More than constipation - bowel symptoms in Parkinson's disease and their connection to gut microbiota.

BACKGROUND AND PURPOSE: The majority of Parkinson's disease (PD) patients suffer from gastrointestinal symptoms of which constipation is considered the most prominent. Recently, in addition to constipation, a diagnosis of irritable bowel syndrome (IBS) was also found to be associated with increased PD risk. Gut microbiota alterations have been reported in IBS and recently also in PD. IBS-like bowel symptoms in PD and their possible connection to other non-motor symptoms and faecal microbiota were assessed. METHODS: This case-control study compared 74 PD patients with 75 controls without any signs of parkinsonism or potential premotor symptoms. IBS-like symptoms were assessed using the Rome III questionnaire. The non-motor symptoms were assessed using the Non-Motor Symptoms Questionnaire and Non-Motor Symptom Scale. Faecal microbiota were assessed by pyrosequencing of the V1-V3 regions of the bacterial 16S ribosomal RNA gene. RESULTS: Symptoms that were IBS-like were significantly more prevalent in PD patients than in controls (24.3% vs. 5.3%; P = 0.001). Criteria for functional constipation were met by 12.2% of PD patients and 6.7% of controls (P = 0.072). PD patients with IBS-like symptoms had more non-motor symptoms and a lower faecal abundance of Prevotella bacteria than those without IBS-like symptoms. CONCLUSION: Our results indicate that PD patients may suffer from colonic dysfunction beyond pure constipation. Therefore, a more comprehensive assessment of bowel symptoms could provide valuable information. The lower abundance of Prevotella bacteria in PD patients with IBS-like symptoms suggests that the microbiota-gut-brain axis may be implicated in the gastrointestinal dysfunction of PD patients.

Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer's disease.

Scopolamine administration may be considered as a psychopharmacological model of Alzheimer's disease (AD). Here, we studied a group of healthy elderly under scopolamine to test whether it elicits similar changes in brain connectivity as those observed in AD, thereby verifying a possible model of AD impairment. We did it by testing healthy elderly subjects in two experimental conditions: glycopyrrolate (placebo) and scopolamine administration. We then analyzed magnetoencephalographic (MEG) data corresponding to both conditions in resting-state with eyes closed. This analysis was performed in source space by combining a nonlinear frequency band-specific measure of functional connectivity (phase locking value, PLV) with network analysis methods. Under scopolamine, functional connectivity between several brain areas was significantly reduced as compared to placebo, in most frequency bands analyzed. Besides, regarding the two complex network indices studied (clustering and shortest path length), clustering significantly decreased in the alpha band while shortest path length significantly increased also in alpha band both after scopolamine administration. Overall our findings indicate that both PLV and graph analysis are suitable tools to measure brain connectivity changes induced by scopolamine, which causes alterations in brain connectivity apparently similar to those reported in AD.

Dynamic tension EMG to characterize the effects of DBS treatment of advanced Parkinson's disease.

Deep brain stimulation (DBS) is an effective treatment method for motor symptoms of advanced Parkinson's disease. DBS-electrode is implanted to subthalamic nucleus to give precisely allocated electrical stimuli to brain. The optimal stimulus type has to be adjusted individually. Disease severity, main symptoms and biological factors play a role in correctly setting up the device. Currently there are no objective methods to assess the efficacy of DBS, hence the adjustment is based solely on clinical assessment. In optimal case an objectively measurable feature would point the right settings of DBS. Surface electromyographic and kinematic measurements have been used in Parkinson's disease research. As Parkinson's disease symptoms are known to change the EMG signal properties, these methods could be helpful aid in the clinical adjustment of DBS. In this study, 13 patients with advanced Parkinson's disease who received DBS treatment were measured. The patients were measured with seven different settings of the DBS in clinical range including changes in stimulation amplitude, frequency and pulse width. The EMG analysis was based on parameters that characterize EMG signal morphology. Correlation dimension and recurrence rate made the most significant difference in relation to optimal settings. In conclusion, EMG analysis is able to detect differences between the DBS setups, and can help in finding the correct parameters.

Effect of duodenal levodopa infusion on blood pressure and sweating.

BACKGROUND: Non-motor symptoms are a major contributor to quality of life in patients with advanced Parkinson's disease (PD). Duodenal levodopa infusion (DLI) has been shown to alleviate motor fluctuations, but data on its possible effect on non-motor symptoms are scarce. The aim of the study was to assess the effect of DLI on blood pressure (BP), sweating, and non-motor symptoms. METHODS: We evaluated prospectively and open-label nine male patients with advanced PD (age 68.5 ± 6.2 years) treated with DLI because of daily motor fluctuations. Patients were evaluated using orthostatic test, sweating and skin temperature measurements, Unified Parkinson's Disease Rating Scale (UPDRS), Non-motor Symptom Scale (NMSS), and PDQ-39 before and after 2 months of treatment. RESULTS: Orthostatic BP drop worsened after 1 week of DLI compared with oral medication (24.1 vs 11.9 mmHg, P = 0.011) and remained significant after 2 months of treatment. UPDRS motor scores improved significantly in 2 months compared with baseline (25 vs 19, P < 0.01). Sweating or skin temperatures did not change. Several domains in NMSS (sleep/fatigue, gastrointestinal symptoms, sweating) and PDQ-39 (mobility, bodily discomfort, communication) improved significantly. CONCLUSIONS: BP should be monitored during initiation of DLI because of the risk of orthostatic hypotension. Our results indicate that DLI improves both motor and non-motor symptoms in patients with advanced PD.

Effects of haloperidol on selective attention: a combined whole-head MEG and high-resolution EEG study.

We used 122-channel magnetoencephalography (MEG) and 64-channel electroencephalogrphy (EEG) simultaneously to study the effects of dopaminergic transmission on human selective attention in a randomized, double-blind placebo-controlled cross-over design. A single dose of dopamine D2 receptor antagonist haloperidol (2 mg) or placebo was given orally to 12 right-handed healthy volunteers 3 hours before measurement. In a dichotic selective attention task, subjects were presented with two trains of standard (700 Hz to the left ear, 1,100 Hz to the right ear) and deviant (770 and 1,210 Hz, respectively) tones. Subjects were instructed to count the tones presented to one ear; whereas, the tones presented to the other ear were to be ignored. Haloperidol significantly attenuated processing negativity (PN), an event-related potential (ERP) component elicited by selectively attended standard tones at 300-500 ms after stimulus presentation. These results, indicating impaired selective attention by a blockade of dopamine D2 receptors, were further accompanied with increased mismatch negativity (MMN), elicited by involuntary detection of task-irrelevant deviants. Taken together, haloperidol seemed to induce functional changes in neural networks accounting for both selective and involuntary attention, suggesting modulation of these functions by dopamine D2 receptors.

No evidence for dependence of early cortical auditory processing on dopamine D(2)-receptor modulation: a whole-head magnetoencephalographic study.

Magnetoencephalography (MEG) was used to determine the effect of neuroleptic challenge on brain responses in healthy subjects. In a double-blind, randomized, placebo-controlled, cross-over design study, the dopamine D(2) receptor antagonist haloperidol (2 mg) was given orally to 12 healthy volunteers. The middle-latency auditory evoked magnetic fields (MAEF) were recorded 3 h after administration of haloperidol or placebo with a whole-head 122-channel MEG. Haloperidol did not significantly affect MAEF responses. The dipole moments and source locations of the responses were not significantly influenced by haloperidol. These results suggest that dopamine D(2) receptors are not involved in the early phases of auditory cortical processing.

The processing of sound duration after left hemisphere stroke: event-related potential and behavioral evidence.

The ability of left-hemisphere stroke patients (n = 8) and healthy control subjects (n = 8) to process sounds preattentively and attentively was studied by recording auditory event-related potentials (ERPs) and behavioral responses. For the right-ear stimulation, the mismatch negativity (MMN) was significantly smaller in the patients than control subjects over both hemispheres. For the left-ear stimuli, the MMN was significantly smaller in the patient group than in the control group over the left hemisphere, whereas no group differences were obtained over the right hemisphere. In addition, the N1 amplitude was reduced bilaterally for the right-ear stimulation (with the reduction being larger over the left hemisphere), whereas no significant effects on the N1 amplitude were found for the left-ear stimulation. Behaviorally, the patients detected significantly fewer deviant tones than did the control subjects irrespective of the stimulated ear. The present results thus suggest that the long-latency ERPs can be used to probe such auditory processing deficits that are difficult to define with behavioral measures. Especially by recording MMN to monaural stimuli, the discrimination accuracy can be separately determined for the left and right temporal lobes.

Auditory sensory memory and the cholinergic system: implications for Alzheimer's disease.

Auditory sensory memory represents one of the simplest types of short-term memory that can be studied electrophysiologically with mismatch negativity (MMN); a specific auditory event-related potential indexing automatic comparison of incoming stimuli to an existing memory trace. Previous results suggest that auditory sensory memory deteriorates in aging and especially in Alzheimer's disease (AD). It has remained unsettled, however, whether MMN is regulated by the cholinergic system, which is deteriorated in AD contributing to cognitive impairments. We recorded cortical auditory responses with a magnetometer from 13 healthy subjects after intravenous injection of scopolamine, centrally acting cholinergic antagonist, or glycopyrrolate, a drug with a peripheral anticholinergic properties without penetrating the blood-brain barrier, using a double-blind protocol. Scopolamine reduced MMNm amplitude in response to frequency, but not duration, change, increased P50m amplitude, and delayed N100m latency. These findings suggest that the cholinergic system regulates the frequency-specific comparison of incoming stimuli to existing memory trace and modulates the preattentive processing related to stimulus detection. Further, neural mechanisms responsible for cortical frequency- and duration-specific discrimination appear to have different sensitivities to cholinergic modulation. Auditory evoked potentials might be suitable to monitor cholinergic activity in AD.

Preserved stimulus deviance detection in Alzheimer's disease.

Aging attenuates automatic auditory discrimination to duration change, whereas frequency change detection is relatively unimpaired in aging and in Alzheimer's disease (AD). Here we studied with a whole-head magnetometer whether cortical auditory discrimination to duration change as shown by magnetic mismatch negativity (MMNm) response is impaired in AD. Twenty AD patients with mild to moderate cognitive impairment and 18 age-matched healthy subjects were monaurally presented a sequence of frequent standard tones embedded with occasional deviants with shorter duration. MMNm was significantly delayed in the left hemisphere ipsilaterally to the ear stimulated in the patient group, whereas the MMNm amplitudes over both hemispheres were quite similar in both groups. This suggests that although MMNm is delayed in the left hemisphere, the automatic discrimination to duration change in the auditory cortex is not attenuated in the early stages of AD.

Scopolamine reduces the P35m and P60m deflections of the human somatosensory evoked magnetic fields.

Acetylcholine (ACh) is a potent neuromodulator in the brain with multiple, complex effects on neuronal function, most of which are mediated by muscarinic receptors. Generally, the most significant effect is excitation of pyramidal neurones and facilitation of responses to afferent stimulation. Much of the information on the ACh effects comes from studies utilizing in vitro or anesthetized in vivo preparations, while fewer data are available from awake animals or humans. We studied human somatosensory evoked magnetic fields (SEFs), which reflect summated postsynaptic currents in pyramidal neurones in area 3b, and in the opercular somatosensory cortex, when cholinergic transmission was modulated either by a central (scopolamine, 0.3 mg, i.v.) or peripheral (glycopyrrolate, 0.2 mg, i.v.) muscarinic antagonist. A randomized, double-blind, cross-over design was employed. SEFs were elicited by right median nerve stimulation at the wrist with constant-current pulses above motor threshold. The first excitatory cortical response from area 3b (N20m) was not affected by the central muscarinic blockade, while later P35m and P60m deflections were significantly reduced. The responses from the opercular somatosensory cortex showed some tendency toward reduction, but no significant alterations. The results show that somatosensory cortical processing can be modulated by muscarinic transmission at a relatively early stage. Relative membrane hyperpolarization of pyramidal neurons due to scopolamine (caused by blocking an ACh-induced tonic depolarization) is discussed as a possible mechanism underlying the observed effects.

Suppression of transient 40-Hz auditory response by haloperidol suggests modulation of human selective attention by dopamine D2 receptors.

Cognitive processes including selective attention may depend on synchronous activity of neurons at the gamma-band (around 40Hz). To determine the effect of neuroleptic challenge on transient auditory evoked 40-Hz response, simultaneous measurement of 122-channel magnetoencephalogram (MEG) and 64-channel electroencephalogram (EEG) was used. Either 2mg of dopamine D(2)-receptor antagonist haloperidol or a placebo was administered orally to 11healthy subjects in a double-blind randomized crossover design in two separate sessions. The subjects attended to tones presented to one ear and ignored those presented to the other ear. Haloperidol significantly suppressed the transient 40-Hz electric response to the attended stimuli, while no significant effect was observed in the electric responses to the unattended tones or in the magnetic responses. The present result suggests that dopamine D(2) receptors modulate selective attention.

Mismatch negativity in aging and in Alzheimer's and Parkinson's diseases.

Mismatch negativity (MMN) is an auditory event-related potential (ERP) that reflects automatic stimulus discrimination in the human auditory system. By varying the interstimulus intervals (ISIs), the MMN can be used as an index of auditory sensory memory. This paper focuses on MMN findings in aging and in Alzheimer's (AD) and Parkinson's diseases (PD). The accumulated data suggest that MMN to duration deviance, unlike MMN to frequency deviance, is reduced in amplitude in aging at short ISIs. The attenuated MMN to frequency deviance observed at long ISIs in elderly subjects seems to be caused by age-related memory trace decay. Existing results suggest that automatic discrimination for the frequency change is not affected in the early phase of AD, whereas the memory trace seems to decay faster in AD patients. The present findings on PD are not as conclusive, although they tentatively suggest deteriorated automatic change detection. The MMN appears to offer an objective tool for studying auditory processing and memory trace decay in different neurological disorders.

Global field power of auditory N1 correlates with impaired verbal-memory performance in human alcoholics.

First weeks after alcohol withdrawal, associated with profound changes in neural transmission, constitute the critical period for relapse prevention and pharmacological intervention in alcoholism. Here, 20 male alcoholics with 1-6 weeks of abstinence and 20 age-matched healthy controls were studied using auditory event-related potentials (ERP), measured with a 32-channel electroencephalogram, and neuropsychological tests of auditory-verbal memory. Global field power maximum of ERP during 80-150 ms period after presentation of unattended tones (binaural 700 Hz pure tones, inter-stimulus interval 2.5 s) was significantly (P<0.01) larger in the alcoholics than controls. This effect, reflecting augmented N1 generation, significantly correlated (r=0.5) with impaired memory performance in the alcoholics. The profound change in pre-attentive auditory processing, predicting impaired memory performance, might reflect impaired cerebral inhibitory transmission in alcoholics.

Dose-dependent suppression by ethanol of transient auditory 40-Hz response.

RATIONALE: Acute alcohol (ethanol) challenge is known to induce various cognitive disturbances, yet the neural basis of the effect is poorly known. The auditory transient evoked gamma-band (40-Hz) oscillatory responses have been suggested to be associated with various perceptual and cognitive functions in humans; however, alcohol effects on auditory 40-Hz responses have not been investigated to date. OBJECTIVES: The objective of the study was to test the dose-related impact of alcohol on auditory transient evoked 40-Hz responses during a selective-attention task. METHODS: Ten healthy social drinkers ingested, in four separate sessions, 0.00, 0. 25, 0.50, or 0.75 g/kg of 10% (v/v) alcohol solution. The order of the sessions was randomized and a double-blind procedure was employed. During a selective attention task, 300-Hz standard and 330-Hz deviant tones were presented to the left ear, and 1000-Hz standards and 1100-Hz deviants to the right ear of the subjects (P=0. 425 for each standard, P=0.075 for each deviant). The subjects attended to a designated ear, and were to detect the deviants therein while ignoring tones to the other ear. RESULTS: The auditory transient evoked 40-Hz responses elicited by both the attended and unattended standard tones were significantly suppressed by the 0.50 and 0.75 g/kg alcohol doses. CONCLUSIONS: Alcohol suppresses auditory transient evoked 40-Hz oscillations already with moderate blood alcohol concentrations. Given the putative role of gamma-band oscillations in cognition, this finding could be associated with certain alcohol-induced cognitive deficits.

Increased distractibility by task-irrelevant sound changes in abstinent alcoholics.

BACKGROUND: Chronic alcoholism is accompanied by "frontal" neuropsychological deficits that include an inability to maintain focus of attention. This might be associated with pronounced involuntary attention shifting to task-irrelevant stimulus changes and, thereafter, an impaired reorienting to the relevant task. The neural abnormalities that underlie such deficits in alcoholics were explored with event-related potential (ERP) components that disclosed different phases of detection and orienting to stimulus changes. METHODS: Twenty consecutive abstinent male alcoholics (DSM-IV) and 20 age-matched male controls (healthy social drinkers) were instructed to discriminate equiprobable 100 and 200 msec tones in a reaction-time task (RT) and to ignore occasional, either slight (7%) or wide (70%), frequency changes (hypothesized to increase RT) during an ERP measurement. RESULTS: In the alcoholics, we found pronounced distractibility, evidenced by a RT lag (p < 0.01) caused by deviants, that correlated (Spearman p = 0.5) with a significantly enhanced (p < 0.01) amplitude of mismatch negativity (MMN) to deviants. Significantly increased RT lag for trials subsequent to deviants (slight p < 0.001, wide p < 0.05) in the alcoholics suggested impaired reorienting to the relevant task. The MMN enhancement also predicted poorer hit rates in the alcoholics (Spearman p = 0.6-0.7). Both the MMN enhancement and pronounced distractibility correlated (Spearman p = 0.4) with an early onset of alcoholism. CONCLUSIONS: Attentional deficits in the abstinent alcoholics were indicated by the increased distractibility by irrelevant sound changes. The MMN enhancement suggested that this reflects impaired neural inhibition of involuntary attention shifting, being most pronounced in early-onset alcoholics.

Impaired preconscious auditory processing and cognitive functions in Alzheimer's disease.

OBJECTIVE: To study whether preconscious auditory processing is deteriorated in patients with Alzheimer's disease (AD) having mild to moderate cognitive symptoms. To investigate whether auditory processing correlates with the impairment of the higher cortical functions. METHODS: P50m and N100m responses elicited by a sequence of repetitive tones were recorded with a whole-head magnetometer from 22 patients with probable AD and from 18 healthy age-matched controls. In addition, an extensive neuropsychological test battery assessing main cognitive domains was administered to all subjects. RESULTS: The patients with AD had significantly delayed N100m responses in the left hemisphere that correlated with the impairment of the language functions. CONCLUSIONS: N100m auditory responses measured with magnetoencephalography may be useful in evaluating the severity and progression of the cortical dysfunction in dementia.

Suppression of mismatch negativity by backward masking predicts impaired working-memory performance in alcoholics.

BACKGROUND: Pronounced disruption of memory traces by subsequent distractors may result in impaired behavioral memory performance in alcoholics. METHODS: This hypothesis was investigated with an electrophysiological index of auditory sensory-memory traces, mismatch negativity, a preattentive event-related potential component elicited by a "deviant" tone within a train of "standard" tones. RESULTS: Inserting a masking stimulus after these tones abolished mismatch negativity in alcoholics (DSM-IV) but not in social-drinker controls. This effect predicted working-memory impairment in alcoholics, and correlated significantly with self-reported alcohol consumption of the subjects. Furthermore, the backward-masking mismatch negativity paradigm detected sensory-memory impairment in 9 of 20 alcoholics (sensitivity 45%), whereas all 20 social drinkers were unimpaired (specificity 100%). CONCLUSIONS: Vulnerability to memory trace disruption by shortly following sounds may be one of the factors contributing to behavioral memory dysfunction in alcoholics. The present result may provide an objective neurophysiological tool for investigation of alcohol-induced and other degenerative brain disorders.

Altered parallel auditory processing in schizophrenia patients.

Patients with schizophrenia have impaired auditory processing that has been demonstrated by diminished P50 response to paired auditory stimuli in event-related potential (ERP) studies. Cerebral processing can also be studied with magnetoencephalography (MEG). With a whole-head MEG, which enables one to simultaneously measure brain activity in both hemispheres, we investigated whether early parallel auditory processing is impaired in schizophrenia. Sequences of tones were monaurally presented to schizophrenia patients and healthy controls in a passive condition, and the event-related magnetic fields were recorded simultaneously over both auditory cortices. The interhemispheric latency difference of the P50m, but not that of the N100m, was significantly shorter in the patient group in the right-ear but not in the left-ear stimulus condition. Further, the ipsilateral P50m was significantly earlier in schizophrenia patients in the right-ear condition. This result suggests that schizophrenia affects the consecutive preconscious auditory processing in a different manner.

Post-withdrawal changes in middle-latency auditory evoked potentials in abstinent human alcoholics.

We investigated the effects of chronic alcoholism on middle-latency auditory evoked potentials (MAEP) in 14 male alcoholics with 1-6 weeks of abstinence (without other severe disorders) and 13 age-matched male social-drinker controls. The peak amplitude of a positive deflection (Pa) of the MAEP, peaking at about 30 ms post-stimulus, was significantly larger in the alcoholics than in the controls (P < 0.01), and notably, a significant negative correlation (r = -0.65) was observed between the Pa amplitude and duration of abstinence in the alcoholics. The present results suggest that the post-withdrawal brain hyperexcitability in the alcoholic brain, gradually recovering with abstinence, could be objectively and non-invasively studied with the MAEP.

Benzodiazepine temazepam suppresses the transient auditory 40-Hz response amplitude in humans.

To discern the role of the GABA(A) receptors in the generation and attentive modulation of the transient auditory 40-Hz response, the effects of the benzodiazepine temazepam (10 mg) were studied in 10 healthy social drinkers, using a double-blind placebo-controlled design. Three hundred Hertz standard and 330 Hz rare deviant tones were presented to the left, and 1000 Hz standards and 1100 Hz deviants to the right ear of the subjects. Subjects attended to a designated ear and were to detect deviants therein while ignoring tones to the other. Temazepam significantly suppressed the amplitude of the 40-Hz response, the effect being equal for attended and non-attended tone responses. This suggests involvement of GABA(A) receptors in transient auditory 40-Hz response generation, however, not in the attentive modulation of the 40-Hz response.