The human globus pallidus internus is sensitive to rewards - Evidence from intracerebral recordings.

BACKGROUND: The globus pallidus internus (GPi) is the final output relay of the basal ganglia for the control of movements but has also been shown to belong to a second pathway projecting to the lateral habenula. This latter pathway is related to reward processing. METHOD: This prompted us to record, in eight patients receiving deep brain stimulation of the GPi for the alleviation of various movement disorders, local field potentials (LFP) while these patients performed a lottery task. The task entailed choosing between a higher and a lower number, which changed their color after the patient's choice with red (green) signaling a loss (win, in Euro cents) corresponding to the chosen number. RESULTS: Surface recordings showed a feedback related negativity from a frontal midline site, while time domain averages in the GPi showed differential modulation depending on the valence of the stimulus with polarity inversion indicating that this reward-modulated activity was indeed generated locally. Furthermore, wavelet decomposition of the LFP showed a reward-related response in the high beta/low gamma range. CONCLUSION: We conclude that human GPi is involved in reward processing, possibly in relation to the lateral habenula.

The mental number line electrified: brain potentials in a numerical flanker task.

It has been suggested that the mental representation of numbers is spatial in nature such that numbers are ordered on a mental number line. In the present investigation we use a variant of the Eriksen flanker task requiring a magnitude decision (smaller or larger than 5) for a central target number by pressing a response button with the right or left hand. The target number is flanked by irrelevant distracters that are either identical to the target, different from the target but biasing the same response, or different from the target and biasing a different response. Response latencies and event-related brain potentials were obtained in a group of healthy adults. Besides the typical response congruency effects on response latency and the N2 component of the ERP, we observed several other effects. First, numerical distance of the target to the standard 5 influenced decision latencies and amplitude and latency of the P3 component with smaller distances leading to longer decision latencies, longer P3 latencies and smaller P3 amplitudes. Second, smaller numerical distance between target and distracters led to faster decisions for response congruent and to slower decisions for response-incongruent trials. For response-incongruent trials P3 amplitude was small/large and P3 latency was long/short for small/large distances. These findings underscore the spatial character of number representation and further show that the relation between targets and distracters, although task irrelevant, is assessed automatically with facilitatory and inhibitory effects driven by spatial distance on the mental number line.

Neurophysiological markers of novelty processing are modulated by COMT and DRD4 genotypes.

Humans are faced with the dilemma to maintain a stable cognitive set on the one hand and to be able to redirect and switch attention to novel stimuli of potential importance. The dopaminergic system has been implicated in the balance between these two antagonistic constraints and in particular in novelty processing. Here we studied the impact of two polymorphisms affecting dopaminergic functioning (COMT Val108/158Met and DRD4 SNP -521) on neurophysiological correlates of novelty processing. Recording event-related potentials (ERPs) and oscillatory activity in a modified oddball task that featured infrequent but task-irrelevant novel sounds in addition to frequent standard and rare target tones, we examined participants homozygous for the Met or Val variant of COMT as well as homozygous for the C or T variant of DRD4. We found effects mainly on the P3a component to novel stimuli. A greater P3a amplitude was found for the COMT-ValVal group relative to MetMet. There was a tendency for DRD4-TT participants to show greater P3a amplitude and shorter P3a latency. Finally, DRD4-TT and COMT-ValVal participants showed the greatest increase of theta-power to novel stimuli. By contrast, the P3b component to target stimuli showed little influence of the studied polymorphism. Individual differences in dopaminergic genes explain part of the interindividual variance in the neural correlates of novelty but not target processing.

The effects of COMT (Val108/158Met) and DRD4 (SNP -521) dopamine genotypes on brain activations related to valence and magnitude of rewards.

People's sensitivity to reinforcing stimuli such as monetary gains and losses shows a wide interindividual variation that might in part be determined by genetic differences. Because of the established role of the dopaminergic system in the neural encoding of rewards and negative events, we investigated young healthy volunteers being homozygous for either the Valine or Methionine variant of the catechol-O-methyltransferase (COMT) codon 158 polymorphism as well as homozygous for the C or T variant of the SNP -521 polymorphism of the dopamine D4 receptor. Participants took part in a gambling paradigm featuring unexpectedly high monetary gains and losses in addition to standard gains/losses of expected magnitude while undergoing functional magnetic resonance imaging at 3 T. Valence-related brain activations were seen in the ventral striatum, the anterior cingulate cortex, and the inferior parietal cortex. These activations were modulated by the COMT polymorphism with greater effects for valine/valine participants but not by the D4 receptor polymorphism. By contrast, magnitude-related effects in the anterior insula and the cingulate cortex were modulated by the D4 receptor polymorphism with larger responses for the CC variant. These findings emphasize the differential contribution of genetic variants in the dopaminergic system to various aspects of reward processing.

Genetic variability in the dopamine system (dopamine receptor D4, catechol-O-methyltransferase) modulates neurophysiological responses to gains and losses.

BACKGROUND: Interindividual variability in the processing of reward might be partially explained by genetic differences in the dopamine system. Here, we study whether brain responses (event-related potentials [ERPs], oscillatory activity) to monetary gains and losses in normal human subjects are modulated as a function of two dopaminergic polymorphisms (catechol-O-methyltransferase [COMT] valine [Val]158methionine [Met], dopamine receptor D4 [DRD4] single nucleotide polymorphism [SNP] -521). METHODS: Forty participants homozygous for the different alleles of both polymorphisms were selected from a larger population to assess the main effects and interactions. Based on the phasic/tonic dopamine hypothesis, we expected increased brain responses to losses and gains in participants homozygous for the Val/Val variant of the COMT polymorphism (related to higher enzyme activity). RESULTS: The medial frontal negativity (MFN) of the ERP and the increase in beta power for gains were enhanced for participants homozygous for the COMT ValVal allele when compared with homozygous MetMet participants. In contrast, no modulations in gain- and loss-related brain activity were found to be a function of the DRD4 SNP -521 polymorphism. CONCLUSIONS: The results demonstrate the role of the COMT Val/Met polymorphism in the processing of reward, consistent with theoretical explanations that suggest the possible role of dopamine in the MFN and beta power increase generation. In addition, the present results might agree with the phasic/tonic dopamine theory that predicts higher phasic dopamine responses in ValVal participants.

Attention to human speakers in a virtual auditory environment: brain potential evidence.

Listening to a speech message requires the accurate selection of the relevant auditory input especially when distracting background noise or other speech messages are present. To investigate such auditory selection processes we presented three different speech messages simultaneously spoken by different actors at separate spatial locations (-70, 0, 70/ azimuth). Stimuli were recorded using an artificial head with microphones embedded in the "auditory canals" to capture the interaural time and level differences as well as some of the filter properties of the outer ear structures as auditory spatial cues, thus creating a realistic virtual auditory space. In a given experimental run young healthy participants listened via headphones and either attended to the rightmost or the leftmost message in order to comprehend the story. Superimposed on the speech messages task irrelevant probe stimuli (syllables sharing spatial and spectral characteristics, 4 probes/s) were presented that were used for the generation of event-related brain potentials computed from 29 channels of EEG. ERPs to probe stimuli were characterized by a negativity starting at 250 ms with a contralateral frontal maximum for the probes sharing spatial/spectral features of the attended story relative to those for the unattended message. The relatively late onset of this attention effect was interpreted to reflect the task demands in this complex auditory environment. This study demonstrates the feasibility to use virtual auditory environments in conjunction with the probe technique to study auditory selection under realistic conditions.

The impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring.

Dynamic adaptations of one's behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMT Val allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.

[Scurvy--a wrongly forgotten avitaminosis]. / Skorbut--eine zu Unrecht vergessene Hypovitaminose.

We treated a chronic alcoholic patient who showed all the symptoms of scurvy (petechiae, greyish skin colour, areas of thinning hair on the head, gingivitis, elevated liver enzyme levels, hyponatraemia, hypalbuminaemia and hypothyroidism) at admission. Even today, alcoholics and chronically ill people in particular can develop symptoms of diet-related vitamin C deficiency.

Perception of emotional speech in Parkinson's disease.

Nonmotor symptoms in Parkinson's disease (PD) involving cognition and emotionality have progressively received attention. The objective of the present study was to investigate recognition of emotional prosody in patients with PD (n = 14) in comparison to healthy control subjects (HC, n = 14). Event-related brain potentials (ERP) were recorded in a modified oddball paradigm under passive listening and active target detection instructions. Results showed a poorer performance of PD patients in classifying emotional prosody. ERP generated by emotional deviants (happy/sad) during passive listening revealed diminished amplitudes of the mismatch-related negativity for sad deviants, indicating an impairment of early preattentive processing of emotional prosody in PD.

Crossmodal attention effects on brain responses to different stimulus classes.

BACKGROUND: Attending to a point in space in one modality may facilitate processing to information from the same region in another modality. The involvement of sensory-specific cortical areas in intramodal and crossmodal selective spatial attention can be assessed with event-related brain potentials (ERPs). ERPs were recorded in two groups of young participants (each n = 11). Stimulus sequences comprised visual standard stimuli (p = 0.4, a white square), visual deviant stimuli (p = 0.05, a white square with small black rectangle) and visual novel stimuli (p = 0.05, different multicolored checkerboards) as well as auditory standard (p = 0.4, 800 Hz tone), deviant (p = 0.05, 900 Hz tone), and novel (p = 0.05, random combination of three sine-wave tones) stimuli, occurring in random order at locations 30 degrees left and right of a fixation point. The "auditory group" of participants attended either to the left or to the right speaker in order to respond to the infrequent auditory deviants at that location by a speeded button press. Visual stimuli were irrelevant for this group. The "visual group" had the analogue task for the visual modality. For these participants auditory stimuli were irrelevant throughout the experiment. RESULTS: ERPs showed a typical enhancement of early sensory specific components by intramodal spatial attention (visual group: visual P1 and N1; auditory group: auditory Nd). Crossmodal spatial attention effects included a modulation of the Nd to auditory standards in the visual group and a modulation of the P1 to visual novels and N1 for visual standards for the auditory group. Similar to previous studies crossmodal spatial attention effects on visual standard and novel stimuli also included a frontocentral positivity in the 200-400 ms range that was not seen for intramodal spatial visual attention suggesting involvement of later supramodal areas. CONCLUSION: These findings are consistent with an action of crossmodal spatial attention on early, sensory specific processing stages.

Transcranial magnetic stimulation to the parietal lobes reduces detection of contralateral somatosensory stimuli.

OBJECTIVES: Neglect has been described in patients with lesions of the parietal cortex and has been interpreted as a disorder of the allocation of spatial attention. The persistence of neglect has been linked to poor rehabilitation outcome in patients suffering from acute stroke. Transcranial magnetic stimulation (TMS) applied to the parietal cortex has been shown to induce changes in the perception of stimuli including tactile stimulation of the fingers contra- and ipsilateral to the stimulated hemisphere. MATERIAL AND METHODS: In the current study, eleven normal young subjects performed a detection task for cutaneous electrical stimuli to the left or right forearm that had been precued by a preceding visual warning stimulus. To investigate the role of the parietal cortical areas for attentional processes TMS was applied to frontal and parietal scalp sites of each hemisphere in the cue-target interval before the somatosensory stimulus. RESULTS: Right and left parietal stimulation led to reduced detection sensitivity for near threshold stimuli to the forearm contralateral to the stimulated hemisphere without hemispheric differences. Ipsilateral tactile perception was not influenced by parietal TMS and there was no change in perception after frontal stimulation to left or right scalp sites. CONCLUSION: This pattern of results is consistent with a role of the right and left parietal lobe in the distribution of spatial attention and provides an experimental basis for possible therapeutical application of TMS to improve attentional deficits in stroke patients.

Specialization of the specialized: electrophysiological investigations in professional musicians.

Several event-related brain potential (ERP) studies examining the processing of auditory stimuli by professional musicians compared with non-musicians are reviewed. In the first study, musicians (string players) and non-musicians attended to one of two streams of auditory stimuli characterized by a specific pitch. Musicians showed a prolonged ERP attention effect, the late portion of which was more frontally distributed than was that of the non-musicians. In the second study, we investigated auditory spatial processing in conductors, pianists, and nonmusicians. Only the conductors showed behavioral selectivity of sound sources located in the peripheral auditory space. In addition, this group showed a negative/positive mismatch response for deviant stimuli occurring outside the focus of spatial attention. Finally, a group of drummers was compared to woodwind players and nonmusicians in a passive listening task. A real continuous drum sequence was manipulated so that some beats were anticipated by 80 ms. The drummers showed a mismatch response not only for the anticipated beats but also for the subsequent beats, suggesting a more complex representation of the temporal aspects stimulus sequence in this subject group. Together, these studies suggest qualitative differences of the neural correlates of auditory processing between musicians and non-musicians. Moreover, these differences appear to be shaped by the specific training of a musician.

Preattentive evaluation of multiple perceptual streams in human audition.

To analyze an auditory scene, the segregation of the input into separate streams of information is necessary. Here, the mismatch negativity (MMN) of the event-related potential was used to trace the number of simultaneously monitored streams in auditory scene analysis. Subjects passively listened to sounds belonging to either one, two, or three auditory streams defined by spatial position and pitch. An MMN was obtained for deviants within either one, two or three auditory streams albeit with a smaller amplitude in the latter condition. Control experiments ruled out that this effect was due to variations in stimulation rate. Thus, a preattentive deviant detection system based on simple auditory features provides the basis for subsequent attentive processing directed to a selected stream.

Tracking of multiple sound sources defined by interaural time differences: brain potential evidence in humans.

Among other cues, interaural time differences (ITD) can be used to compute the location of a sound. To investigate whether ITD can be used for the preattentive detection of sounds coming from a different location than standard sounds (P=0.7, no ITD), left and right 'far' (900 micros ITD, 80 degrees excentricity) and 'near ' (300 micros ITD, 30 degrees ) deviant stimuli (each deviant P=0.075) were presented via headphones. While 15 young healthy subjects passively listened to these sequences, the mismatch negativity (MMN) of the event-related potential was obtained for the deviant sounds. MMN was reliable for all four deviants but larger for the far-lateralized sounds. Moreover, MMN was larger contralateral to the location of the deviant. This indicates a role of preattentive mechanisms in the spatial analysis of auditory scenes.

The fate of sounds in conductors' brains: an ERP study.

Professional music conductors are required to home in on a particular musician but at the same time have to monitor the entire orchestra. It was hypothesized that this unique experience should be reflected by superior auditory spatial processing. Event-related brain potentials were obtained, while conductors, professional pianists, and non-musicians listened to sequences of bandpass-filtered noise-bursts presented in random order from six speakers, three located in front and three to the right of the subjects. In different runs, subjects either attended the centermost or the most peripheral speaker in order to detect slightly deviant noise-bursts. For centrally located speakers, the ERPs showed a typical Nd attention effect for the relevant location with a steep decline for the neighboring speakers in all subject groups. For peripheral speakers, only the conductors showed attentional selectivity, while the Nd effect was of similar size for all three peripheral speakers in the other two groups. These ERP effects were paralleled by an enhanced behavioral selectivity in peripheral auditory space in conductors. Moreover, the pre-attentive monitoring of the entire auditory scene indexed by the mismatch negativity was superior in musicians compared to non-musicians. In conductors, the MMN was followed by a positivity suggesting an attention shift towards the deviant stimuli in this group only.

Tourette syndrome and obsessive-compulsive disorder: event-related brain potentials show similar mechanisms [correction of mechansims] of frontal inhibition but dissimilar target evaluation processes.

OBJECTIVES: Tourette Syndrome (TS) and Obsessive-Compulsive Disorders (OCD) share many clinical similarities and show a strong comorbidity. Current theories view a frontal-striatal dysfunction as the underlying cause of many clinical aspects of both disorders. This study sought to investigate mechanisms of conceptual integration and attention in both disorders. We hypothesized that the processing of stimuli with interfering aspects would be altered in a similar way while attentional mechanisms could differ. METHODS: Event-related brain potentials (ERPs) were recorded in a modified STROOP-paradigm in groups of TS and OCD patients and in a control group. The paradigm involved the presentation of color words in a range of different colors. The subjects had to respond to words of matching word content and color and to ignore mismatching stimuli. RESULTS: Incongruent stimuli elicited a frontal negative component ("N450") which was enhanced in amplitude and prolonged in latency in both patient groups. Matching stimuli evoked enhanced N2 and P3b components representing target evaluation mechanisms. The OCD group alone displayed a larger P3b amplitude in comparison to both other groups. CONCLUSIONS: The data are interpreted to indicate that frontal inhibitory mechanisms are altered alike in TS and OCD. In contrast, only the OCD group showed evidence for aberrant target evaluation.

Excessive action monitoring in Tourette syndrome.

Tourette Syndrome (TS) has been related to hyperactive basal-ganglia thalamocortical pathways. This suggests that action monitoring might also be hyperactive. The present study used the event-related brain potential (ERP) technique to investigate this hypothesis. A simple "oddball" reaction time experiment was administered to a group of TS patients and a matched control group. In order to investigate variations in attentional allocation separate experimental runs were undertaken with target frequencies of 50% and 80%. The P3b component to targets was taken as an indicator of the target evaluation process and the response locked error-related negativity (ERN) served as an indicator of action monitoring. We hypothesized that the amplitudes of ERN and P3b would vary with respect to target frequency. The TS group would show an overall enhanced ERN but an unchanged P3b.ERN and P3b amplitudes were lower in the 80% target condition than in the 50% condition. In comparison with control subjects TS patients displayed an ERN of overall higher amplitude but with similar variations between target conditions. P3b amplitudes did not differ between groups. The data are interpreted to support the assumption of an abnormal action monitoring system in TS. A number of similarities to Obsessive-Compulsive Disorder are outlined and it is argued that the findings could be related to a hyperactive frontal-striatal-thalamic-frontal circuit.

The costs of freedom: an ERP -- study of non-canonical sentences.

OBJECTIVES: The present investigation explored the electrophysiological correlates of working memory during sentence comprehension. METHODS: Event-related brain potentials (ERP) were recorded from 29 channels in 22 subjects, while they read German sentences having subject-first (canonical) or object-first (non-canonical) word orders. RESULTS: Three different ERP effects were observed: a negativity (maximum at Fc5) differentiating unambiguous object-first and subject-first sentences, interpreted as reflecting the demands of the object-first sentences on working memory; a second negativity (maximum at F7) to the subject noun-phrase in object-first sentences, interpreted as indicating retrieval of verbal material. Finally, a parietal positivity was found for ambiguous sentences that turned out to have a non-canonical word order, which was interpreted as indicating revision and reevaluation processes. CONCLUSIONS: The present data underscore the different roles of working memory in comprehension.

Implicit memory for words played during isoflurane- or propofol-based anesthesia: the lexical decision task.

BACKGROUND: Unconscious processing of words during general anesthesia has been suggested after surgery with several tests of implicit memory. Patients can neither recall those words nor do they have explicit memories of other intraoperative events. It is unclear to what degree information is processed during general anesthesia and which tests are best suited to detect implicit memory. In the current study, a lexical decision paradigm not previously used to demonstrate implicit memory during anesthesia was used. METHODS: Sixty patients undergoing lumbar disc surgery were assigned to receive isoflurane infusion- or propofol infusion-based anesthesia combined with alfentanil infusions and a nitrous oxide-oxygen mixture. A control group of 10 medical students listened to tapes without receiving anesthesia. Two tapes, each containing a list of 30 low-frequency German nouns repeated for 15 min, were prepared, with half of the patients listening to tape A and the other half listening to tape B during the operation. Exposure time was 15 min from the time of skin incision onward. In the test phase, approximately 7 h later, words from lists A and B plus 60 nonwords were presented in random order by a computer program. Subjects were asked to indicate, by pressing one of two response buttons, whether the spoken word was or was not a legal German word (lexical decision). RESULTS: A recognition test revealed chance recognition for words presented during anesthesia. Lexical decision responses, however, were slightly faster to primed (previously presented) words than to unprimed (not previously presented) words when the entire group of patients was tested, suggesting a small implicit memory effect, which barely failed to reach the significance level. When the two medication groups were tested separately, no significant implicit memory effect could be ascertained statistically. The effects of previous exposure were much more pronounced in the control group. CONCLUSIONS: Balanced anesthesia techniques with isoflurane or propofol lead to only a minimal, statistically borderline implicit memory effect in the lexical decision paradigm.