Tomáš Paus

Why do many psychiatric disorders emerge during adolescence

The peak age of onset for many psychiatric disorders is adolescence, a time of remarkable physical and behavioural changes. The processes in the brain that underlie these behavioural changes have been the subject of recent investigations. What do we know about the maturation of the human brain during adolescence? Do structural changes in the cerebral cortex reflect synaptic pruning? Are increases in white-matter volume driven by myelination? Is the adolescent brain more or less sensitive to reward? Finding answers to these questions might enable us to further our understanding of mental health during adolescence.

Location and function of the human frontal eye-field: A selective review

The location and possible function of the human frontal eye-field (FEF) were evaluated by reviewing results of cerebral blood-flow (CBF) and lesion studies. A remarkable consistency was found regarding the rostro-caudal (Y: from -6 to 1 mm) and dorso-ventral (Z: from 44 to 51 mm) location of the FEF, as defined by the CBF method within a standardized stereotaxic system (the zero point for all X, Y and Z coordinates coinciding with the anterior commissure, Talairach and Tournoux [Co-planar Stereotactic Atlas of the Human Brain, Georg Thieme, Stuttgart, 1988]. In contrast, there was a marked variability along the mediolateral axis (X: from -24 to -40 mm for the left hemisphere and from 21 to 40 mm for the right hemisphere). The human FEF is thus located either in the vicinity of the precentral sulcus and/or in the depth of the caudalmost part of the superior frontal sulcus. In either case, this location challenges the commonly held view of the FEF being located in Broadmanns area 8. With regard to FEF function, the results of CBF studies failed to support a role for the FEF in the cognitive aspects of oculomotor control, such as the execution of anti-saccades. Blood-flow activation data are consistent in this respect with the results of lesion studies. It is proposed that future research on FEF function in human subjects may benefit from focusing on the visuomotor rather than the cognitive aspects of oculomotor control.

Transcranial Magnetic Stimulation during Positron Emission Tomography: A New Method for Studying Connectivity of the Human Cerebral Cortex

We describe a new technique permitting the mapping of neural connections in the living human brain. The method combines two well established tools of brain research: transcranial magnetic stimulation (TMS) and positron emission tomography (PET). We use TMS to stimulate directly a selected cortical area while simultaneously measuring changes in brain activity, indexed by cerebral blood flow (CBF), with PET. The exact location of the stimulation site is achieved by means of frameless stereotaxy. In the first study using this technique, we found significant positive correlations between CBF and the number of TMS pulse trains at the stimulation site, namely the left frontal eye field (FEF) and, most importantly, in the visual cortex of the superior parietal and medial parieto-occipital regions. The pattern of these distal effects was consistent with the known anatomic connectivity of the monkey FEF. We suggest that the combined TMS/PET technique offers an objective tool for assessing the state of functional connectivity without requiring the subject to engage in any specific behavior.

Repetitive Transcranial Magnetic Stimulation of the Human Prefrontal Cortex Induces Dopamine Release in the Caudate Nucleus

Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinsons disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.

Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex : a review of 107 PET activation studies

WE reviewed 107 blood flow activation studies carried out with positron emission tomography and published between January 1993 and November 1996. These studies had reported their findings as peaks of significant difference in cerebral blood-flow (CBF) between two scans/tasks and had located the peaks in standardized stereotaxic space. We coded each task along several dimensions, including the type and rate of input and output, the types of cognitive processes, and the relative difficulty of tasks within a study. Based on this coding, a difference score (A–B) was calculated for each subtraction. Subsequently, the frequency distributions of the difference scores for subtractions yielding a peak in the anterior cingulate region (cingulate peak) were compared with those distributions obtained from subtractions without a cingulate peak (no cingulate-peak). The cingulate peak subtractions (n = 158) differed from the no cingulate peak subtractions (n = 229) in terms of difficulty level (p = 0.001) and the presence of a remote memory component (p = 0.01). Regional differences in the frequency distribution of certain task parameters, such as difficulty level, recent memory and the use of the hand for responding, were also observed when peaks found in the anterior cingulate cortex (ACC) were further classified as located in the rostral vs caudal ACC, supracallosal vs subcallosal ACC, and limbic vs paralimbic parts of the supracallosal ACC. We conclude that task difficulty plays a major role in modulating blood-flow response in the ACC, possibly interacting with other parameters such as the nature of the response and memory demands.

Modulation of cortical excitability during action observation: a transcranial magnetic stimulation study.

Paired-pulse transcranial magnetic stimulation (TMS) was used to examine changes in cortical excitability during action observation. We stimulated the left primary motor cortex (M1) of eight healthy volunteers during rest, observation of handwriting and observation of arm movements. Motor evoked potentials (MEP) were recorded from the first dorsal intereosseous (FDI) and biceps (BIC) muscles. Our results showed that action observation induced a facilitation of the MEP amplitude evoked by the single test stimulus and reduced intracortical inhibition and facilitation at 3 ms and 12 ms interstimulus intervals (ISIs), respectively, during paired-pulse stimulation. These changes were specific for the muscle involved in the observed action. Our study presents further evidence that motor excitability is significantly modified when the subject observes an action performed by another individual.

Brain Mechanisms of Propofol-Induced Loss of Consciousness in Humans: a Positron Emission Tomographic Study

In the present study, we used positron emission tomography to investigate changes in regional cerebral blood flow (rCBF) during a general anesthetic infusion set to produce a gradual transition from the awake state to unconsciousness. Five right-handed human volunteers participated in the study. They were given propofol with a computer-controlled infusion pump to achieve three stable levels of plasma concentrations corresponding to mild sedation, deep sedation, and unconsciousness, the latter defined as unresponsiveness to verbal commands. During awake baseline and each of the three levels of sedation, two scans were acquired after injection of an H215O bolus. Global as well as regional CBF were determined and correlated with propofol concentrations. In addition, blood flow changes in the thalamus were correlated with those of the entire scanned volume to determine areas of coordinated changes. In addition to a generalized decrease in global CBF, large regional decreases in CBF occurred bilaterally in the medial thalamus, the cuneus and precuneus, and the posterior cingulate, orbitofrontal, and right angular gyri. Furthermore, a significant covariation between the thalamic and midbrain blood flow changes was observed, suggesting a close functional relationship between the two structures. We suggest that, at the concentrations attained, propofol preferentially decreases rCBF in brain regions previously implicated in the regulation of arousal, performance of associative functions, and autonomic control. Our data support the hypothesis that anesthetics induce behavioral changes via a preferential, concentration-dependent effect on specific neuronal networks rather than through a nonspecific, generalized effect on the brain.

Cerebral Mechanisms of Hypnotic Induction and Suggestion

The neural mechanisms underlying hypnotic states and responses to hypnotic suggestions remain largely unknown and, to date, have been studied only with indirect methods. Here, the effects of hypnosis and suggestions to alter pain perception were investigated in hypnotizable subjects by using positron emission tomography (PET) measures of regional cerebral blood flow (rCBF) and electroencephalographic (EEG) measures of brain electrical activity. The experimental conditions included a restful state (Baseline) followed by hypnotic relaxation alone (Hypnosis) and by hypnotic relaxation with suggestions for altered pain unpleasantness (Hypnosis-with-Suggestion). During each scan, the left hand was immersed in neutral (35C) or painfully hot (47C) water in the first two conditions and in painfully hot water in the last condition. Hypnosis was accompanied by significant increases in both occipital rCBF and delta EEG activity, which were highly correlated with each other (r = 0.70, p < 0.0001). Peak increases in rCBF were also observed in the caudal part of the right anterior cingulate sulcus and bilaterally in the inferior frontal gyri. Hypnosis-related decreases in rCBF were found in the right inferior parietal lobule, the left precuneus, and the posterior cingulate gyrus. Hypnosis-with-suggestions produced additional widespread increases in rCBF in the frontal cortices predominantly on the left side. Moreover, the medial and lateral posterior parietal cortices showed suggestion-related increases overlapping partly with regions of hypnosis-related decreases. Results support a state theory of hypnosis in which occipital increases in rCBF and delta activity reflect the alteration of consciousness associated with decreased arousal and possible facilitation of visual imagery. Frontal increases in rCBF associated with suggestions for altered perception might reflect the verbal mediation of the suggestions, working memory, and top-down processes involved in the reinterpretation of the perceptual experience. These results provide a new description of the neurobiological basis of hypnosis, demonstrating specific patterns of cerebral activation associated with the hypnotic state and with the processing of hypnotic suggestions.

Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation.

Modulation of cortico‐cortical connectivity in specific neural circuits might underlie some of the behavioural effects observed following repetitive transcranial magnetic stimulation (rTMS) of the human frontal cortex. This possibility was tested by applying rTMS to the left mid‐dorsolateral frontal cortex (MDL‐FC) and subsequently measuring functional connectivity of this region with positron emission tomography (PET) and TMS. The results showed a strong rTMS‐related modulation of brain activity in the fronto‐cingulate circuit. These results were confirmed in a parallel experiment in the rat using electrical stimulation and field‐potential recordings. Future studies are needed to provide a direct link between the rTMS‐induced modulation of cortical connectivity and its effects on specific behaviours.

Growth of white matter in the adolescent brain: myelin or axon?

White matter occupies almost half of the human brain. It contains axons connecting spatially segregated modules and, as such, it is essential for the smooth flow of information in functional networks. Structural maturation of white matter continues during adolescence, as reflected in age-related changes in its volume, as well as in its microstructure. Here I review recent observations obtained with magnetic resonance imaging in typically developing adolescents and point out some of the known variations in structural properties of white matter vis-à-vis brain function in health and disease. I conclude by re-focusing the interpretations of MR-based studies of white matter from myelin to axon.