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.

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.

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.

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.

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.

Reversal of cerebral asymmetry in schizophrenia measured with magnetoencephalography.

It has been suggested that schizophrenic patients fail to develop left-hemisphere dominance because of an early disturbance in neuronal development. This hypothesis has been supported by some post-mortem. CT and magnetic resonance imaging (MRI) studies, while other in-vivo studies have given contradicting results. We used 122-channel whole-head magnetoencephalography and MRI to locate the sources of auditory evoked responses in 19 schizophrenic patients and in 20 healthy controls. Auditory evoked responses were detected in all subjects. The left-right hemisphere asymmetry of cerebral sources for auditory evoked responses was markedly dispersed among patients when compared with controls. The source locations for left auditory cortex were clearly anterior with respect to the right hemisphere in 32% of the patients, while the corresponding prevalence of this abnormal asymmetry was 0% in controls (p = 0.008. Fisher's exact test). The reversed asymmetry appeared to be associated with a shorter anterior-posterior distance between the auditory cortex and the anterior tip of the temporal lobe in the left side when compared with the right side. The reversed asymmetry was associated with higher PANSS general psychopathological score, and especially with higher guilt feelings and motor retardation scores. The large 2.5-fold standard deviation in the inter-hemispheric anterior posterior difference in the location of the auditory cortex among patients (p 0.001 for the difference in the magnitude of variance between controls and patients) clearly reflects the dispersion of the left right asymmetry into both direction, and three of the patients with 'normal asymmetry' had a greater left-right asymmetry than any of the controls. Markedly greater reversal of hemispheric asymmetry among patients implies that regulation of the development of brain asymmetry is disturbed among schizophrenic patients. Abnormality in the cerebral asymmetry may be a crucial factor in the development of schizophrenic disorder in a substantial proportion of patients. The results suggest that the reversed asymmetry is associated with the higher severity of general psychopathological symptoms.

Parkinson's disease selectively impairs preattentive auditory processing: an MEG study.

Auditory stimuli elicit auditory evoked magnetic fields (AEFs) called P50m and N100m, which index preconscious auditory processing in human. We investigated with a whole-head magnetometer whether Parkinson's disease (PD) impairs parallel preattentive auditory processing between the hemispheres. Stimulus blocks consisting of standard (80%) and deviant (20%) tones were monaurally presented in a passive condition to 11 PD patients with unilateral motor symptoms and to 11 age-matched healthy controls. The constant interstimulus intervals (ISIs) were 0.5 s and 2.5 s in separate blocks. The interhemispheric latency differences of the P50m and N100m were significantly lengthened in PD patients in the left-ear condition. This might be caused by the basal ganglia dysfunction in PD together with the simultaneous age-related neural degeneration predominant in the left auditory cortex.

Auditory sensory memory impairment in Alzheimer's disease: an event-related potential study.

Auditory event-related potentials (ERP) were recorded from 10 healthy older subjects and 9 patients with Alzheimer's disease (AD) to investigate whether auditory sensory memory is impaired in AD. Standard (85%) and deviant (15%) tones were presented in random order with interstimulus intervals (ISI) of 1 s or 3 s in separate blocks. Deviant tones elicited a specific ERP component called mismatch negativity (MMN) which reflects automatic stimulus change detection and thus presumably, the neural basis of sensory memory in audition. The MMN amplitude decreased as a function of the ISI more in the AD group than in the control group. This suggests that the memory trace decays faster in the AD patients than in age-matched healthy controls.

Auditory stimuli activate parietal brain regions: a whole-head MEG study.

Previous studies using magnetoencephalographic (MEG) recordings have revealed neuronal populations responding to discrete auditory stimuli in the supratemporal cortex of the human brain. We used the novel whole-head magnetometer (Neuromag-122) to determine whether regions outside the auditory cortex are activated by auditory stimulation as well. In the present study we report evidence for activation of the parietal cortex of the human brain in response to auditory stimuli.

Decay of cortical pre-attentive sound discrimination in middle-age.

Ageing effects on pre-attentive cortical detection of sound change, as indexed by magnetic mismatch negativity (MMNm), were disclosed with whole-head magnetoencephalography (MEG). Seventy healthy subjects (aged 17-82 years) were presented with a sequence of homogeneous standard tones and occasional deviants of shorter duration. The MMNm elicited by the shorter tones was diminished in amplitude (r = -0.42, p < 0.001) and increased in latency in the hemisphere ipsilateral to the ear stimulated (r = 0.38, p < 0.01), these effects being significant even in middle-aged subjects. The results suggest that pre-attentive comparison of incoming stimuli to a short-lived sensory memory trace in the central auditory system is impaired, and delayed in the ipsilateral hemisphere, already by the middle-age.

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.

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.

Alzheimer's disease affects parallel processing between the auditory cortices.

Auditory evoked magnetic fields (AEFs) were recorded from 11 patients with Alzheimer's disease (AD) and 11 age-matched controls using the 122-channel whole-head magnetometer. Auditory stimuli were monaurally presented with interstimulus intervals (ISI) of 0.5 and 2.5 s in different blocks. The peak latencies of P50m and N100m responses were significantly longer in AD patients than in controls over the ipsilateral but not over the contralateral auditory cortex with respect to the ear stimulated. This finding suggests that parallel auditory processing is impaired between the auditory cortices in AD patients. The present MEG measurement might provide an objective index to evaluate auditory dysfunction in AD.

Age-related functional differences between auditory cortices: a whole-head MEG study.

Auditory evoked magnetic fields (AEFs) were recorded from 10 healthy younger and 10 older subjects using a whole-head magnetometer. Two blocks of tone pips were presented to the left ear with constant inter-stimulus intervals (ISIs) of 0.5 and 2.5 s. The amplitude of P50m, unlike that of N100m, was larger in the older subjects. In both groups, the peak latencies of P50m and N100m responses were significantly shorter over the contralateral than ipsilateral cortex. The interhemispheric latency difference of N100m was significantly increased with age. These findings suggest that ageing delays signal processing in the ipsilateral auditory cortex and that ageing affects consecutive AEFs in a different manner.

Sustained fields of tones and glides reflect tonotopy of the auditory cortex.

Cortical activation in response to two types of auditory stimuli, constant-frequency tones and frequency glides, was studied by measuring the magnetic field outside the head using a whole-head 122-channel magnetometer. Both the magnetic N1m and sustained responses were located in the supratemporal plane of the primary auditory cortex. The sustained responses both to constant-frequency tones and frequency glides reflect tonotopic organization of the auditory cortex both in depth and direction, thus revealing the underlying neuroanatomical structure of the auditory cortex.

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.

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.

Scopolamine enhances middle-latency auditory evoked magnetic fields.

To study the influence of central cholinergic muscarinic transmission on human cortical middle-latency auditory evoked magnetic fields (MAEF), centrally acting antagonist scopolamine hydrobromide (0.3 mg, i.v.), and peripheral muscarinic receptor antagonist glycopyrrolate (0.2 mg, i.v.), were administered to 13 healthy subjects in a double-blind randomized cross-over design. MAEF, measured with whole-head magnetoencephalography (MEG), were elicited with clicks applied at 10-Hz rate to the left ear. The amplitudes of N(b)m and P(a)m responses were augmented by scopolamine (P < 0.01 and P < 0.08). These effects were about equally strong for responses from ipsi- and contralateral auditory cortices. Thus, the present MEG findings revealed specific modulation of cortical generators of middle-latency auditory evoked responses by muscarinic transmission. These findings might be associated with auditory processing deficits observed in dementias with cholinergic disturbances.

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.

Scopolamine augments transient auditory 40-hz magnetic response in humans.

The influence of neocortical muscarinic transmission on auditory-evoked 40-Hz magnetic response was studied in 13 healthy subjects in a double-blind randomized cross-over design. Either a centrally (scopolamine hydrobromide, 0.3 mg, i.v.) or a peripherally (glycopyrrolate, 0.2 mg, i.v.) acting antagonist of muscarinic transmission was administered during two sessions of magnetoencephalographic recording of 40-Hz response elicited by monaural tones. Scopolamine significantly (P < 0.01) augmented the 40-Hz magnetic response over the hemispheres ipsi- and contralateral to the ear stimulated. This finding suggests muscarinic modulation of the auditory evoked transient 40-Hz response.