Discrete Relationships between Spatiotemporal Gait Characteristics and Domain-Specific Neuropsychological Performance in Midlife.

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline-with the aim of identifying individuals who may benefit from potential preventative interventions.

Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease.

Non-invasive sensory stimulation in the range of the brain's gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.

Brain-Computer Interfaces for Treatment of Focal Dystonia.

Task-specificity in isolated focal dystonias is a powerful feature that may successfully be targeted with therapeutic brain-computer interfaces. While performing a symptomatic task, the patient actively modulates momentary brain activity (disorder signature) to match activity during an asymptomatic task (target signature), which is expected to translate into symptom reduction.

Envelope reconstruction of speech and music highlights stronger tracking of speech at low frequencies.

The human brain tracks amplitude fluctuations of both speech and music, which reflects acoustic processing in addition to the encoding of higher-order features and one's cognitive state. Comparing neural tracking of speech and music envelopes can elucidate stimulus-general mechanisms, but direct comparisons are confounded by differences in their envelope spectra. Here, we use a novel method of frequency-constrained reconstruction of stimulus envelopes using EEG recorded during passive listening. We expected to see music reconstruction match speech in a narrow range of frequencies, but instead we found that speech was reconstructed better than music for all frequencies we examined. Additionally, models trained on all stimulus types performed as well or better than the stimulus-specific models at higher modulation frequencies, suggesting a common neural mechanism for tracking speech and music. However, speech envelope tracking at low frequencies, below 1 Hz, was associated with increased weighting over parietal channels, which was not present for the other stimuli. Our results highlight the importance of low-frequency speech tracking and suggest an origin from speech-specific processing in the brain.

Gait Characteristics and Cognitive Function in Middle-Aged Adults with and without Type 2 Diabetes Mellitus: Data from ENBIND.

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life. Both gait speed and spatiotemporal gait characteristics have been associated with later cognitive decline in community-dwelling older adults. Thus, the assessment of gait characteristics in uncomplicated midlife T2DM may be important in selecting-out those with T2DM at greatest risk of later cognitive decline. We assessed the relationship between Inertial Motion Unit (IMUs)-derived gait characteristics and cognitive function assessed via Montreal Cognitive Assessment (MoCA)/detailed neuropsychological assessment battery (CANTAB) in middle-aged adults with and without uncomplicated T2DM using both multivariate linear regression and a neural network approach. Gait was assessed under (i) normal walking, (ii) fast (maximal) walking and (iii) cognitive dual-task walking (reciting alternate letters of the alphabet) conditions. Overall, 138 individuals were recruited (n = 94 with T2DM; 53% female, 52.8 ± 8.3 years; n = 44 healthy controls, 43% female, 51.9 ± 8.1 years). Midlife T2DM was associated with significantly slower gait velocity on both slow and fast walks (both p < 0.01) in addition to a longer stride time and greater gait complexity during normal walk (both p < 0.05). Findings persisted following covariate adjustment. In analyzing cognitive performance, the strongest association was observed between gait velocity and global cognitive function (MoCA). Significant associations were also observed between immediate/delayed memory performance and gait velocity. Analysis using a neural network approach did not outperform multivariate linear regression in predicting cognitive function (MoCA) from gait velocity. Our study demonstrates the impact of uncomplicated T2DM on gait speed and gait characteristics in midlife, in addition to the striking relationship between gait characteristics and global cognitive function/memory performance in midlife. Further studies are needed to evaluate the longitudinal relationship between midlife gait characteristics and later cognitive decline, which may aid in selecting-out those with T2DM at greatest-risk for preventative interventions.

Neurophysiological correlates of dual tasking in people with Parkinson's disease and freezing of gait.

Freezing of gait in people with Parkinson's disease (PwP) is associated with executive dysfunction and motor preparation deficits. We have recently shown that electrophysiological markers of motor preparation, rather than decision-making, differentiate PwP with freezing of gait (FOG +) and without (FOG -) while sitting. To examine the effect of locomotion on these results, we measured behavioural and electrophysiological responses in PwP with and without FOG during a target response time task while sitting (single-task) and stepping-in-place (dual-task). Behavioural and electroencephalographic data were acquired from 18 PwP (eight FOG +) and seven young controls performing the task while sitting and stepping-in-place. FOG + had slower response times while stepping compared with sitting. However, response times were significantly faster while stepping compared with sitting for controls. Electrophysiological responses showed no difference in decision-making potentials (centroparietal positivity) between groups or conditions but there were differences in neurophysiological markers of response inhibition (N2) and motor preparation (lateralized readiness potential, LRP) in FOG + while performing a dual-task. This suggests that the addition of a second complex motor task (stepping-in-place) impacts automatic allocation of resources in FOG +, resulting in delayed response times. The impact of locomotion on the generation of the N2 and LRP potentials, particularly in freezers, indirectly implies that these functions compete with locomotion for resources. In the setting of multiple complex tasks or cognitive impairment, severe motor dysfunction may result, leading to freezing of gait.

The development of visuotactile congruency effects for sequences of events.

Sensitivity to the temporal coherence of visual and tactile signals increases perceptual reliability and is evident during infancy. However, it is not clear how, or whether, bidirectional visuotactile interactions change across childhood. Furthermore, no study has explored whether viewing a body modulates how children perceive visuotactile sequences of events. Here, children aged 5-7 years (n = 19), 8 and 9 years (n = 21), and 10-12 years (n = 24) and adults (n = 20) discriminated the number of target events (one or two) in a task-relevant modality (touch or vision) and ignored distractors (one or two) in the opposing modality. While participants performed the task, an image of either a hand or an object was presented. Children aged 5-7 years and 8 and 9 years showed larger crossmodal interference from visual distractors when discriminating tactile targets than the converse. Across age groups, this was strongest when two visual distractors were presented with one tactile target, implying a "fission-like" crossmodal effect (perceiving one event as two events). There was no influence of visual context (viewing a hand or non-hand image) on visuotactile interactions for any age group. Our results suggest robust interference from discontinuous visual information on tactile discrimination of sequences of events during early and middle childhood. These findings are discussed with respect to age-related changes in sensory dominance, selective attention, and multisensory processing.

Normal Temporal Discrimination in Musician's Dystonia Is Linked to Aberrant Sensorimotor Processing.

OBJECTIVES: Alterations in sensory discrimination are a prominent nonmotor feature of dystonia. Abnormal temporal discrimination in focal dystonia is considered to represent its mediational endophenotype, albeit unclear pathophysiological correlates. We examined the associations between the visual temporal discrimination threshold (TDT) and brain activity in patients with musician's dystonia, nonmusician's dystonia, and healthy controls. METHODS: A total of 42 patients and 41 healthy controls participated in the study. Between-group differences in TDT z scores were computed using inferential statistics. Statistical associations of TDT z scores with clinical characteristics of dystonia and resting-state functional brain activity were examined using nonparametric rank correlations. RESULTS: The TDT z scores of healthy controls were significantly different from those of patients with nonmusician's dystonia, but not of patients with musician's dystonia. Healthy controls showed a significant relationship between normal TDT levels and activity in the inferior parietal cortex. This relationship was lost in all patients. Instead, TDT z scores in musician's dystonia established additional correlations with activity in premotor, primary somatosensory, ventral extrastriate cortices, inferior occipital gyrus, precuneus, and cerebellum, whereas nonmusician's dystonia showed a trending correlation in the lingual gyrus extending to the cerebellar vermis. There were no significant relationships between TDT z scores and dystonia onset, duration, or severity. CONCLUSIONS: TDT assessment as an endophenotypic marker may only be relevant to nonmusician forms of dystonia because of the lack of apparent alterations in musician's dystonia. Compensatory adaptation of neural circuitry responsible for TDT processing likely adjusted the TDT performance to the behaviorally normal levels in patients with musician's dystonia, but not nonmusician's dystonia. © 2020 International Parkinson and Movement Disorder Society.

Place field assembly distribution encodes preferred locations.

The hippocampus is the main locus of episodic memory formation and the neurons there encode the spatial map of the environment. Hippocampal place cells represent location, but their role in the learning of preferential location remains unclear. The hippocampus may encode locations independently from the stimuli and events that are associated with these locations. We have discovered a unique population code for the experience-dependent value of the context. The degree of reward-driven navigation preference highly correlates with the spatial distribution of the place fields recorded in the CA1 region of the hippocampus. We show place field clustering towards rewarded locations. Optogenetic manipulation of the ventral tegmental area demonstrates that the experience-dependent place field assembly distribution is directed by tegmental dopaminergic activity. The ability of the place cells to remap parallels the acquisition of reward context. Our findings present key evidence that the hippocampal neurons are not merely mapping the static environment but also store the concurrent context reward value, enabling episodic memory for past experience to support future adaptive behavior.

Sequential bilateral implantation in older children: Inter-implant map differences and their effects on functional outcomes.

OBJECTIVES: It is well established that sequential bilateral implantation offers functional benefits in speech in noise and sound localisation, although it can be challenging to get long-term unilateral users to adapt to the second implant. The aim of this study was to investigate programming differences between the two cochlear implants that can impact on performance outcomes. DESIGN: Cohort Study. PARTICIPANTS: Sixteen older children who received sequential implants in Ireland and with at least one-year experience with their sequential implant were included in this study. Children were categorised into two groups according to the time interval between the two implants: short if the time between the two implants was less than eight years and long if more than eight years. MAIN OUTCOME MEASURES: Dynamic ranges and current levels were compared for both implants. Functional outcome measures included sentence discrimination in quiet and in noise and sound localisation. RESULTS: Results show that for the children with long inter-implant delays, the dynamic range of their second implant was on average 34% less than the dynamic range of their first implant. This difference was driven by smaller comfort levels in the second implant compared to the first. Children with longer inter-implant delays also show lower speech discrimination scores with their second implant compared to children with shorter delays, in addition to no bilateral advantage in speech in noise, that is their performance in unilateral mode does not differ from the performance in bilateral mode. Finally, children with longer delays demonstrate poor performance in sound localisation compared to the children with shorter delays. CONCLUSION: Sequentially implanted older children show limited functional benefits from the second implant. The observed functional benefits are determined both by a short inter-implant delay and by having balanced dynamic ranges between the two implants.

Complexity based measures of postural stability provide novel evidence of functional decline in fragile X premutation carriers.

BACKGROUND: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative movement disorder characterized by tremor, ataxic gait, and balance issues resulting from a premutation of the Fragile X Mental Retardation 1 (FMR1) gene. No biomarkers have yet been identified to allow early diagnosis of FXTAS, however, recent studies have reported subtle issues in the stability of younger premutation carriers, before disease onset. This study investigates the efficacy of multiscale entropy analysis (MSE) in detecting early changes in the motor system of premutation carriers without FXTAS. METHODS: Sway complexity of 12 female Premutation carriers and 15 healthy Controls were measured under four conditions: eyes open, closed, and two dual-task conditions. A Sustained Attention Response Task (SART) and a working memory based N-Back task were employed to increase cognitive load while standing on the forceplate. A Complexity Index (Ci) was calculated for anterior-posterior (AP) and mediolateral (ML) sway. Independent t-tests were used to assess between-group differences and Oneway repeated measures ANOVA were used to assess within group differences with Bonferroni corrections to adjust for multiple comparisons. RESULTS: Group performances were comparable with eyes open and closed conditions. The Carrier group's Ci was consistent across tasks and conditions while the Control group's AP Ci increased significantly during the cognitive dual-task (p = 0.001). There was also a strong correlation between CGG repeat length and complexity for the Carrier group (p = 0.004). SIGNIFICANCE: Increased sway complexity is believed to stem from reallocation of attention to facilitate the increased cognitive demands of dual-tasks. Carriers' complexity did not change during dual-tasks, possibly indicating capacity interference and inefficient division of attention. Lower sway complexity in carriers suggests diminished adaptive capacity under stress as well as degradation of motor functioning. Therefore, sway complexity may be a useful tool in identifying early functional decline in FMR1 premutation carriers as well as monitoring progression towards disease onset.

A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma.

In severe asthma, poor control could reflect issues of medication adherence or inhaler technique, or that the condition is refractory. This study aimed to determine if an intervention with (bio)feedback on the features of inhaler use would identify refractory asthma and enhance inhaler technique and adherence.Patients with severe uncontrolled asthma were subjected to a stratified-by-site random block design. The intensive education group received repeated training in inhaler use, adherence and disease management. The intervention group received the same intervention, enhanced by (bio)feedback-guided training. The primary outcome was rate of actual inhaler adherence. Secondary outcomes included a pre-defined assessment of clinical outcome. Outcome assessors were blinded to group allocation. Data were analysed on an intention-to-treat and per-protocol basis.The mean rate of adherence during the third month in the (bio)feedback group (n=111) was higher than that in the enhanced education group (intention-to-treat, n=107; 73% versus 63%; 95% CI 2.8%-17.6%; p=0.02). By the end of the study, asthma was either stable or improved in 54 patients (38%); uncontrolled, but poorly adherent in 52 (35%); and uncontrolled, but adherent in 40 (27%).Repeated feedback significantly improved inhaler adherence. After a programme of adherence and inhaler technique assessment, only 40 patients (27%) were refractory and adherent, and might therefore need add-on therapy.

Machine Learning EEG to Predict Cognitive Functioning and Processing Speed Over a 2-Year Period in Multiple Sclerosis Patients and Controls.

Event-related potentials (ERPs) show promise to be objective indicators of cognitive functioning. The aim of the study was to examine if ERPs recorded during an oddball task would predict cognitive functioning and information processing speed in Multiple Sclerosis (MS) patients and controls at the individual level. Seventy-eight participants (35 MS patients, 43 healthy age-matched controls) completed visual and auditory 2- and 3-stimulus oddball tasks with 128-channel EEG, and a neuropsychological battery, at baseline (month 0) and at Months 13 and 26. ERPs from 0 to 700 ms and across the whole scalp were transformed into 1728 individual spatio-temporal datapoints per participant. A machine learning method that included penalized linear regression used the entire spatio-temporal ERP to predict composite scores of both cognitive functioning and processing speed at baseline (month 0), and months 13 and 26. The results showed ERPs during the visual oddball tasks could predict cognitive functioning and information processing speed at baseline and a year later in a sample of MS patients and healthy controls. In contrast, ERPs during auditory tasks were not predictive of cognitive performance. These objective neurophysiological indicators of cognitive functioning and processing speed, and machine learning methods that can interrogate high-dimensional data, show promise in outcome prediction.

Objective Assessment of Adherence to Inhalers by Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Objective adherence to inhaled therapy by patients with chronic obstructive pulmonary disease (COPD) has not been reported. OBJECTIVES: To objectively quantify adherence to preventer Diskus inhaler therapy by patients with COPD with an electronic audio recording device (INCA). METHODS: This was a prospective observational study. On discharge from hospital patients were given a salmeterol/fluticasone inhaler with an INCA device attached. Analysis of this audio quantified the frequency and proficiency of inhaler use. MEASUREMENTS AND MAIN RESULTS: Patients with COPD (n = 244) were recruited. The mean age was 71 years, mean FEV1 was 1.3 L, and 59% had evidence of mild/moderate cognitive impairment. By combining time of use, interval between doses, and critical technique errors, thus incorporating both intentional and unintentional nonadherence, a measure "actual adherence" was calculated. Mean actual adherence was 22.6% of that expected if the doses were taken correctly and on time. Six percent had an actual adherence greater than 80%. Hierarchical clustering found three equally sized well-separated clusters corresponding to distinct patterns. Cluster 1 (34%) had low inhaler use and high error rates. Cluster 2 (25%) had high inhaler use and high error rates. Cluster 3 (36%) had overall good adherence. Poor lung function and comorbidities were predictive of poor technique, whereas age and cognition with poor lung function distinguished those with poor adherence and frequent errors in technique. CONCLUSIONS: These data may inform clinicians in understanding why a prescribed inhaler is not effective and to devise strategies to promote adherence in COPD.

Refined Multiscale Fuzzy Entropy to Analyse Post-Exercise Cardiovascular Response in Older Adults With Orthostatic Intolerance.

Orthostatic intolerance syndrome occurs when the autonomic nervous system is incapacitated and fails to respond to the demands associated with the upright position. Assessing this syndrome among the elderly population is important in order to prevent falls. However, this problem is still challenging. The goal of this work was to determine the relationship between orthostatic intolerance (OI) and the cardiovascular response to exercise from the analysis of heart rate and blood pressure. More specifically, the behavior of these cardiovascular variables was evaluated in terms of refined composite multiscale fuzzy entropy (RCMFE), measured at different scales. The dataset was composed by 65 older subjects, 44.6% (n = 29) were OI symptomatic and 55.4% (n = 36) were not. Insignificant differences were found in age and gender between symptomatic and asymptomatic OI participants. When heart rate was evaluated, higher differences between groups were observed during the recovery period immediately after exercise. With respect to the blood pressure and other hemodynamic parameters, most significant results were obtained in the post-exercise stage. In any case, the symptomatic OI group exhibited higher irregularity in the measured parameters, as higher RCMFE levels in all time scales were obtained. This information could be very helpful for a better understanding of cardiovascular instability, as well as to recognize risk factors for falls and impairment of functional status.

Signal Propagation in the Human Visual Pathways: An Effective Connectivity Analysis.

Although the visual system has been extensively investigated, an integrated account of the spatiotemporal dynamics of long-range signal propagation along the human visual pathways is not completely known or validated. In this work, we used dynamic causal modeling approach to provide insights into the underlying neural circuit dynamics of pattern reversal visual-evoked potentials extracted from concurrent EEG-fMRI data. A recurrent forward-backward connectivity model, consisting of multiple interacting brain regions identified by EEG source localization aided by fMRI spatial priors, best accounted for the data dynamics. Sources were first identified in the thalamic area, primary visual cortex, as well as higher cortical areas along the ventral and dorsal visual processing streams. Consistent with hierarchical early visual processing, the model disclosed and quantified the neural temporal dynamics across the identified activity sources. This signal propagation is dominated by a feedforward process, but we also found weaker effective feedback connectivity. Using effective connectivity analysis, the optimal dynamic causal modeling revealed enhanced connectivity along the dorsal pathway but slightly suppressed connectivity along the ventral pathway. A bias was also found in favor of the right hemisphere consistent with functional attentional asymmetry. This study validates, for the first time, the long-range signal propagation timing in the human visual pathways. A similar modeling approach can potentially be used to understand other cognitive processes and dysfunctions in signal propagation in neurological and neuropsychiatric disorders. Significance statement: An integrated account of long-range visual signal propagation in the human brain is currently incomplete. Using computational neural modeling on our acquired concurrent EEG-fMRI data under a visual evoked task, we found not only a substantial forward propagation toward "higher-order" brain regions but also a weaker backward propagation. Asymmetry in our model's long-range connectivity accounted for the various observed activity biases. Importantly, the model disclosed the timing of signal propagation across these connectivity pathways and validates, for the first time, long-range signal propagation in the human visual system. A similar modeling approach could be used to identify neural pathways for other cognitive processes and their dysfunctions in brain disorders.

Exploring the unknown: electrophysiological and behavioural measures of visuospatial learning.

Visuospatial memory describes our ability to temporarily store and manipulate visual and spatial information and is employed for a wide variety of complex cognitive tasks. Here, a visuospatial learning task requiring fine motor control is employed to investigate visuospatial learning in a group of typically developing adults. Electrophysiological and behavioural data are collected during a target location task under two experimental conditions: Target Learning and Target Cued. Movement times (MTs) are employed as a behavioural metric of performance, while dynamic P3b amplitudes and power in the alpha band (approximately 10 Hz) are explored as electrophysiological metrics during visuospatial learning. Results demonstrate that task performance, as measured by MT, is highly correlated with P3b amplitude and alpha power at a consecutive trial level (trials 1-30). The current set of results, in conjunction with the existing literature, suggests that changes in P3b amplitude and alpha power could correspond to different aspects of the learning process. Here it is hypothesized that changes in P3b correspond to a diminishing inter-stimulus interval and reduced stimulus relevance, while the corresponding changes in alpha power represent an automation of response as habituation occurs in participants. The novel analysis presented in the current study demonstrates how gradual electrophysiological changes can be tracked during the visuospatial learning process under the current paradigm.

Sun exposure is an environmental factor for the development of blepharospasm.

BACKGROUND: Adult-onset isolated focal dystonia may present with various phenotypes including blepharospasm and cervical dystonia. Although inherited in an autosomal dominant manner with a markedly reduced penetrance, environmental factors are considered important in disease penetrance and expression. We observed a marked variation by latitude in the reports of the frequency of patients with blepharospasm relative to those with cervical dystonia; we hypothesised that sun exposure is an environmental risk factor for the development of blepharospasm in genetically susceptible individuals. METHODS: From published clinic cohorts and epidemiological reports, the ratio of the number of cases of blepharospasm to cervical dystonia (phenotype case ratio) at each study site was analysed with regard to latitude and measures of annual insolation. Meta-regression analyses of the phenotype case ratio to these environmental factors were performed. RESULTS: The phenotype case ratio in 15 eligible study sites over 41° of latitude demonstrated a statistically significant inverse association with latitude (p=0.0004, R(2)=53.5%). There were significant positive associations between the phenotype case ratio and quarter-one (January-March) insolation (p=0.0005, R(2)=53%) and average annual insolation (p=0.003, R(2)=40%). CONCLUSION: The increase in the blepharospasm: cervical dystonia case ratio with decreasing latitude and increasing insolation suggests that sunlight exposure is an environmental risk factor for the development of blepharospasm (rather than cervical dystonia) in individuals genetically susceptible to adult-onset dystonia.

An evaluation of the role of environmental factors in the disease penetrance of cervical dystonia.

BACKGROUND: Adult onset primary torsion dystonia (AOPTD) is a poorly penetrant autosomal dominant disorder; most gene carriers are non-manifesting despite having reached an adequate age for penetrance. It is hypothesised that genetic, epigenetic and environmental factors may exert protective or deleterious effects on penetrance of AOPTD. By examining environmental exposure history in cervical dystonia patients and their similarly aged unaffected siblings we aimed to determine the role of previous environmental exposures in relation to disease penetrance. METHODS: A case-control study of 67 patients with cervical dystonia and 67 of their age-matched unaffected siblings was performed. Past environmental exposures were assessed using a detailed 124-question standardised questionnaire. RESULTS: By univariate analysis, cervical dystonia patients, compared to their unaffected siblings, had an increased frequency of a history of car accidents with hospital attendance (OR 10.1, 95% CI 2.1 to 47.4, p=0.004) and surgical episodes (OR 6.5, 95% CI 1.76 to 23.61, p=0.005). Following multivariate analysis, car accidents with hospital attendance (OR 7.3, 95% CI 1.4 to 37.6, p=0.017) and all surgical episodes (OR 4.9, 95% CI 1.24 to 19.31, p=0.023) remained significantly associated with case status. CONCLUSIONS: Cervical dystonia patients had a history, prior to symptom onset, of significantly more frequent episodes of surgery and of car accidents with hospital attendance than their age-matched unaffected siblings. Soft tissue trauma appears to increase risk of development of cervical dystonia in genetically predetermined individuals.

The irregular firing properties of thalamic head direction cells mediate turn-specific modulation of the directional tuning curve.

Head direction cells encode an animal's heading in the horizontal plane. However, it is not clear why the directionality of a cell's mean firing rate differs for clockwise, compared with counterclockwise, head turns (this difference is known as the "separation angle") in anterior thalamus. Here we investigated in freely behaving rats whether intrinsic neuronal firing properties are linked to this phenomenon. We found a positive correlation between the separation angle and the spiking variability of thalamic head direction cells. To test whether this link is driven by hyperpolarization-inducing currents, we investigated the effect of thalamic reticular inhibition during high-voltage spindles on directional spiking. While the selective directional firing of thalamic neurons was preserved, we found no evidence for entrainment of thalamic head direction cells by high-voltage spindle oscillations. We then examined the role of depolarization-inducing currents in the formation of separation angle. Using a single-compartment Hodgkin-Huxley model, we show that modeled neurons fire with higher frequencies during the ascending phase of sinusoidal current injection (mimicking the head direction tuning curve) when simulated with higher high-threshold calcium channel conductance. These findings demonstrate that the turn-specific encoding of directional signal strongly depends on the ability of thalamic neurons to fire irregularly in response to sinusoidal excitatory activation. Another crucial factor for inducing phase lead to sinusoidal current injection was the presence of spike-frequency adaptation current in the modeled neurons. Our data support a model in which intrinsic biophysical properties of thalamic neurons mediate the physiological encoding of directional information.