Predictors of falls in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy: a retrospective study.

INTRODUCTION: Recurrent falling is a major clinical milestone in Parkinsonian syndromes. It has a detrimental impact on quality of life, further prognosis, and life expectancy. AIM OF THE STUDY: To improve fall management and prevention, we aimed at identifying clinical parameters predicting fall frequency. To this end, we retrospectively analysed records of fall events of patients with Parkinson's disease (PD), or progressive supranuclear palsy (PSP), or multiple system atrophy (MSA), during their two-week inpatient stay at the Parkinson-Klinik Ortenau, Wolfach, Germany. This data served as an objective proxy for patients' fall frequency and allowed us to estimate the impact of several demographic and clinical variables on the occurrence of falling. MATERIAL AND METHODS: Of 2,111 patients admitted to our hospital, 1,810 presented with PD, 191 with PSP, and 110 with MSA. We employed a multiple (quasi-) poisson regression analysis to model the fall frequency as a function of various demographic variables (age at diagnosis, gender) and clinical variables (disease duration and sub-type, motor and cognitive impairment, autonomic dysfunction). RESULTS: Statistically significant predictors for falls in PD were cognitive impairment, motor impairment, and autonomic dysfunction. In PSP, significant predictors for falls were motor and autonomic dysfunction, while in MSA only disease duration predicted falls, but with only marginal statistical significance. CONCLUSIONS: Our results stress the importance of different factors in predicting falls in the different types of Parkinsonian syndrome. Preventive interventions should address these disease-specific targets for optimal success.

Time-course of decline in different cognitive domains in Parkinson's disease: a retrospective study.

Cognitive impairment and dementia are common non-motor symptoms in Parkinson's disease (PD). To elucidate the potentially typical progression of cognitive decline in PD and its variation, we retrospectively surveyed neuropsychological data obtained at the Parkinson-Klinik Ortenau, Germany in the years 1996-2015. Many of the patients in the surveyed period were repeatedly admitted to our clinic and we were thus able to compile neuropsychological re-test data for 252 patients obtained at varying time intervals. Neuropsychological testing was conducted with the NAI (Nürnberger Alters-Inventar). This battery provides sub-tests that examine cognitive processing speed, executive function, working memory, and verbal/visual memory functions. The re-test time span varied across patients from below 1 year up to about 12 years. Most patients were seen twice, but some patients were tested up to eight times. The steepest rates of cognitive decline were observed for the NAI sub-tests Trail-Making, Maze Test, and Stroop-Word Reading/Color Naming. Intermediate rates of decline were found for Digit Span, Word List-Immediate Recall, and Picture Test. Stroop Test-Interference, Word List-Delayed Recognition, and Figure Test exhibited the slowest decline rates. We did not observe a significant effect of age at diagnosis or gender on the rate of decline. In sum, this study retrospectively evaluated cognitive decline in a sample of patients with PD. Our data suggest a broad cognitive decline that particularly affects the cognitive capacities for processing speed, executive functions, and immediate memory functions.

Processing of self-initiated sound motion in the human brain.

Interacting with objects in our environment usually leads to audible noise. Brain responses to such self-initiated sounds have been shown to be attenuated, in particular the so-called N1 component measured with electroencephalography (EEG). This attenuation has been proposed to be the effect of an internal forward model that allows for cancellation of the sensory consequences of a motor command. In the current study we asked whether the attenuation due to self-initiation of a sound also affects a later event-related potential - the so-called motion-onset response - that arises in response to moving sounds. To this end, volunteers were instructed to move their index fingers either left or rightward which resulted in virtual movement of a sound either to the left or to the right. In Experiment 1, sound motion was induced with in-ear head-phones by shifting interaural time and intensity differences and thus shifting the intracranial sound image. We compared the motion-onset responses under two conditions: a) congruent, and b) incongruent. In the congruent condition, the sound image moved in the direction of the finger movement, while in the incongruent condition sound motion was in the opposite direction of the finger movement. Clear motion-onset responses with a negative cN1 component peaking at about 160 ms and a positive cP2 component peaking at about 230 ms after motion-onset were obtained for both the congruent and incongruent conditions. However, the motion-onset responses did not significantly differ between congruent and incongruent conditions in amplitude or latency. In Experiment 2, in which sounds were presented with loudspeakers, we observed attenuation for self-induced versus externally triggered sound motion-onset, but again, there was no difference between congruent and incongruent conditions. In sum, these two experiments suggest that the motion-onset response measured by EEG can be attenuated for self-generated sounds. However, our result did not indicate that this attenuation depended on congruency of action and sound motion direction.

Dose per muscle in cervical dystonia: pooled data from seven movement disorder centres.

AIM OF STUDY: Botulinum neurotoxin type A (BoNT/A) injections are the established treatment in cervical dystonia (CD). But clinical practice regarding the choice of muscles into which injections are made varies between centres. Until now, there have been no dose-per-muscle recommendations based on 'searching the dose' clinical trial data. CLINICAL RATIONALE FOR STUDY: We therefore examined the dosages under real world conditions at seven international movement disorders centres, using an identical clinical approach. RESULTS: We examined 305 patients with CD (55.6 ± 13.2 years, 204 female). The most commonly injected muscles were the splenius capitis (84.9%), sternocleidomastoid (80.3%), trapezius (59.7%), levator scapulae (49.8%), semispinalis capitis (39%), and obliquus capitis inferior (36.7%). The mean total dose per treatment session with aboBoNT/A was 652.5 (SD = 285.5), with onaBoNT/A it was 159.5 (SD = 62.4), and with incoBoNT/A it was 173.4 (SD = 99.2) units. The doses injected into each muscle in the ona- or incoBoNT/A groups were between 19.7 and 48.2 units, with the highest dose for the splenius capitis with 49.2 ± 26.0 units. The doses in the aboBoNT/A group were between 69.6 and 146.4 units, and the highest dose being injected into the splenius capitis (139.6 ± 80.7 units). CONCLUSIONS AND CLINICAL IMPLICATIONS: In clinical trials the doses per muscle are based on an arbitrary decision. In our study, the doses were lower than in other studies, which may be due to the number of muscles per session, the use of ultrasound guidance (and therefore more precise injections), as well as the use of the Col-Cap concept. Our results exemplify everyday practice, and may help as the basis for recommendations and further investigations.

Frequency of different subtypes of cervical dystonia: a prospective multicenter study according to Col-Cap concept.

Patients with cervical dystonia (CD) may present with head and/or neck movements in the coronal, sagittal or transverse plane. According to the Col-Cap concept, CD postures are classified in torti-, latero-, ante- and retrocollis/caput patterns. The frequency of these different subtypes has to be evaluated. Between January and June 2019, we examined 306 patients (55.5 ± 13.1 years, 67% female) with CD according to the Col-Cap concept. They were all treated with botulinum toxin. This prospective study took place in seven different movement disorder centers. The most common primary form was torticaput (49%), the second most common was laterocaput (16.7%). All other subtypes were less than 10% of the study population. Pure forms were observed in 16.3% of patients only. Torticaput was combined in 46% with laterocaput, and in 20.7% with retrocaput. Laterocaput was combined mainly with torticaput (45.1%), laterocollis (33.2%) or retrocaput (23.5%). Shift forms were found in 14.7%, but diagnosed only in 3.9%. On average, the patients had 2.51 (± SD 1.09) subtypes each. Tremor was observed in 55.6%. The mean number of injected muscles was 4.4 (SD 1.6). The most often injected muscles were splenius capitis (83%), sternocleidomatoideus (79.1%), and upper trapezius (58.5%). This is the first multicenter study to examine the frequency of different subtypes of CD according to the Col-Cap concept. The caput subforms are more common than the cervical types, with torticaput as the most common one. Shift forms were diagnosed less often than described. Pure forms are very rare, combinations of 2-6 subtypes are common (83.7%). Sternocleidomatoideus, splenius capitis and trapezius muscles were still injected most often, but the muscles rarely injected in the past such as levator scapulae (48.7%), obliquus capitis inferior (35.3%) and longissimus (16.7%) were considered quite often. Since optimal therapy results depend on the injection of the right muscles, the correct classification should optimize the treatment outcome.

Front-Presented Looming Sound Selectively Alters the Perceived Size of a Visual Looming Object.

In spite of accumulating evidence for the spatial rule governing cross-modal interaction according to the spatial consistency of stimuli, it is still unclear whether 3D spatial consistency (i.e., front/rear of the body) of stimuli also regulates audiovisual interaction. We investigated how sounds with increasing/decreasing intensity (looming/receding sound) presented from the front and rear space of the body impact the size perception of a dynamic visual object. Participants performed a size-matching task (Experiments 1 and 2) and a size adjustment task (Experiment 3) of visual stimuli with increasing/decreasing diameter, while being exposed to a front- or rear-presented sound with increasing/decreasing intensity. Throughout these experiments, we demonstrated that only the front-presented looming sound caused overestimation of the spatially consistent looming visual stimulus in size, but not of the spatially inconsistent and the receding visual stimulus. The receding sound had no significant effect on vision. Our results revealed that looming sound alters dynamic visual size perception depending on the consistency in the approaching quality and the front-rear spatial location of audiovisual stimuli, suggesting that the human brain differently processes audiovisual inputs based on their 3D spatial consistency. This selective interaction between looming signals should contribute to faster detection of approaching threats. Our findings extend the spatial rule governing audiovisual interaction into 3D space.

The effect of illusionary perception on mismatch negativity (MMN): An electroencephalography study.

Mismatch negativity (MMN) is a unique brain response elicited by any discernible change of features in a tone sequence. Although the occurrence of MMN is dependent upon the difference of a stimulus parameter, such as frequency or intensity, recent studies have suggested that MMN occurs as a result of a comparison between an internal representation created by perception and an incoming tone. The present study aimed to investigate MMN occurs based upon the physical properties of stimuli or as a result of the perception of the scale illusion. A scale illusion occurs during presentation of ascending and descending musical scales between C4 and C5. The tones of these scales are presented to the right and left ear alternately using a dichotic listening paradigm. Although the ascending/descending sequences are alternated between ears after each tone, we perceive the illusion of progressively ascending/descending tones as being separated by ear. The experiment was designed as an oddball task using the illusionary sequence and three different types of tone sequences as control conditions. Brain response to these sequences and infrequently presented deviants was measured using electroencephalography (EEG). All of the control sequences showed MMN in response to the deviant. However, the illusionary sequence did not result in a significant MMN. These results suggest that in the case of scale illusion, the occurrence of MMN is based upon the representation of tones created by perception, but not upon the physical properties of a tone sequence.

Trading of dynamic interaural time and level difference cues and its effect on the auditory motion-onset response measured with electroencephalography.

Interaural time (ITD) and level differences (ILD) constitute the two main cues for sound localization in the horizontal plane. Despite extensive research in animal models and humans, the mechanism of how these two cues are integrated into a unified percept is still far from clear. In this study, our aim was to test with human electroencephalography (EEG) whether integration of dynamic ITD and ILD cues is reflected in the so-called motion-onset response (MOR), an evoked potential elicited by moving sound sources. To this end, ITD and ILD trajectories were determined individually by cue trading psychophysics. We then measured EEG while subjects were presented with either static click-trains or click-trains that contained a dynamic portion at the end. The dynamic part was created by combining ITD with ILD either congruently to elicit the percept of a right/leftward moving sound, or incongruently to elicit the percept of a static sound. In two experiments that differed in the method to derive individual dynamic cue trading stimuli, we observed an MOR with at least a change-N1 (cN1) component for both the congruent and incongruent conditions at about 160-190 ms after motion-onset. A significant change-P2 (cP2) component for both the congruent and incongruent ITD/ILD combination was found only in the second experiment peaking at about 250 ms after motion onset. In sum, this study shows that a sound which - by a combination of counter-balanced ITD and ILD cues - induces a static percept can still elicit a motion-onset response, indicative of independent ITD and ILD processing at the level of the MOR - a component that has been proposed to be, at least partly, generated in non-primary auditory cortex.

Auditory Mismatch Negativity in Response to Changes of Counter-Balanced Interaural Time and Level Differences.

Interaural time differences (ITD) and interaural level differences (ILD) both signal horizontal sound source location. To achieve a unified percept of our acoustic environment, these two cues require integration. In the present study, we tested this integration of ITD and ILD with electroencephalography (EEG) by measuring the mismatch negativity (MMN). The MMN can arise in response to spatial changes and is at least partly generated in auditory cortex. In our study, we aimed at testing for an MMN in response to stimuli with counter-balanced ITD/ILD cues. To this end, we employed a roving oddball paradigm with alternating sound sequences in two types of blocks: (a) lateralized stimuli with congruently combined ITD/ILD cues and (b) midline stimuli created by counter-balanced, incongruently combined ITD/ILD cues. We observed a significant MMN peaking at about 112-128 ms after change onset for the congruent ITD/ILD cues, for both lower (0.5 kHz) and higher carrier frequency (4 kHz). More importantly, we also observed significant MMN peaking at about 129 ms for incongruently combined ITD/ILD cues, but this effect was only detectable in the lower frequency range (0.5 kHz). There were no significant differences of the MMN responses for the two types of cue combinations (congruent/incongruent). These results suggest that-at least in the lower frequency ranges (0.5 kHz)-ITD and ILD are processed independently at the level of the MMN in auditory cortex.

Neural correlates of perceptual grouping effects in the processing of sound omission by musicians and nonmusicians.

Perceptual grouping is the process of organizing sounds into perceptually meaningful elements. Psychological studies have found that tones presented as a regular frequency or temporal pattern are grouped according to gestalt principles, such as similarity, proximity, and good continuity. Predictive coding theory suggests that this process helps create an internal model for the prediction of sounds in a tone sequence and that an omission-related brain response reflects the violation of this prediction. However, it remains unclear which brain areas are related to this process, especially in paying attention to the stimuli. To clarify this uncertainty, the present study investigated the neural correlates of perceptual grouping effects. Using magnetoencephalography (MEG), we recorded the evoked response fields (ERFs) of amateur musicians and nonmusicians to sound omissions in tone sequences with a regular or random pattern of three different frequencies during an omission detection task. Omissions in the regular sequences were detected faster and evoked greater activity in the left Heschl's gyrus (HG), right postcentral gyrus, and bilateral superior temporal gyrus (STG) than did omissions in the irregular sequences. Additionally, an interaction between musical experience and regularity was found in the left HG/STG. Tone-evoked responses did not show this difference, indicating that the expertise effect did not reflect the superior tone processing acquired by amateur musicians due to musical training. These results suggest that perceptual grouping based on repetition of a pattern of frequencies affects the processing of omissions in tone sequences and induces more activation of the bilateral auditory cortex by violating internal models. The interaction in the left HG/STG may suggest different styles of processing for musicians and nonmusicians, although this difference was not reflected at the behavioral level.

Categorical speech perception during active discrimination of consonants and vowels.

Categorical perception of phonemes describes the phenomenon that, when phonemes are classified they are often perceived to fall into distinct categories even though physically they follow a continuum along a feature dimension. While consonants such as plosives have been proposed to be perceived categorically, the representation of vowels has been described to be more continuous. We aimed at testing this difference in representation at a behavioral and neurophysiological level using human magnetoencephalography (MEG). To this end, we designed stimuli based on natural speech by morphing along a phonological continuum entailing changes of the voiced stop-consonant or the steady-state vowel of a consonant-vowel (CV) syllable. Then, while recording MEG, we presented participants with consecutive pairs of either same or different CV syllables. The differences were such that either both CV syllables were from within the same category or belonged to different categories. During the MEG experiment, the participants actively discriminated the stimulus pairs. Behaviorally, we found that discrimination was easier for the between-compared to the within-category contrast for both consonants and vowels. However, this categorical effect was significantly stronger for the consonants compared to vowels, in line with a more continuous representation of vowels. At the neural level, we observed significant repetition suppression of MEG evoked fields, i.e. lower amplitudes for physically same compared to different stimulus pairs, at around 430 to 500ms after the onset of the second stimulus. Source reconstruction revealed generating sources of this repetition suppression effect within left superior temporal sulcus and gyrus, posterior to Heschl׳s gyrus. A region-of-interest analysis within this region showed a clear categorical effect for consonants, but not for vowels, providing further evidence for the important role of left superior temporal areas in categorical representation during active phoneme discrimination.

Independent or integrated processing of interaural time and level differences in human auditory cortex?

Sound localization in the horizontal plane is mainly determined by interaural time differences (ITD) and interaural level differences (ILD). Both cues result in an estimate of sound source location and in many real-life situations these two cues are roughly congruent. When stimulating listeners with headphones it is possible to counterbalance the two cues, so called ITD/ILD trading. This phenomenon speaks for integrated ITD/ILD processing at the behavioral level. However, it is unclear at what stages of the auditory processing stream ITD and ILD cues are integrated to provide a unified percept of sound lateralization. Therefore, we set out to test with human electroencephalography for integrated versus independent ITD/ILD processing at the level of preattentive cortical processing by measuring the mismatch negativity (MMN) to changes in sound lateralization. We presented a series of diotic standards (perceived at a midline position) that were interrupted by deviants that entailed either a change in a) ITD only, b) ILD only, c) congruent ITD and ILD, or d) counterbalanced ITD/ILD (ITD/ILD trading). The sound stimuli were either i) pure tones with a frequency of 500 Hz, or ii) amplitude modulated tones with a carrier frequency of 4000 Hz and a modulation frequency of 125 Hz. We observed significant MMN for the ITD/ILD traded deviants in case of the 500 Hz pure tones, and for the 4000 Hz amplitude-modulated tone. This speaks for independent processing of ITD and ILD at the level of the MMN within auditory cortex. However, the combined ITD/ILD cues elicited smaller MMN than the sum of the MMN induced in response to ITD and ILD cues presented in isolation for 500 Hz, but not 4000 Hz, suggesting independent processing for the higher frequency only. Thus, the two markers for independent processing - additivity and cue-conflict - resulted in contradicting conclusions with a dissociation between the lower (500 Hz) and higher frequency (4000 Hz) bands.

Representation of frequency-modulated sounds in the human brain.

Frequency-modulation is a ubiquitous sound feature present in communicative sounds of various animal species and humans. Functional imaging of the human auditory system has seen remarkable advances in the last two decades and studies pertaining to frequency-modulation have centered around two major questions: a) are there dedicated feature-detectors encoding frequency-modulation in the brain and b) is there concurrent representation with amplitude-modulation, another temporal sound feature? In this review, we first describe how these two questions are motivated by psychophysical studies and neurophysiology in animal models. We then review how human non-invasive neuroimaging studies have furthered our understanding of the representation of frequency-modulated sounds in the brain. Finally, we conclude with some suggestions on how human neuroimaging could be used in future studies to address currently still open questions on this fundamental sound feature. This article is part of a Special Issue entitled Human Auditory Neuroimaging.

Preattentive processing of horizontal motion, radial motion, and intensity changes of sounds.

Localization of sound sources is critical for an appropriate behavioral response. This is not only true for localization in the horizontal plane but also for localization in depth. Depth ranging of sound sources implicates various distance cues, among others sound intensity. In this study, we measured human electroencephalography and compared mismatch negativity (MMN) amplitudes and latencies for horizontal motion, radial motion, and pure intensity changes in the free field. We observed similar MMN latencies for horizontal and radial motion, whereas MMN responses to pure intensity changes were comparably delayed. MMN amplitudes and latencies were not different for approaching and receding sounds. Our data suggest similar fast processing for horizontal and radial motion, whereas pure intensity changes are possibly processed with less priority.

Environmental reverberation affects processing of sound intensity in right temporal cortex.

Although sound reverberation is considered a nuisance variable in most studies investigating auditory processing, it can serve as a cue for loudness constancy, a phenomenon describing constant loudness perception in spite of changing sound source distance. In this study, we manipulated room reverberation characteristics to test their effect on psychophysical loudness constancy and we tested with magnetoencephalography on human subjects for neural responses reflecting loudness constancy. Psychophysically, we found that loudness constancy was present in strong, but not weak, reverberation conditions. In contrast, the dependence of sound distance judgment on actual distance was similar across conditions. We observed brain activity reflecting behavioral loudness constancy, i.e. inverse scaling of the evoked magnetic fields with distance for weak reverberation but constant responses across distance for strong reverberation from ~210 to 270 ms after stimulus onset. Distributed magnetoencephalography source reconstruction revealed underlying neural generators within the right middle temporal and right inferior anterior temporal lobe. Our data suggest a dissociation of loudness constancy and distance perception, implying a direct usage of reverberation cues for constructing constant loudness across distance. Furthermore, our magnetoencephalography data suggest involvement of auditory association areas in the right middle and right inferior anterior temporal cortex in this process.

Effects of regularity on the processing of sound omission in a tone sequence in musicians and non-musicians.

Numerous studies have reported that perceptual grouping affects the pre-attentive processing of sound omission in a sequence of tones. However, it remains unclear whether or not the perceptual grouping and musical experience affect the attentive processing of sound omission. To this end, we created a sequence of loud (L) and soft (S) tones grouped as 'LLSLLS…' and a random sequence of the L and S tones. The omission of the L tones was inserted pseudo-randomly in the random sequence, and there were two positions at which it was inserted. For within-group omission, the omission was after the first L tone within the 'LLS' pattern. For between-group omission, the omission was inserted between the patterns. The brain response to the omission in musicians and non-musicians was measured using magnetoencephalography. During the magnetoencephalography measurement, the subjects' performance in a task to detect the omission was faster in the random sequence than in the group sequence. Source analysis showed that the omission in the random sequence caused greater activity than that in the group sequence. The increase was found in the right inferior parietal lobe in musicians, whereas it was found in the left superior temporal gyrus in non-musicians. These results suggest that the attentive processing of perceptual grouping might implicate the left superior temporal gyrus or right inferior parietal lobe, depending on musical experience.

Allocentric or craniocentric representation of acoustic space: an electrotomography study using mismatch negativity.

The world around us appears stable in spite of our constantly moving head, eyes, and body. How this is achieved by our brain is hardly understood and even less so in the auditory domain. Using electroencephalography and the so-called mismatch negativity, we investigated whether auditory space is encoded in an allocentric (referenced to the environment) or craniocentric representation (referenced to the head). Fourteen subjects were presented with noise bursts from loudspeakers in an anechoic environment. Occasionally, subjects were cued to rotate their heads and a deviant sound burst occurred, that deviated from the preceding standard stimulus either in terms of an allocentric or craniocentric frame of reference. We observed a significant mismatch negativity, i.e., a more negative response to deviants with reference to standard stimuli from about 136 to 188 ms after stimulus onset in the craniocentric deviant condition only. Distributed source modeling with sLORETA revealed an involvement of lateral superior temporal gyrus and inferior parietal lobule in the underlying neural processes. These findings suggested a craniocentric, rather than allocentric, representation of auditory space at the level of the mismatch negativity.

Visual distance cues modulate neuromagnetic auditory N1m responses.

OBJECTIVE: Auditory distance judgment relies on several acoustic cues and can be modulated by visual information. Sound intensity serves as one such cue as it decreases with increasing distance. In this magnetoencephalography (MEG) experiment, we tested whether N1m MEG responses, previously described to scale with sound intensity, are modulated by visual distance cues. METHODS: We recorded behavioral and MEG data from 15 healthy normal hearing participants. Noise bursts at different sound pressure levels were paired with synchronous visual cues at different distances. We hypothesized that noise paired with far visual cues will be represented louder and result in increased N1m amplitudes compared to a pairing with close visual cues. This might be based on a compensation of visually induced distance when processing loudness. RESULTS: Psychophysically, we observed no significant modulation of loudness judgments by visual cues. However, N1m MEG responses at about 100ms after stimulus onset were significantly stronger with distal compared to proximal visual cues in the left auditory cortex. CONCLUSIONS: Our results suggest an audio-visual interaction at an early stage in the left auditory cortex, possibly related to cue integration for auditory distance processing. SIGNIFICANCE: Sound distance processing could prove itself as a promising model system for the investigation of intra-modal and cross-modal integration principles.