Brain stimulation in obesity.

Obesity is taking up epidemic proportions worldwide with significant impacts on the health of both the affected individual and on society as a whole. Treatment approaches consist of behavioural and pharmacological approaches, however, these are often found to be ineffective. In severe obesity, bariatric surgery is frequently performed. Unfortunately, 40% of patients show substantial weight gain over the long term or display the associated metabolic syndrome, making the development of novel therapies necessary. This review summarizes some of the current conceptual models, in particularly the 'food addiction' model, and then discusses specific therapeutic targets of brain stimulation, both non-invasive (transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcutaneous vagus nerve stimulation (VNS)) and invasive (deep brain stimulation and invasive VNS). As we will show, neuromodulatory approaches represent a promising tool for targeting specific brain structures implicated in the pathophysiology of obesity. Non-invasive techniques such as TMS, tDCS and transcutaneous VNS need further investigation before they may become ready for clinical usage. The currently available study data suggest that deep brain stimulation may become an effective and acceptable therapy for otherwise treatment-resistant obese patients. The results of the currently undergoing clinical trials are eagerly awaited.

Striatal dysfunction in X-linked dystonia-parkinsonism is associated with disease progression.

BACKGROUND AND PURPOSE: X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset movement disorder associated with striatal atrophy. As the dopaminergic system has not yet been systemically studied in this basal ganglia model disease, it is unclear whether nigrostriatal dysfunction contributes to parkinsonism in XDP. METHODS: Pre- and post-synaptic dopaminergic function was assessed in XDP. A total of 10 123 jod-benzamide (IBZM) single-photon emission computed tomography (SPECT) images were obtained for nine patients aged 42.3 ± 9.5 years (SD; range 30-52) and one asymptomatic mutation carrier (38 years), and four ioflupane (FP-CIT) SPECT images were obtained for four patients, aged 41.5 ± 11.6 years (range 30-52 years). Structural magnetic resonance imaging was also performed for all mutation carriers and 10 matched healthy controls. RESULTS: All patients were men who suffered from severe, disabling segmental or generalized dystonia and had varying degrees of parkinsonism. IBZM SPECT images were pathological in 8/9 symptomatic patients with distinct reduced post-synaptic tracer uptake in the caudate nucleus and putamen, and unremarkable in the asymptomatic mutation carrier. Longer disease duration was correlated with lower IBZM binding ratios. All subjects exhibited slightly reduced FP-CIT uptake values compared to controls for each analyzed region (-37% to -41%) which may be linked to basal ganglia volume loss. Visual inspection revealed physiological FP-CIT uptake in 1/4 patients. CONCLUSIONS: This nuclear imaging study provides evidence that the functional decline of post-synaptic dopaminergic neurotransmission is related to disease duration and ongoing neurodegeneration. Given the severe striatal cell loss which could be verified with post-synaptic nuclear imaging, both parkinsonism and dystonia in XDP are probably mainly due to striatal dysfunction.

Changes in attentional resources during the acquisition of laparoscopic surgical skills.

BACKGROUND: Increasing familiarity and practice might free up mental resources during laparoscopic surgical skills training. The aim of the study was to track changes in mental resource allocation during acquisition of laparoscopic surgical skills. METHODS: Medical students with no previous experience in laparoscopic surgery took part in a 5-week laparoscopic training curriculum. At the beginning and end of the training period, one of the training tasks was combined with a secondary auditory detection task that required pressing a foot switch for defined target tones, creating a dual-task situation. During execution of the two concurrent tasks, continuous electroencephalographic measurements were made, with special attention to the P300 component, an index of mental resources. Accuracy and reaction times of the secondary task were determined. RESULTS: All 14 participants successfully completed the training curriculum. Target times for successful completion of individual tasks decreased significantly during training sessions (P <0.001 for all tasks). Comparing results before and after training showed a significant decrease in event-related brain potential amplitude at the parietal electrode cluster (P300 component, W = 67, P = 0.026), but there were no differences in accuracy (percentage correct responses: W = 48, P = 0.518) or reaction times (W = 42, P = 0.850) in the auditory detection task. CONCLUSION: The P300 decrease in the secondary task over training demonstrated a shift of mental resources to the primary task: the surgical exercise. This indicates that, with more practice, mental resources are freed up for additional tasks.

Sensory MEG responses predict successful and failed inhibition in a stop-signal task.

In the present study magnetoencephalographic recordings were performed to investigate the neural mechanisms underlying the stopping of manual responses. Subjects performed in a Stop-signal task in which Go-stimuli (S1), requiring a rapid motor response, were sometimes rapidly followed by a Stop-stimulus (S2) indicating to withhold the already initiated response to S1. Success of stopping strongly depended on the early perceptual processing of S1 and S2 reflected by the magnetic N1 component. Enhanced processing of S1 facilitated the execution of the movement, whereas enhanced processing of S2 favored its inhibition. This suggests that the processing resources for the subsequent stimuli are limited and need to be shared. This sharing of resources appeared to arise from adjustments made on a trial-by-trial basis, in that systematic reaction time prolongations on Go-trials following Stop-trials versus following Go-trials were accompanied by attenuated sensory processing to the Go-stimulus similar to that seen in successful versus unsuccessful stopping in Stop-trials.

Audiovisual integration of speech is disturbed in schizophrenia: an fMRI study.

Speech perception is an essential part of social interaction. Visual information (lip movements, facial expression) may supplement auditory information in particular under inadvertent listening situations. Schizophrenia patients have been shown to have a deficit in integrating articulatory motions with the auditory speech input. The goal of this study was to investigate the neural basis of this deficit in audiovisual speech processing in schizophrenia patients by using fMRI. Disyllabic nouns were presented in congruent (audio matches visual information) and incongruent conditions in a slow event related fMRI design. Schizophrenia patients (n=15) were compared to age and gender matched control participants. The statistical examination was conducted by analysis of variance with main factors: audiovisual congruency and group membership. The patients' brain activity differed from the control group as evidenced by congruency by group interaction effects. The pertinent brain sites were located predominantly in the right hemisphere and comprised the pars opercularis, middle frontal sulcus, and superior temporal gyrus. In addition, we observed interactions bilaterally in the fusiform gyrus and the nucleus accumbens. We suggest that schizophrenia patients' deficits in audiovisual integration during speech perception are due to a dysfunction of the speech motor system in the right hemisphere. Furthermore the results can be also seen as a reflection of reduced lateralization of language functions to the left hemisphere in schizophrenia.

Theta EEG oscillatory activity and auditory change detection.

The mismatch negativity is an electrophysiological marker of auditory change detection in the event-related brain potential and has been proposed to reflect an automatic comparison process between an incoming stimulus and the representation of prior items in a sequence. There is evidence for two main functional subcomponents comprising the MMN, generated by temporal and frontal brain areas, respectively. Using data obtained in an MMN paradigm, we performed time-frequency analysis to reveal the changes in oscillatory neural activity in the theta band. The results suggest that the frontal component of the MMN is brought about by an increase in theta power for the deviant trials and, possibly, by an additional contribution of theta phase alignment. By contrast, the temporal component of the MMN, best seen in recordings from mastoid electrodes, is generated by phase resetting of theta rhythm with no concomitant power modulation. Thus, frontal and temporal MMN components do not only differ with regard to their functional significance but also appear to be generated by distinct neurophysiological mechanisms.

Automatic and attentive processing of sounds in cochlear implant patients - electrophysiological evidence.

PURPOSE: Processing auditory scenes requires the automatic detection of unexpected acoustic irregularities which allows to reorient the attentional focus for further in-depth analysis. Even if cochlea implants (CI) may partly restore hearing capabilities in patients suffering from profound peripheral deafness, CI users complain about difficulties in identifying novel and unexpected acoustic events. To assess whether this impairment is attributable to preattentive auditory deficits, impaired automatic orienting to novel events and/or to deficits in attentional processing we recorded event-related potentials (ERPs) in an auditory novelty oddball paradigm. METHODS: ERPs were obtained in 7 postlingually deafened CI patients and their age-matched controls in passive and active listening conditions. Subjects had to press a button for infrequent novel sounds but not for frequent standard sounds in the active condition. RESULTS: In the active condition patients and controls did not differ with regard to hit-rates and reaction times. ERPs to novel stimuli in the active condition were characterized by enhanced N2b and P3b components that did not differ between groups. By contrast, the P3a component to novel sounds in the passive condition, an index of automatic orienting of attention, was greatly attenuated in the CI users. CONCLUSIONS: CI-users are impaired in the preattentive registration of novel auditory events while attentive processing of a designated auditory stream appears intact.

Using musical instruments to improve motor skill recovery following a stroke.

In previous studies, it was shown that there is a need for efficient motor rehabilitation approaches. For this purpose, we evaluated a music-supported training program designed to induce an auditory-sensorimotor co-representation of movements in 20 stroke patients (10 affected in the left and 10 in the right upper extremity). Patients without any previous musical experience participated in an intensive step by step training, first of the paretic extremity, followed by training of both extremities. Training was applied 15 times over 3 weeks in addition to conventional treatment. Fine as well as gross motor skills were addressed by using either a MIDI-piano or electronic drum pads. As a control, 20 stroke patients (10 affected left and 10 right) undergoing exclusively conventional therapies were recruited. Assignment to the training and control groups was done pseudo-randomly to achieve an equal number of left- and right-affected patients in each group. Pre- and post-treatment motor functions were monitored using a computerized movement analysis system (Zebris) and an established array of motor tests (e. g., Action Research Arm Test, Box & Block Test). Patients showed significant improvement after treatment with respect to speed, precision and smoothness of movements as shown by 3D movement analysis and clinical motor tests. Furthermore, compared to the control subjects, motor control in everyday activities improved significantly. In conclusion, this innovative therapeutic strategy is an effective approach for the motor skill neurorehabilitation of stroke patients.

Mild Thyrotoxicosis Leads to Brain Perfusion Changes: An Arterial Spin Labelling Study.

Hypo- and hyperthyroidism have effects on brain structure and function, as well as cognitive processes, including memory. However, little is known about the influence of thyroid hormones on brain perfusion and the relationship of such perfusion changes with cognition. The present study aimed to demonstrate the effect of short-term experimental hyperthyroidism on brain perfusion in healthy volunteers and to assess whether perfusion changes, if present, are related to cognitive performance. It is known that an interaction exists between brain perfusion and cerebral oxygen consumption rate and it is considered that neural activation increases cerebral regional perfusion rate in brain areas associated with memory. Measuring cerebral blood flow may therefore represent a proxy for neural activity. Therefore, arterial spin labelling (ASL) measurements were conducted and later analysed to evaluate brain perfusion in 29 healthy men before and after ingesting thyroid hormones for 8 weeks. Psychological tests concerning memory were performed at the same time-points and the results were correlated with the imaging results. In the hyperthyroid condition, perfusion was increased in the posterior cerebellum in regions connected with cerebral networks associated with cognitive control and the visual cortex compared to the euthyroid condition. In addition, these perfusion changes were positively correlated with changes of performance in the German version of the Auditory Verbal Learning Task [AVLT, Verbaler Lern-und-Merkfähigkeits-Test (VLMT)]. Cerebellar perfusion and function therefore appears to be modulated by thyroid hormones, likely because the cerebellum hosts a high number of thyroid hormone receptors.

Temporal dynamics of early perceptual processing.

Recordings of electrical and magnetic brain responses to sensory stimulation provide high-resolution measures of the time course of early perceptual processing. Spatio-temporal analyses of brain activity patterns during the first 200 ms after stimulus presentation have characterized the timing of attentional selection processes and different stages of feature encoding and pattern analyses. Recent studies that incorporate blood flow neuroimaging techniques provide support for mechanisms of early selection of attended visual inputs in extrastriate cortical pathways. The spatial tuning properties of early auditory selection have also been delineated. Electrical and magnetic responses that index the encoding of higher-order pattern information have been identified in both visual and auditory modalities and localized to specific cortical areas.

Music supported therapy promotes motor plasticity in individuals with chronic stroke.

Novel rehabilitation interventions have improved motor recovery by induction of neural plasticity in individuals with stroke. Of these, Music-supported therapy (MST) is based on music training designed to restore motor deficits. Music training requires multimodal processing, involving the integration and co-operation of visual, motor, auditory, affective and cognitive systems. The main objective of this study was to assess, in a group of 20 individuals suffering from chronic stroke, the motor, cognitive, emotional and neuroplastic effects of MST. Using functional magnetic resonance imaging (fMRI) we observed a clear restitution of both activity and connectivity among auditory-motor regions of the affected hemisphere. Importantly, no differences were observed in this functional network in a healthy control group, ruling out possible confounds such as repeated imaging testing. Moreover, this increase in activity and connectivity between auditory and motor regions was accompanied by a functional improvement of the paretic hand. The present results confirm MST as a viable intervention to improve motor function in chronic stroke individuals.

Brain potentials related to self-generated and external information used for performance monitoring.

OBJECTIVE: Humans need to supervise and adjust their own behavior by means of an error detection and correction system as well as by using externally available information. The purpose of the present study was to compare the electrophysiological effects related to self-generated internal and to external (feedback) information used for performance monitoring. METHODS: Fourteen young normal subjects learned to associate each of several line-drawings with either a left-hand or right-hand response. In the experiment proper multi-channel ERPs were obtained time-locked to (a) the line-drawings, (b) the button-press, and (c) subsequent feedback stimuli. Feedback was either affirmative, negative, or equivocal. Event-related potentials were quantified and statistically evaluated using standard methodology. RESULTS: Response-locked ERPs showed a typical error-related negativity (ERN) for erroneous responses. ERPs to negative and equivocal feedback stimuli contained a negativity with a more posterior distribution than that of the ERN, which occurred earlier and had a higher peak amplitude in the equivocal condition. Dipole modeling suggests that this feedback-related negativity is generated by medial prefrontal and posterior cingulate cortex areas. CONCLUSIONS: Different brain systems support the use of internal and external information necessary for performance monitoring and modification. SIGNIFICANCE: The flexible use of internal and external information for performance control is a core executive function. The delineation of the corresponding brain correlates will further our understanding of executive dysfunction in neurological disorders.

Performance monitoring and behavioral adaptation during task switching: an fMRI study.

Despite significant advances, the neural correlates and neurochemical mechanisms involved in performance monitoring and behavioral adaptation are still a matter for debate. Here, we used a modified Eriksen-Flanker task in a magnetic resonance imaging (MRI) study that required the participants to derive the correct stimulus-response association based on a feedback given after each flanker stimulus. Participants had to continuously monitor and adapt their performance as the stimulus-response association switched after a jittered time interval without notice. After every switch an increase of reaction times was observed. At the neural level, the feedback indicating the need to switch was associated with activation of the precuneus, the cingulate cortex, the insula and a brainstem region tentatively identified as the locus coeruleus. This brainstem system appears to interact with this cortical network and seems to be essential for performance monitoring and behavioral adaptation. In contrast, the cerebellum crus and prefrontal areas are activated during error feedback processing. Furthermore we found activations of the hippocampus and parahippocampal gyrus bilaterally after a correct feedback in learnable stimulus-response associations. These results highlight the contribution of brainstem nuclei to performance adaptation.

Transcranial magnetic stimulation reveals complex cognitive control representations in the rostral frontal cortex.

Convergent evidence suggests that the lateral frontal cortex is at the heart of a brain network subserving cognitive control. Recent theories assume a functional segregation along the rostro-caudal axis of the lateral frontal cortex based on differences in the degree of complexity of cognitive control. However, the functional contribution of specific rostral and caudal sub-regions remains elusive. Here we investigate the impact of disrupting rostral and caudal target regions on cognitive control processes, using Transcranial Magnetic Stimulation (TMS). Participants performed three different task-switching conditions that assessed differences in the degree of complexity of cognitive control processes, after temporally disrupting rostral, or caudal target regions, or a control region. Disrupting the rostral lateral frontal region specifically impaired behavioral performance of the most complex task-switching condition, in comparison to the caudal target region and the control region. These novel findings shed light on the neuroanatomical architecture supporting control over goal-directed behavior.

Audiovisual perception of natural speech is impaired in adult dyslexics: an ERP study.

The present study used event-related brain potentials (ERPs) to investigate audiovisual integration processes in the perception of natural speech in a group of German adult developmental dyslexic readers. Twelve dyslexic and twelve non-dyslexic adults viewed short videos of a male German speaker. Disyllabic German nouns served as stimulus material. The auditory and the visual stimulus streams were segregated to create four conditions: in the congruent condition, the spoken word and the auditory word were identical. In the incongruent condition, the auditory and the visual word (i.e., the lip movements of the utterance) were different. Furthermore, on half of the trials, white noise (45 dB SPL) was superimposed on the auditory trace. Subjects had to say aloud the word they understood after they viewed the video. Behavioral data. Dyslexic readers committed more errors compared to normal readers in the noise conditions, and this effect was particularly present for congruent trials. ERPs showed a distinct N170 component at temporo-parietal electrodes that was smaller in amplitude for dyslexic readers. Both, normal and dyslexic readers, showed a clear effect of noise at centro-parietal electrodes between 300 and 600 ms. An analysis of error trials reflecting audiovisual integration (verbal responses in the incongruent noise condition that are a mix of the visual and the auditory word) revealed more positive ERPs for dyslexic readers at temporo-parietal electrodes 200-500 ms poststimulus. For normal readers, no such effect was present. These findings are discussed as reflecting increased effort in dyslexics under circumstances of distorted acoustic input. The superimposition of noise leads dyslexics to rely more on the integration of auditory and visual input (lip reading). Furthermore, the smaller N170-amplitudes indicate deficits in the processing of moving faces in dyslexic adults.

The neural bases of the pseudohomophone effect: Phonological constraints on lexico-semantic access in reading.

We investigated phonological processing in normal readers to answer the question to what extent phonological recoding is active during silent reading and if or how it guides lexico-semantic access. We addressed this issue by looking at pseudohomophone and baseword frequency effects in lexical decisions with event-related functional magnetic resonance imaging (fMRI). The results revealed greater activation in response to pseudohomophones than for well-controlled pseudowords in the left inferior/superior frontal and middle temporal cortex, left insula, and left superior parietal lobule. Furthermore, we observed a baseword frequency effect for pseudohomophones (e.g., FEAL) but not for pseudowords (e.g., FEEP). This baseword frequency effect was qualified by activation differences in bilateral angular and left supramarginal, and bilateral middle temporal gyri for pseudohomophones with low- compared to high-frequency basewords. We propose that lexical decisions to pseudohomophones involves phonology-driven lexico-semantic activation of their basewords and that this is converging neuroimaging evidence for automatically activated phonological representations during silent reading in experienced readers.

Dissociable cerebellar activity during spatial navigation and visual memory in bilateral vestibular failure.

OBJECTIVE: Spatial orientation and navigation depends on information from the vestibular system. Previous work suggested impaired spatial navigation in patients with bilateral vestibular failure (BVF). The aim of this study was to investigate event-related brain activity by functional magnetic resonance imaging (fMRI) during spatial navigation and visual memory tasks in BVF patients. METHODS: Twenty-three BVF patients and healthy age- and gender matched control subjects performed learning sessions of spatial navigation by watching short films taking them through various streets from a driver's perspective along a route to the Cathedral of Cologne using virtual reality videos (adopted and modified from Google Earth). In the scanner, participants were asked to respond to questions testing for visual memory or spatial navigation while they viewed short video clips. From a similar but not identical perspective depicted video frames of routes were displayed which they had previously seen or which were completely novel to them. RESULTS: Compared with controls, posterior cerebellar activity in BVF patients was higher during spatial navigation than during visual memory tasks, in the absence of performance differences. This cerebellar activity correlated with disease duration. CONCLUSIONS: Cerebellar activity during spatial navigation in BVF patients may reflect increased non-vestibular efforts to counteract the development of spatial navigation deficits in BVF. Conceivably, cerebellar activity indicates a change in navigational strategy of BVF patients, i.e. from a more allocentric, landmark or place-based strategy (hippocampus) to a more sequence-based strategy. This interpretation would be in accord with recent evidence for a cerebellar role in sequence-based navigation.

Brain potentials reveal deficits of language processing after closed head injury.

OBJECTIVE: To delineate deficits in language processing after closed head injury with use of behavioral measures and event-related brain potentials. DESIGN: Case-control design. All subjects participated in three verbal event-related brain potential experiments, and the resulting measures were compared both within and between groups. PATIENTS/CONTROLS: Eleven patients at least 2 years after severe closed head injury (Glasgow Coma Scale score < 8 at admission and duration of posttraumatic amnesia > 48 hours) were compared with a control group matched for age and educational level. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Reaction times and percentage correct as behavioral measures in the three experiments (sentence verification, semantic and repetition priming with lexical decision task, and continuous word recognition). Event-related brain potentials were quantified by area measures in successive time windows for the different experimental conditions and for different experiments. RESULTS: The reaction times of the patient group were significantly longer than those of the controls (P < .005). Similarly, the patients' accuracy was significantly worse in all experiments (P < .03). The event-related brain potentials of the controls showed a clear and significant reduction of a negative component (N400) to terminal words of true sentences (sentence verification experiment), semantically primed words and repeated words (lexical decision experiment), and recognized words (continuous word recognition). For the patients, a clear N400 effect was seen only in the sentence verification task (delayed by about 100 milliseconds), while only later event-related brain potential modulations were seen in the other tasks. CONCLUSION: Language functions are disturbed after closed head injury. The electrophysiologic data suggest difficulties in the integration of incoming linguistic stimuli with the previous context as a possible underlying cause.

An electrophysiological analysis of altered cognitive functions in Huntington disease.

BACKGROUND: Neuropsychological deficits are a main feature of Huntington disease (HD) with previous data suggesting involvement of memory functions and visual processing. OBJECTIVE: To increase the knowledge about cognitive malfunction in HD in the domains of visual processing and memory by the use of modern electrophysiological techniques (event-related potentials [ERPs]). DESIGN: A case-control design was used. Three ERP paradigms were used; a parallel visual search paradigm allowed for the simultaneous processing of a multi-element visual array in search of a target stimulus, while a serial search paradigm with varied numbers of distractor items necessitated a serial one by one scanning of the arrays. The third experiment was a word-recognition memory task. SETTING: The measurements were obtained in a neurophysiological laboratory of a university hospital. PATIENTS AND CONTROLS: Nine patients with HD and 9 control subjects matched for age, sex, and education were studied. MAIN OUTCOME MEASURES: Components of averaged ERPs were quantified by latency and amplitude measures and subjected to statistical analysis. Behavioral measures (search time, hit rate, and recognition accuracy) were assessed as well. RESULTS: The early visual components showed a significant latency shift (delay of about 50 milliseconds) in HD. In the search paradigms the P3 components differentiating target and standard stimuli were virtually absent in HD as was the ERP effect indexing word recognition. This was accompanied by a marked delay in search times and lower hit rates in the search tasks and a grossly reduced recognition accuracy in the memory task. CONCLUSIONS: The results suggest marked impairments of patients with HD in early visual sensory processing (early components). Deficits in visual search might be attributed to an impairment to deploy attentional resources across the visual field and/or an inability to control eye movements. The ERPs in the memory task differed grossly from similar data obtained by others in patients with Alzheimer disease, suggesting a different neural basis for the amnesia in HD.

Electrophysiological correlates of hierarchical stimulus processing: dissociation between onset and later stages of global and local target processing.

In the discussion of whether the processing of hierarchically structured stimuli proceeds from the more global to the more local level or vice versa, it is frequently assumed that the relative speed of global/local target identification (response time (RT) advantage) and the direction of interference from local/global distractors reflect the order of processing. Studies both in brain-injured patients and in normals, however, have demonstrated that RT advantage and interference are dissociable, leading to the conclusion that they do not provide a valid index of the order of global/local processing. The aim of the present event-related brain potential (ERP) study was to assess electrophysiological correlates of global/local processing and to determine how the relative speed of responding to global and local targets is related to these ERP measurements. In a divided-attention paradigm, subjects were asked to respond to hierarchically structured letter stimuli that contained a target letter either at the global or at the local level. The behavioral results confirmed a dissociation between RT advantage and interference. ERP analysis revealed an early posterior negative component (denoted as N250) as a sign of early global/local target perception. It was found that RT advantage is not a valid measure of the onset nor of the time course of this component. Furthermore, the N250 components to global and local targets exhibited a different time course and a different topographical distribution, suggesting that they are determined by separate processing structures. Together, the behavioral and electrophysiological results support the view that global and local target perception may be mediated by separate brain systems acting, at least initially, in parallel.