for theory-driven neuroscientific research on language. [Copyright &y& Elsevier]

Objective: To investigate the effect of vinpocetine on cerebral blood flow (CBF) in the compromised circulation of a stroke affected hemisphere using transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) methods. Methods: 43 patients with ischemic stroke were randomized into vinpocetine (VP) and placebo group in a double blind, placebo-controlled study of the effect of a single-dose i.v. infusion of vinpocetine on cerebral blood perfusion and oxygenation. In the VP group 20 mg VP in 500 ml saline, in the placebo group 500 ml saline alone were administered. The concentrations of oxy-, reduced- and total hemoglobin were measured by NIRS frontolaterally on the side of lesion while the mean cerebral blood flow velocity (CBFV), the pulsatility index (PI) and Doppler spectral intensity (DSI) were monitored by TCD in the middle cerebral artery on the same side. Values were averaged for the first 5 min prior to the infusion and for the last 5 min of infusion and they were compared between groups. Results: The concentration of all three chromophores increased during infusion in the VP group (mean dHbT=1.03, CI95=0.84, P=0.058; mean dHbO=0.92, CI95=0.91, P=0.071; mean dHb=0.10, CI95=0.21, P=0.297). The HbT and HbO showed a substantially smaller increase in the placebo group (mean dHbT=0.31, CI95=0.74, P=0.22; mean dHbO=0.57, CI95=0.80, P=0.094) while the Hb decreased (mean dHb=−0.26, CI95=0.29, P=0.05). Comparing to the placebo group Hb increased significantly in the VP group (P=0.027) while the increase of HbO and HbT did not reach the level of significance (P=0.29 and 0.11). DSI showed a significantly larger increase in the VP than in placebo group (dDSI=25.8 CI95=8.8 [VP]; dDSI=3.3, CI95=3.7 [Placebo], P<0.005). The CBFV and PI did not differ significantly between groups. (dVm=5.0±2.98 cm/s [VP], dVm=4.1±2.57 cm/s [Placebo], P=0.28; dPI=0.08 [VP], dPI=0.09 [Placebo]; P=0.47). Conclusion: VP increases cerebral perfusion and parenchymal oxygen extraction as well. The increased perfusion was indicated by NIRS and by TCD measurement of DSI while conventional velocity and pulsatility measurements failed to detect theses effects. NIRS is a sensitive, feasible method of measuring changes in regional blood flow and tissue oxygenation in the superficial cortex. [Copyright &y& Elsevier]

Positron emission tomography imaging was used to investigate the brain activation patterns of listeners presented monaurally (right ear) with speech and nonspeech stimuli. The major objectives were to identify regions involved with speech and nonspeech processing, and to develop a stimulus paradigm suitable for studies of cochlear-implant subjects. Scans were acquired under a silent condition and stimulus conditions that required listeners to press a response button to repeated words, sentences, time-reversed (TR) words, or TR sentences. Group-averaged data showed activated foci in the posterior superior temporal gyrus (STG) bilaterally and in or near the anterior insula/frontal operculum across all stimulus conditions compared to silence. The anterior STG was activated bilaterally for speech signals, but only on the right side for TR sentences. Only nonspeech conditions showed frontal-lobe activation in both the left inferior frontal gyrus [Brodmann’s area (BA) 47] and ventromedial prefrontal areas (BA 10/11). An STG focus near the superior temporal sulcus was observed for sentence compared to word. The present findings show that both speech and nonspeech engaged a distributed network in temporal cortex for early acoustic and prelexical phonological analysis. Yet backward speech, though lacking semantic content, is perceived as speechlike by engaging prefrontal regions implicated in lexico-semantic processing. [Copyright &y& Elsevier]

This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level. [Copyright &y& Elsevier]

D-Methionine has recently been advocated as a protectant against cisplatin toxicity. The use of systemic D-methionine as a protector was studied in 58 guinea pigs. Kinetics and distribution of [11CH3]D-methionine was analysed by positron emission tomography. Cisplatin and the monohydrated complex of cisplatin was quantified in blood ultrafiltrate using reversed-phase liquid chromatography with post-column derivatisation. Administration of 300 mg/kg of D-methionine caused a 30% decrease in the area under the concentration–time curve (AUC) of cisplatin. The toxic effect of cisplatin was studied after dose adjustment of cisplatin, i.e. with similar cisplatin AUC in the group receiving D-methionine and the saline control group. A significant ototoxic effect, measured as difference in pre- and 96 h post-treatment electrophysiological hearing threshold (auditory brainstem response), was observed at stimulus frequencies of 30 and 20 kHz. There was no difference between the groups in the extent of threshold shift. Quantitative outer hair cell counts showed a similar loss of cells in the two groups. All animals had a significant increase in plasma-creatinine but there was no difference between the groups. The results indicate that protection from cisplatin ototoxicity by systemic D-methionine can be explained by a lowered systemic exposure to the drug. [ABSTRACT FROM AUTHOR]

The purpose of this review is to assess the evidence of healthcare benefits involving the application of artificial neural networks to the clinical functions of diagnosis, prognosis and survival analysis, in the medical domains of oncology, critical care and cardiovascular medicine. The primary source of publications is PUBMED listings under Randomised Controlled Trials and Clinical Trials. The roˆle of neural networks is introduced within the context of advances in medical decision support arising from parallel developments in statistics and artificial intelligence. This is followed by a survey of published Randomised Controlled Trials and Clinical Trials, leading to recommendations for good practice in the design and evaluation of neural networks for use in medical intervention. [Copyright &y& Elsevier]