John H. Missimer

Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG)

To date, the ketamine/PCP model of psychosis has been proposed to be one of the best pharmacological models to mimic schizophrenic psychosis in healthy volunteers, since ketamine can induce both positive and negative symptoms of schizophrenia. At subanesthetic doses, ketamine has been reported to primarily block N-methyl-D-aspartate (NMDA) receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. Positron emission tomography was used to study ketamine-induced psychotic symptom formation in relation to cerebral metabolic alterations in healthy volunteers. Our study shows that NMDA receptor blockade results in a hyperfrontal metabolic pattern. Increased metabolic activity in the frontomedial and anterior cingulate cortex correlated positively with psychotic symptom formation, in particular with ego pathology. Analysis of correlations between syndrome scores and metabolic rate of glucose (CMRglu) or metabolic gradients (ratios) revealed that each psychopathological syndrome was associated with a number of metabolic alterations in cortical and subcortical brain regions, suggesting that not a single brain region, but distributed neuronal networks are involved in acute psychotic symptom formation.

How does the human brain deal with a spinal cord injury

The primary sensorimotor cortex of the adult brain is capable of significant reorganization of topographic maps after deafferentation and de‐efferentation. Here we show that patients with spinal cord injury exhibit extensive changes in the activation of cortical and subcortical brain areas during hand movements, irrespective of normal (paraplegic) or impaired (tetraplegic patients) hand function. Positron emission tomography ([15O]‐H2O‐PET) revealed not only an expansion of the cortical ‘hand area’ towards the cortical ‘leg area’, but also an enhanced bilateral activation of the thalamus and cerebellum. The areas of the brain which were activated were qualitatively the same in both paraplegic and tetraplegic patients, but differed quantitatively as a function of the level of their spinal cord injury. We postulate that the changes in brain activation following spinal cord injury may reflect an adaptation of hand movement to a new body reference scheme secondary to a reduced and altered spino‐thalamic and spino‐cerebellar input.

Reward mechanisms in the brain and their role in dependence: evidence from neurophysiological and neuroimaging studies

This article reviews neuronal activity related to reward processing in primate and human brains. In the primate brain, neurophysiological methods provide a differentiated view of reward processing in a limited number of brain structures. Dopamine neurons respond to unpredictable rewards and produce a global reinforcement signal. Some neurons in the striatum also react to the expectation and detection of reward. Other striatal neurons show reward-related activities related to the preparation, initiation and execution of movement. Orbitofrontal neurons discriminate among different rewards and code reward preferences. In the human brain, regions belonging to a meso-striatal and meso-corticolimbic loop respond to reinforcement stimuli in control subjects. These observations corroborate results obtained in primates. Additionally, reward induces activation in regions specific to task performance. Our results also show a similar pattern of reward-related activation in nicotine and opiate addicts. Thus, in contrast to healthy subjects, typical reward-related regions respond in addicts to monetary reward but not to nonmonetary reinforcement. Reduced activation in performance-related regions is also observed in both groups of dependent subjects. The results of animal and human studies suggest that dopamine and dopamine-related regions are associated with the integration of motivational information and movement execution. Dopamine-related pathological disorders can be associated with movement disorders, such as Parkinsons disease or with false motivational attributions such as drug dependence.

Changes in brain activation associated with reward processing in smokers and nonsmokers

Abstract. Tobacco smoking is the most frequent form of substance abuse. Several studies have shown that the addictive action of nicotine is mediated by the mesolimbic dopamine system. This system is implicated in reward processing. In order to better understand the relationship between nicotine addiction and reward in humans, we investigated differences between smokers and nonsmokers in the activation of brain regions involved in processing reward information. Using [H215O] positron emission tomography (PET), we measured regional cerebral blood flow (rCBF) in healthy smokers and nonsmokers while they performed a prelearned, pattern-recognition task. We compared two conditions involving nonmonetary reinforcement or monetary reward with a baseline condition in which nonsense feedback was presented. With monetary reward, we found activation in the frontal and orbitofrontal cortex, occipital cortex, cingulate gyrus, cerebellum, and midbrain in both groups. Additionally, monetary reward activated typical dopaminergic regions such as the striatum in nonsmokers but not in smokers. We found a similar pattern of activation associated with nonmonetary reinforcement in nonsmokers, whereas activation was found in smokers only in the cerebellum. The different patterns of activation suggest that the brains of smokers react in a different way to reward than those of nonsmokers. This difference involves in particular the regions of the dopaminergic system including the striatum. In principle these observations could be interpreted either as a consequence of tobacco use or as a primitive condition of the brain that led people to smoke. Supported by related nonimaging studies, we interpret these differences as a consequence of tobacco smoking, even if a short-term effect of smoking prior to the experiment cannot be excluded.

Molecular basis of coiled-coil formation.

Coiled coils have attracted considerable interest as design templates in a wide range of applications. Successful coiled-coil design strategies therefore require a detailed understanding of coiled-coil folding. One common feature shared by coiled coils is the presence of a short autonomous helical folding unit, termed “trigger sequence,” that is indispensable for folding. Detailed knowledge of trigger sequences at the molecular level is thus key to a general understanding of coiled-coil formation. Using a multidisciplinary approach, we identify and characterize here the molecular determinants that specify the helical conformation of the monomeric early folding intermediate of the GCN4 coiled coil. We demonstrate that a network of hydrogen-bonding and electrostatic interactions stabilize the trigger-sequence helix. This network is rearranged in the final dimeric coiled-coil structure, and its destabilization significantly slows down GCN4 leucine zipper folding. Our findings provide a general explanation for the molecular mechanism of coiled-coil formation.

Changes in reward-induced brain activation in opiate addicts

Many studies indicate a role of the cerebral dopaminergic reward system in addiction. Motivated by these findings, we examined in opiate addicts whether brain regions involved in the reward circuitry also react to human prototypical rewards. We measured regional cerebral blood flow (rCBF) with H215O positron emission tomography (PET) during a visuo‐spatial recognition task with delayed response in control subjects and in opiate addicts participating in a methadone program. Three conditions were defined by the types of feedback: nonsense feedback; nonmonetary reinforcement; or monetary reward, received by the subjects for a correct response. We found in the control subjects rCBF increases in regions associated with the meso‐striatal and meso‐corticolimbic circuits in response to both monetary reward and nonmonetary reinforcement. In opiate addicts, these regions were activated only in response to monetary reward. Furthermore, nonmonetary reinforcement elicited rCBF increases in limbic regions of the opiate addicts that were not activated in the control subjects. Because psychoactive drugs serve as rewards and directly affect regions of the dopaminergic system like the striatum, we conclude that the differences in rCBF increases between controls and addicts can be attributed to an adaptive consequence of the addiction process.

Configurational entropy elucidates the role of salt-bridge networks in protein thermostability

Detailed knowledge of how networks of surface salt bridges contribute to protein thermal stability is essential not only to understand protein structure and function but also to design thermostable proteins for industrial applications. Experimental studies investigating thermodynamic stability through measurements of free energy associated with mutational alterations in proteins provide only macroscopic evidence regarding the structure of salt‐bridge networks and assessment of their contribution to protein stability. Using explicit‐solvent molecular dynamics simulations to provide insight on the atomic scale, we investigate here the structural stability, defined in terms of root‐mean‐square fluctuations, of a short polypeptide designed to fold into a stable trimeric coiled coil with a well‐packed hydrophobic core and an optimal number of intra‐ and interhelical surface salt bridges. We find that the increase of configurational entropy of the backbone and side‐chain atoms and decreased pair correlations of these with increased temperature are consistent with nearly constant atom‐positional root‐mean‐square fluctuations, increased salt‐bridge occupancies, and stronger electrostatic interactions in the coiled coil. Thus, our study of the coiled coil suggests a mechanism in which well‐designed salt‐bridge networks could accommodate stochastically the disorder of increased thermal motion to produce thermostability.

Performance evaluation of the 16-module quad-HIDAC small animal PET camera.

The quad-HIDAC small animal PET camera is a quadratic array of high-density avalanche chambers; the camera described in this publication consists of 16 modules. We present the system response using point and line sources and a mouse phantom. The quad-HIDAC camera exhibits a count rate stability of better than 1% and linearity of response to coincidences up to 2.2 x 10(5) cps at 16 MBq activity. Corrected for deadtime and random coincidences, the efficiency for the line source is 0.011, of which unscattered coincidences yield 0.009. The scatter fraction originating from the detectors is 0.22. Absorption within the mouse phantom was 20% and the scatter fraction increased to 0.29. Resolution is uniform within the entire field-of-view, which is 28 cm axially and 17 cm radially. Reconstruction of a point source yields a resolution of 1.1 mm FWHM for all three components. The performance of the camera demonstrates its excellent suitability for the functional imaging of small animals.

Neural activity related to the processing of increasing monetary reward in smokers and nonsmokers

This study investigated the processing of increasing monetary reward in nonsmoking and smoking subjects. The choice of the subject populations has been motivated by the observation of differences between nonsmokers and smokers in response to rewarding stimuli in a previous study. Subjects performed a pattern recognition task with delayed response, while rCBF was measured with [\mathrm{H}^{15}_{2}O] PET. Correct responses to the task were reinforced with three different amounts of monetary reward. The subjects received the sum of the rewards at the end of the experiment. The results show that a cortico‐subcortical loop, including the dorsolateral prefrontal cortex, the orbitofrontal cortex, the cingulate gyrus and the thalamus is involved in processing increasing monetary reward. Furthermore, the striatal response differentiates nonsmokers from smokers. Thus, we found significant correlations between rCBF increases in striatum and increasing monetary reward and between striatal rCBF increases and mood in nonsmokers, but not in smokers. Moreover, no significant mood changes among the different monetary rewards could be observed in smokers. We infer that the response of the striatum to reward is related to changes in subjective feelings. The differences between smokers and nonsmokers confirm our previous conclusions that the association between blood flow, performance, mood and amount of reward is more direct in nonsmokers.

Insights into EB1 structure and the role of its C-terminal domain for discriminating microtubule tips from the lattice

EBs, key microtubule (MT) tip–tracking proteins, are elongated molecules with two interacting calponin homology (CH) domains, an arrangement reminiscent of MT- and actin-binding CH proteins. In addition, electrostatic interactions between the C-terminus of EBs and MTs drive the specificity of EBs for growing MT ends.