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.

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.

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.

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.

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.

Audiovisual functional magnetic resonance imaging adaptation reveals multisensory integration effects in object-related sensory cortices.

Information integration across different sensory modalities contributes to object recognition, the generation of associations and long-term memory representations. Here, we used functional magnetic resonance imaging adaptation to investigate the presence of sensory integrative effects at cortical levels as early as nonprimary auditory and extrastriate visual cortices, which are implicated in intermediate stages of object processing. Stimulation consisted of an adapting audiovisual stimulus S(1) and a subsequent stimulus S(2) from the same basic-level category (e.g., cat). The stimuli were carefully balanced with respect to stimulus complexity and semantic congruency and presented in four experimental conditions: (1) the same image and vocalization for S(1) and S(2), (2) the same image and a different vocalization, (3) different images and the same vocalization, or (4) different images and vocalizations. This two-by-two factorial design allowed us to assess the contributions of auditory and visual stimulus repetitions and changes in a statistically orthogonal manner. Responses in visual regions of right fusiform gyrus and right lateral occipital cortex were reduced for repeated visual stimuli (repetition suppression). Surprisingly, left lateral occipital cortex showed stronger responses to repeated auditory stimuli (repetition enhancement). Similarly, auditory regions of interest of the right middle superior temporal gyrus and sulcus exhibited repetition suppression to auditory repetitions and repetition enhancement to visual repetitions. Our findings of crossmodal repetition-related effects in cortices of the respective other sensory modality add to the emerging view that in human subjects sensory integrative mechanisms operate on earlier cortical processing levels than previously assumed.

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.

Processing of auditory location changes after horizontal head rotation.

Under natural conditions, our sound localization capabilities enable us to move constantly while keeping a stable representation of our auditory environment. However, since most auditory studies focus on head-restrained conditions, it is still unclear whether neurophysiological markers of auditory spatial processing reflect representation in a head-centered or an allocentric coordinate system. Therefore, we used human electroencephalography to test whether the spatial mismatch negativity (MMN) as a marker of spatial change processing is elicited by changes of sound source position in terms of a head-related or an allocentric coordinate system. Subjects listened to a series of virtually localized band-passed noise tones and were occasionally cued visually to conduct horizontal head movements. After these head movements, we presented deviants either in terms of a head-centered or an allocentric coordinate system. We observed significant MMN responses to the head-related deviants only but a change-related novelty P3-like component for both head-related and allocentric deviants. These results thus suggest that the spatial MMN is associated with a representation of auditory space in a head-related coordinate system and that the integration of motor output and auditory input possibly occurs at later stages of the auditory "where" processing stream.

Distinct gamma-band components reflect the short-term memory maintenance of different sound lateralization angles.

Oscillatory activity in human electro- or magnetoencephalogram has been related to cortical stimulus representations and their modulation by cognitive processes. Whereas previous work has focused on gamma-band activity (GBA) during attention or maintenance of representations, there is little evidence for GBA reflecting individual stimulus representations. The present study aimed at identifying stimulus-specific GBA components during auditory spatial short-term memory. A total of 28 adults were assigned to 1 of 2 groups who were presented with only right- or left-lateralized sounds, respectively. In each group, 2 sample stimuli were used which differed in their lateralization angles (15 degrees or 45 degrees) with respect to the midsagittal plane. Statistical probability mapping served to identify spectral amplitude differences between 15 degrees versus 45 degrees stimuli. Distinct GBA components were found for each sample stimulus in different sensors over parieto-occipital cortex contralateral to the side of stimulation peaking during the middle 200-300 ms of the delay phase. The differentiation between "preferred" and "nonpreferred" stimuli during the final 100 ms of the delay phase correlated with task performance. These findings suggest that the observed GBA components reflect the activity of distinct networks tuned to spatial sound features which contribute to the maintenance of task-relevant information in short-term memory.

Temporal dynamics of adaptation to natural sounds in the human auditory cortex.

We aimed at testing the cortical representation of complex natural sounds within auditory cortex by conducting 2 human magnetoencephalography experiments. To this end, we employed an adaptation paradigm and presented subjects with pairs of complex stimuli, namely, animal vocalizations and spectrally matched noise. In Experiment 1, we presented stimulus pairs of same or different animal vocalizations and same or different noise. Our results suggest a 2-step process of adaptation effects: first, we observed a general item-unspecific reduction of the N1m peak amplitude at 100 ms, followed by an item-specific amplitude reduction of the P2m component at 200 ms after stimulus onset for both animal vocalizations and noise. Multiple dipole source modeling revealed the right lateral Heschl's gyrus and the bilateral superior temporal gyrus as sites of adaptation. In Experiment 2, we tested for cross-adaptation between animal vocalizations and spectrally matched noise sounds, by presenting pairs of an animal vocalization and its corresponding or a different noise sound. We observed cross-adaptation effects for the P2m component within bilateral superior temporal gyrus. Thus, our results suggest selectivity of the evoked magnetic field at 200 ms after stimulus onset in nonprimary auditory cortex for the spectral fine structure of complex sounds rather than their temporal dynamics.

Integration of local features into global shapes: monkey and human FMRI studies.

The integration of local image features into global shapes was investigated in monkeys and humans using fMRI. An adaptation paradigm was used, in which stimulus selectivity was deduced by changes in the course of adaptation of a pattern of randomly oriented elements. Accordingly, we observed stronger activity when orientation changes in the adapting stimulus resulted in a collinear contour than a different random pattern. This selectivity to collinear contours was observed not only in higher visual areas that are implicated in shape processing, but also in early visual areas where selectivity depended on the receptive field size. These findings suggest that unified shape perception in both monkeys and humans involves multiple visual areas that may integrate local elements to global shapes at different spatial scales.

Probing category selectivity for environmental sounds in the human auditory brain.

Earlier studies reported evidence suggesting distinct category-related auditory representations for environmental sounds such as animal vocalizations and tool sounds in superior and middle temporal regions of the temporal lobe. However, the degree of selectivity of these representations remains to be determined. The present study combined functional magnetic resonance imaging (fMRI) adaptation with a silent acquisition protocol to further investigate category-related auditory processing of environmental sounds. To this end, we consecutively presented pairs of sounds taken from the categories 'tool sounds' or 'animal vocalizations' with either the same or different identity/category. We examined the degree of selectivity as evidenced by adaptation effects to both or only one sound category in the course of whole-brain as well as functionally and anatomically constrained region of interest analyses. While most regions predominately in the temporal cortex showed an adaptation to both sound categories, particularly the left superior temporal gyrus (STG) and the left posterior middle temporal gyrus (pMTG) selectively adapted to animal vocalizations and tool sounds, respectively. However, the activation profiles of these regions differed with respect to the general responsiveness to sounds. While tool sounds still produced fMRI signals significantly different from fixation baseline in the STG, this was not the case for animal vocalizations in pMTG. Consistent with the interpretation of STG as an intermediate auditory processing stage, this region might differentiate auditory stimuli into categories based on variations of physical stimulus properties. However, processing in left pMTG seems to be even more restricted to action-related sounds of man-made objects.

Perceptual organization of local elements into global shapes in the human visual cortex.

The question of how local image features on the retina are integrated into perceived global shapes is central to our understanding of human visual perception. Psychophysical investigations have suggested that the emergence of a coherent visual percept, or a "good-Gestalt", is mediated by the perceptual organization of local features based on their similarity. However, the neural mechanisms that mediate unified shape perception in the human brain remain largely unknown. Using human fMRI, we demonstrate that not only higher occipitotemporal but also early retinotopic areas are involved in the perceptual organization and detection of global shapes. Specifically, these areas showed stronger fMRI responses to global contours consisting of collinear elements than to patterns of randomly oriented local elements. More importantly, decreased detection performance and fMRI activations were observed when misalignment of the contour elements disturbed the perceptual coherence of the contours. However, grouping of the misaligned contour elements by disparity resulted in increased performance and fMRI activations, suggesting that similar neural mechanisms may underlie grouping of local elements to global shapes by different visual features (orientation or disparity). Thus, these findings provide novel evidence for the role of both early feature integration processes and higher stages of visual analysis in coherent visual perception.

Alpha synchronization during auditory spatial short-term memory.

Recent studies have suggested an active role of cortical alpha oscillations for cognitive functions including short-term memory. We used magnetoencephalography to assess alpha activity during an auditory spatial delayed matching-to-sample task compared with a nonmemory control condition. In the memory task, participants had to memorize the lateralization angle of a noise stimulus S1 and compare it with another lateralized sound S2 presented after an 800-ms delay phase. Whereas alpha desynchronization following S1 was observed over superior temporal areas under both conditions, only the memory task was accompanied by posterior parietal alpha synchronization during the subsequent delay period. The findings are consistent with the notion of alpha activity reflecting active inhibition of interfering processes during memory maintenance of spatial sounds.

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.