Dopaminergic modulation of novelty repetition in Parkinson's disease: A study of P3 event-related brain potentials.

OBJECTIVE: Parkinson's Disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons. Cognitive impairments have been reported using the event-related potential (ERP) technique. Patients show reduced novelty P3 (nP3) amplitudes in oddball experiments, a response to infrequent, surprising stimuli, linked to the orienting response of the brain. The nP3 is thought to depend on dopaminergic neuronal pathways though the effect of dopaminergic medication in PD has not yet been investigated. METHODS: Twenty-two patients with PD were examined "on" and "off" their regular dopaminergic medication in a novelty 3-stimulus-oddball task. Thirty-four healthy controls were also examined over two sessions, but received no medication. P3 amplitudes were compared throughout experimental conditions. RESULTS: All participants showed sizeable novelty difference ERP effects, i.e. ndP3 amplitudes, during both testing sessions. An interaction of diagnosis, medication and testing order was also found, indicating that dopaminergic medication modulated ndP3 in patients with PD across the two testing sessions: We observed enhanced ndP3 amplitudes from PD patients who were off medication on the second testing session. CONCLUSION: Patients with PD 'off' medication showed ERP evidence for repetition-related enhancement of novelty responses. Dopamine depletion in neuronal pathways that are affected by mid-stage PD possibly accounts for this modulation of novelty processing. SIGNIFICANCE: The data in this study potentially suggest that repetition effects on novelty processing in patients with PD are enhanced by dopaminergic depletion.

Thalamic and basal ganglia regions are involved in attentional processing of behaviorally significant events: evidence from simultaneous depth and scalp EEG.

Extensive descriptions exist on cortical responses to change in the acoustic environment. However, the involvement of subcortical regions is not well understood. Here we present simultaneous recordings of cortical and subcortical event-related potentials (ERPs) to different pure tones in patients undergoing surgery for deep brain stimulation (DBS). These patients had externalized electrodes in the subthalamic nucleus (STN), the ventrolateral posterior thalamus (VLp) or the globus pallidus internus (GPi). Subcortical and cortical ERPs were analyzed upon presentation of one frequent non-target stimulus and two infrequent stimuli, either being a target or a distractor stimulus. The results revealed that amplitudes of scalp-recorded P3 and subcortical late attention-modulated responses (AMR) were largest upon presentation of target stimuli compared with distractor stimuli. This suggests that thalamic and basal ganglia regions are sensitive to behaviorally relevant auditory events. Comparison of the subcortical structures showed that responses in VLp have shorter latency than in GPi and STN. Further, the subcortical responses in VLp and STN emerged significantly prior to the cortical P3 response. Our findings point to higher-order cognitive functions already at a subcortical level. Auditory events are categorized as behaviorally relevant in subcortical loops involving basal ganglia and thalamic regions. This label is then distributed to cortical regions by ascending projections.

Auditory and audio-visual processing in patients with cochlear, auditory brainstem, and auditory midbrain implants: An EEG study.

There is substantial variability in speech recognition ability across patients with cochlear implants (CIs), auditory brainstem implants (ABIs), and auditory midbrain implants (AMIs). To better understand how this variability is related to central processing differences, the current electroencephalography (EEG) study compared hearing abilities and auditory-cortex activation in patients with electrical stimulation at different sites of the auditory pathway. Three different groups of patients with auditory implants (Hannover Medical School; ABI: n = 6, CI: n = 6; AMI: n = 2) performed a speeded response task and a speech recognition test with auditory, visual, and audio-visual stimuli. Behavioral performance and cortical processing of auditory and audio-visual stimuli were compared between groups. ABI and AMI patients showed prolonged response times on auditory and audio-visual stimuli compared with NH listeners and CI patients. This was confirmed by prolonged N1 latencies and reduced N1 amplitudes in ABI and AMI patients. However, patients with central auditory implants showed a remarkable gain in performance when visual and auditory input was combined, in both speech and non-speech conditions, which was reflected by a strong visual modulation of auditory-cortex activation in these individuals. In sum, the results suggest that the behavioral improvement for audio-visual conditions in central auditory implant patients is based on enhanced audio-visual interactions in the auditory cortex. Their findings may provide important implications for the optimization of electrical stimulation and rehabilitation strategies in patients with central auditory prostheses. Hum Brain Mapp 38:2206-2225, 2017. © 2017 Wiley Periodicals, Inc.

Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic lateral sclerosis mouse models based on TDP-43 (Tardbp) and FUS mutations. Finally, we demonstrate that the melanocortin defect is primarily caused by serotonin loss in mutant SOD1(G86R) mice. Altogether, the current study combined clinical evidence and experimental studies in rodents to provide a mechanistic explanation for abnormalities in food intake and weight control observed in patients with amyotrophic lateral sclerosis. Importantly, these results also show that amyotrophic lateral sclerosis progression impairs responsiveness to classical drugs leading to weight gain. This has important implications for pharmacological management of weight loss in amyotrophic lateral sclerosis.

Enhanced audio-visual interactions in the auditory cortex of elderly cochlear-implant users.

Auditory deprivation and the restoration of hearing via a cochlear implant (CI) can induce functional plasticity in auditory cortical areas. How these plastic changes affect the ability to integrate combined auditory (A) and visual (V) information is not yet well understood. In the present study, we used electroencephalography (EEG) to examine whether age, temporary deafness and altered sensory experience with a CI can affect audio-visual (AV) interactions in post-lingually deafened CI users. Young and elderly CI users and age-matched NH listeners performed a speeded response task on basic auditory, visual and audio-visual stimuli. Regarding the behavioral results, a redundant signals effect, that is, faster response times to cross-modal (AV) than to both of the two modality-specific stimuli (A, V), was revealed for all groups of participants. Moreover, in all four groups, we found evidence for audio-visual integration. Regarding event-related responses (ERPs), we observed a more pronounced visual modulation of the cortical auditory response at N1 latency (approximately 100 ms after stimulus onset) in the elderly CI users when compared with young CI users and elderly NH listeners. Thus, elderly CI users showed enhanced audio-visual binding which may be a consequence of compensatory strategies developed due to temporary deafness and/or degraded sensory input after implantation. These results indicate that the combination of aging, sensory deprivation and CI facilitates the coupling between the auditory and the visual modality. We suggest that this enhancement in multisensory interactions could be used to optimize auditory rehabilitation, especially in elderly CI users, by the application of strong audio-visually based rehabilitation strategies after implant switch-on.

Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options.

BACKGROUND: Weight loss is a frequent feature in the motor neuron disease Amyotrophic lateral sclerosis (ALS). In this study we investigated possible causes of weight loss in ALS, its impact on mood/quality of life (QOL) and the benefit of high calorie nutritional/other dietary supplements and percutaneous endoscopic gastrostomy (PEG). METHODS: 121 ALS patients were interviewed and answered standardized questionnaires (Beck depression inventory - II, SF36 Health Survey questionnaire, revised ALS functional rating scale). Two years after the initial survey we performed a follow-up interview. RESULTS: In our ALS-cohort, 56.3% of the patients suffered from weight loss. Weight loss had a negative impact on QOL and was associated with a shorter survival. Patients who took high calorie nutritional supplements respectively had a PEG stated a great benefit regarding weight stabilization and/or QOL.38.2% of our patients had significant weight loss without suffering from dysphagia. To clarify the reasons for weight loss in these patients, we compared them with patients without weight loss. The two groups did not differ regarding severity of disease, depression, frontotemporal dementia or fasciculations, but patients with weight loss declared more often increased respiratory work. CONCLUSIONS: Weight loss is a serious issue in ALS and cannot always be attributed to dysphagia. Symptomatic treatment of weight loss (high calorie nutritional supplements and/ or PEG) should be offered more frequently.

Alterations in early auditory evoked potentials and brainstem transmission time associated with tinnitus residual inhibition induced by auditory electrical stimulation.

INTRODUCTION: Residual inhibition (RI) is the temporary inhibition of tinnitus by use of masking stimuli when the device is turned off. OBJECTIVE: The main aim of this study was to evaluate the effects of RI induced by auditory electrical stimulation (AES) in the primary auditory pathways using early auditory-evoked potentials (AEPs) in subjective idiopathic tinnitus (SIT) subjects. MATERIALS AND METHODS: A randomized placebo-controlled study was conducted on forty-four tinnitus subjects. All enrolled subjects based on the responses to AES, were divided into two groups of RI and Non-RI (NRI). The results of the electrocochleography (ECochG), auditory brain stem response (ABR) and brain stem transmission time (BTT) were determined and compared pre- and post-AES in the studied groups. RESULTS: The mean differences in the compound action potential (CAP) amplitudes and III/V and I/V amplitude ratios were significantly different between the RI, NRI and PES controls. BTT was significantly decreased associated with RI. CONCLUSION: The observed changes in AEP associated with RI suggested some peripheral and central auditory alterations. Synchronized discharges of the auditory nerve fibers and inhibition of the abnormal activity of the cochlear nerve by AES may play important roles associated with RI. Further comprehensive studies are required to determine the mechanisms of RI more precisely.

Speech therapy and communication device: impact on quality of life and mood in patients with amyotrophic lateral sclerosis.

Dysarthria has a drastic impact on the quality of life of ALS patients. Most patients suffering from dysarthria are offered speech therapy. Communication devices are prescribed less frequently. In the present study we investigated the impact of these therapeutic arrangements on quality of life in ALS patients. Thirty-eight ALS patients with dysarthria or anarthria, who underwent speech therapy and/or used communication devices answered three standardized questionnaires (Beck Depression Inventory - II (BDI), SF-36 Health Survey questionnaire (SF-36) and ALS Functional Rating Scale-revised (ALSFRS-R)) and were further interviewed about their experience with and benefit of speech therapy and communication devices. Most of the patients described a high impact of the communication device on their quality of life while the influence of speech therapy was rated less. By multiple regression analysis we confirmed an independent positive effect of communication device use on depression and psychological distress. In conclusion, communication systems improve or at least stabilize quality of life and mood in dysarthric ALS patients, and should be provided early in the disease course.

ERP evidence for the recognition of emotional prosody through simulated cochlear implant strategies.

BACKGROUND: Emotionally salient information in spoken language can be provided by variations in speech melody (prosody) or by emotional semantics. Emotional prosody is essential to convey feelings through speech. In sensori-neural hearing loss, impaired speech perception can be improved by cochlear implants (CIs). Aim of this study was to investigate the performance of normal-hearing (NH) participants on the perception of emotional prosody with vocoded stimuli. Semantically neutral sentences with emotional (happy, angry and neutral) prosody were used. Sentences were manipulated to simulate two CI speech-coding strategies: the Advance Combination Encoder (ACE) and the newly developed Psychoacoustic Advanced Combination Encoder (PACE). Twenty NH adults were asked to recognize emotional prosody from ACE and PACE simulations. Performance was assessed using behavioral tests and event-related potentials (ERPs). RESULTS: Behavioral data revealed superior performance with original stimuli compared to the simulations. For simulations, better recognition for happy and angry prosody was observed compared to the neutral. Irrespective of simulated or unsimulated stimulus type, a significantly larger P200 event-related potential was observed for happy prosody after sentence onset than the other two emotions. Further, the amplitude of P200 was significantly more positive for PACE strategy use compared to the ACE strategy. CONCLUSIONS: Results suggested P200 peak as an indicator of active differentiation and recognition of emotional prosody. Larger P200 peak amplitude for happy prosody indicated importance of fundamental frequency (F0) cues in prosody processing. Advantage of PACE over ACE highlighted a privileged role of the psychoacoustic masking model in improving prosody perception. Taken together, the study emphasizes on the importance of vocoded simulation to better understand the prosodic cues which CI users may be utilizing.

Changes of emotional prosody in Parkinson's disease.

Even though the mesocortical dopamine system is known to play an important role in affect control and reward related behaviour, only little is known about the impact of Parkinson's disease on emotional communication. The ability to perceive and express emotions via speech plays an essential role in every day social life. Here, studies investigating perception and production of emotional prosody in Parkinson's disease will be reviewed and own results will be presented. Evidence will be provided that patients with Parkinson's disease do have changes of emotional prosody processing and that they also show alterations of emotional speech production. Together, these studies highlight the importance of the basal ganglia and their connections for emotional communication.

On emotional conflict: interference resolution of happy and angry prosody reveals valence-specific effects.

To comprehend emotional prosodic cues in speech is a critical function of human social life. However, it is common in everyday communication that conflicting information in emotional prosody and semantic content co-occur. Here, we sought to specify brain regions involved in conflict monitoring of these interfering communication channels. By means of functional magnetic resonance imaging, we obtained signal increases in the right dorsal anterior cingulate cortex and right superior temporal gyrus (STG) and superior temporal sulcus when participants listened to incongruous compared with congruous sentences. Moreover, valence-specific effects were found in the left inferior frontal gyrus and left STG for happily intoned sentences expressing a negative content. The left caudate nucleus along with the thalamus was active when angrily intoned sentences were coupled with positive semantic content. Our results suggest a brain network that monitors conflict in emotional prosody and emotional semantic content comprising of medial prefrontal areas that have previously been associated with cognitive conflict processing. Furthermore, our study extends the knowledge of these processes by suggesting valence-specific differences of emotional conflict processing.

Decreased brain activation to tongue movements in amyotrophic lateral sclerosis with bulbar involvement but not Kennedy syndrome.

Neuroimaging studies in amyotrophic lateral sclerosis (ALS) investigating movements of the hands have in general found increased activation compared to healthy controls, which has been interpreted in terms of cortical adaptation as a result of corticospinal tract damage. Here, we investigated brain activations to vertical tongue movements using functional MRI at 3 tesla. Whereas healthy controls, patients with Kennedy syndrome, and ALS patients without bulbar involvement showed robust and indistinguishable activations in pre- and postcentral areas and the thalamus, ALS patients with bulbar involvement showed a significant decrease of cortical activity and missing thalamic activity. This decrease stands in marked contrast to the increase of activity observed in ALS patients when performing limb movements. We discuss these divergent findings with regard to the different physiological properties of tongue and limb movements. These findings may also help to explain the faster time-course of the disease in patients with bulbar involvement.

Needle acupuncture in chronic poststroke leg spasticity.

OBJECTIVE: To determine whether needle acupuncture may be useful in the reduction of leg spasticity in a chronic state. DESIGN: Single-blind, randomized, placebo-controlled trial. SETTING: Neurologic outpatient department of a medical school in Germany. PARTICIPANTS: Twenty-five patients (14 women) suffering from chronic poststroke leg spasticity with pes equinovarus deformity (Modified Ashworth Scale [MAS] score, >/=1), aged 38 to 77 years (mean +/- standard deviation, 58.5+/-10.4 y), were enrolled in the study. The mean time from stroke to inclusion in the study was approximately 5 years (mean, 65.4+/-48.3 mo; range, 7-180 mo). INTERVENTIONS: Participants were randomly assigned to placebo treatment (n=12) by using a specially designed placebo needling procedure, or verum treatment (n=13). MAIN OUTCOME MEASURES: MAS score of the affected ankle, pain (visual analog scale), and walking speed. RESULTS: There was no demonstrated beneficial clinical effects from verum acupuncture. After 4 weeks of treatment, mean MAS score was 3.3+/-0.9 in the placebo group versus 3.3+/-1.1 in the verum group. The neurophysiologic measure of H-reflex indicated a significant increase of spinal motoneuron excitability after verum acupuncture (H-response/M-response ratio: placebo,.39+/-.19; verum,.68+/-.41; P<.05). CONCLUSIONS: This effect might be explained by afferent input of A delta and C fibers to the spinal motoneuron. The results from our study indicate that needle acupuncture may not be helpful to patients with chronic poststroke spasticity. However, there was neurophysiologic evidence for specific acupuncture effects on a spinal (segmental) level involving nociceptive reflex mechanisms.

Repetitive transcranial magnetic stimulation for the treatment of chronic pain - a pilot study.

Invasive electrical stimulation of the motor cortex has been reported to be of therapeutic value in pain control. We were interested whether noninvasive repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex might also act beneficially. Twelve patients with therapy-resistant chronic pain syndromes (mean age 51.3 +/- 12.6, 6 males) were included in a pilot study. They were treated with rTMS of the corresponding motor cortex area for 20 min (20 Hz, 20 x 2 s trains, intensity 80% of motor threshold) and sham stimulation (sequence-controlled cross-over design). Some of the patients (6/6) had an analgesic effect, but for the whole group, the difference between active and sham stimulation did not reach a level of significance (active rTMS: mean VAS reduction -4.0 +/- 15.6%; sham rTMS: -2.3 +/- 8.8%). Further studies using different rTMS stimulation parameters (duration and frequency of rTMS) or stimulation sites (e.g. anterior cingulate gyrus) are strongly encouraged.