Repetitive Motor Research Articles

Ketogenic diet restores aberrant cortical motor maps and excitation-to-inhibition imbalance in the BTBR mouse model of autism spectrum disorder

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder characterized by deficits in sociability and communication, and restricted and/or repetitive motor behaviors. Amongst the diverse hypotheses regarding the pathophysiology of ASD, one possibility is that there is increased neuronal excitation, leading to alterations in sensory processing, functional integration and behavior. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used in the treatment of medically intractable epilepsy, has already been shown to reduce autistic behaviors in both humans and in rodent models of ASD. While the mechanisms underlying these effects remain unclear, we hypothesized that this dietary approach might shift the balance of excitation and inhibition towards more normal levels of inhibition. Using high-resolution intracortical microstimulation, we investigated basal sensorimotor excitation/inhibition in the BTBR T+Itprtf/J (BTBR) mouse model of ASD and tested whether the KD restores the balance of excitation/inhibition. We found that BTBR mice had lower movement thresholds and larger motor maps indicative of higher excitation/inhibition compared to C57BL/6J (B6) controls, and that the KD reversed both these abnormalities. Collectively, our results afford a greater understanding of cortical excitation/inhibition balance in ASD and may help expedite the development of therapeutic approaches aimed at improving functional outcomes in this disorder.

Striatal Circuits as a Common Node for Autism Pathophysiology.

Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains—deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD.

Abstract WP148: Tactile-enhanced Motor Practice Improves Manual Dexterity Over Visually-guided Practice

Introduction: Manual dexterity requires multi-sensory (e.g., vision and touch) integration with movement, and is often impaired due to sensorimotor deficits in stroke survivors. Currently, neurorehabilitation involves repetitive visually-guided motor practice without particular emphasis on tactile feedback for movement. As a first step to improve post-stroke hand function, we studied the effects of providing enhanced tactile feedback during motor practice on dexterity of the non-dominant hand in healthy volunteers. Hypothesis: We hypothesized that 2, 45-minute sessions of enhanced tactile-motor practice would improve non-dominant hand dexterity more than the same duration of visuo-motor practice. Methods: Twenty healthy adults (8 males; mean age = 27.7 ± 22 years) were randomized to an enhanced tactile-motor (TM) or visuo-motor (VM) group. Volunteers performed 3, 15-minute blocks of motor practice that required 1) sorting small (< 2.5 cm) wood-chips, 2) completing 3-D puzzles using small (<1.25 cm) cubes, and 3) copying patterns using 3.6 cm3 interlocking building bricks. Motor practice was either based on tactile cues of textured objects with vision partially obscured by a blurry screen (TM) or visual cues of smooth colored objects (VM). Motor practice occurred twice, seven days apart, with the non-dominant hand. Nine-hole peg test (9HPT) was the primary outcome to measure manual dexterity of non-dominant hand. Scores on the 9HPT were measured at 4 times: T1) pre-practice day 1, T2) post-practice day 1, T3) pre-practice day 2, and T4) post-practice day 2. A mixed-methods ANOVA was used to test the effect of motor practice (TM, VM), and time (T1, T2, T3, T4) on manual dexterity (9HPT). Results: The 2x4 mixed ANOVA showed a significant interaction between time and motor practice (F (3, 51) = 2.96, p = 0.04, partial η2 = .148), revealing that the change in 9HPT scores over time was different for the 2 groups. The TM group significantly improved on 9HPT from T1 to T4 (Mean difference = 2.7 s, SE = 0.53, p = 0.001), but the VM group did not improve. Conclusions: Tactile enhancement during 2 motor practice sessions can significantly improve dexterity. Future work will translate these methods to stroke rehabilitation.

HEMIFACIAL SPASM IN LATE-ONSET MULTIPLE SCLEROSIS: A CASE REPORT AND LITERATURE REVIEW

Movement disorders are rare manifestations of late-onset multiple sclerosis (LOMS). We report a case of a 62 years old man who presented an acute onset of unilateral sustained, irregular, brief contracture in his left-side facial muscles. Clinical, neurophysological and neuroimaging exams allowed a diagnosis of hemifacial spasm (HFS) in MS. Specifically, needle electromyography revealed repetitive motor unit action potentials firing at high frequency discharge (100-150 Hz) in the affected facial muscles., suggesting that demyelinating lesion involved the lower facial motor neurons in the intra-axial exit zone. Blink reflex findings confirmed the efferent demyelinating injury. In literature HFS explicitly associated with MS are described but not as first presentation symptoms of LOMS. A careful neurophysiological evaluation can modify the interpretation of an atypical clinical presentation, allowing to establish the specific anatomical location and extent of injury, and the most appropriate treatment.

Repetitive Motor Practice Impacts Neuromuscular System Plasticity in Healthy and Stroke Populations

Neuroplasticity is an important factor for upper-extremity stroke rehabilitation, yet the amount of neuromodulation achieved with an acute session of motor practice is not fully characterized. The objective of this study was to determine how engaging in isometric motor practice acutely influences motor control, dexterity, and neuromodulation. Thirteen healthy controls and 5 stroke survivors participated in 2 separate experiments. Assessments [Box and Block Test (BBT), force steadiness, Transcranial Magnetic Stimulation (TMS)] were completed immediately before and following motor practice. Two force steadiness trials were completed at 10 and 20% of the maximum voluntary contraction (MVC). The TMS outcome included an average of 12 suprathreshold stimulations with motor evoked potentials (MEP) amplitudes recorded. Data were analyzed using paired t-tests for each experiment. Both participant groups were able to move significantly more blocks with the hand that practiced, but not with the non-practicing side. Force steadiness and muscle activity significantly improved for both groups, yet the MEP amplitudes did not. These results suggest that a short intervention of isometric wrist extension can influence motor control and dexterity, but may have a slight impact on neuromodulation. This demonstrates the importance of better understanding how possible rehabilitation interventions influence neuroplasticity through neuromodulation.

How does environmental enrichment reduce repetitive motor behaviors? Neuronal activation and dendritic morphology in the indirect basal ganglia pathway of a mouse model

Repetitive motor behaviors are observed in many neurodevelopmental and neurological disorders (e.g., autism spectrum disorders, Tourette syndrome, fronto-temporal dementia). Despite their clinical importance, the neurobiology underlying these highly stereotyped, apparently functionless behaviors is poorly understood. Identification of mechanisms that mediate the development of repetitive behaviors will aid in the discovery of new therapeutic targets and treatment development. Using a deer mouse model, we have shown that decreased indirect basal ganglia pathway activity is associated with high levels of repetitive behavior. Environmental enrichment (EE) markedly attenuates the development of such aberrant behaviors in mice, although mechanisms driving this effect are unknown. We hypothesized that EE would reduce repetitive motor behaviors by increasing indirect basal ganglia pathway function. We assessed neuronal activation and dendritic spine density in basal ganglia of adult deer mice reared in EE and standard housing. Significant increases in neuronal activation and dendritic spine densities were observed only in the subthalamic nucleus (STN) and globus pallidus (GP), and only for those mice that exhibited an EE-induced decrease in repetitive motor behavior. As the STN and GP lie within the indirect pathway, these data suggest that EE-induced attenuation of repetitive motor behaviors is associated with increased functional activation of the indirect basal ganglia pathway. These results are consistent with our other findings highlighting the importance of the indirect pathway in mediating repetitive motor behaviors.

Magnetoencephalographic study of hand and foot sensorimotor organization in 325 consecutive patients evaluated for tumor or epilepsy surgery.

ObjectivesThe presence of intracranial lesions or epilepsy may lead to functional reorganization and hemispheric lateralization. We applied a clinical magnetoencephalography (MEG) protocol for the localization of the contralateral and ipsilateral S1 and M1 of the foot and hand in patients with non-lesional epilepsy, stroke, developmental brain injury, traumatic brain injury and brain tumors. We investigated whether differences in activation patterns could be related to underlying pathology.MethodsUsing dipole fitting, we localized the sources underlying sensory and motor evoked magnetic fields (SEFs and MEFs) of both hands and feet following unilateral stimulation of the median nerve (MN) and posterior tibial nerve (PTN) in 325 consecutive patients. The primary motor cortex was localized using beamforming following a self-paced repetitive motor task for each hand and foot.ResultsThe success rate for motor and sensory localization for the feet was significantly lower than for the hands (motor_hand 94.6% versus motor_feet 81.8%, p < 0.001; sensory_hand 95.3% versus sensory_feet 76.0%, p < 0.001). MN and PTN stimulation activated 86.6% in the contralateral S1, with ipsilateral activation < 0.5%. Motor cortex activation localized contralaterally in 76.1% (5.2% ipsilateral, 7.6% bilateral and 11.1% failures) of all motor MEG recordings. The ipsilateral motor responses were found in 43 (14%) out of 308 patients with motor recordings (range: 8.3–50%, depending on the underlying pathology), and had a higher occurrence in the foot than in the hand (motor_foot 44.8% versus motor_hand 29.6%, p = 0.031). Ipsilateral motor responses tended to be more frequent in patients with a history of stroke, traumatic brain injury (TBI) or developmental brain lesions (p = 0.063).ConclusionsMEG localization of sensorimotor cortex activation was more successful for the hand compared to the foot. In patients with neural lesions, there were signs of brain reorganization as measured by more frequent ipsilateral motor cortical activation of the foot in addition to the traditional sensory and motor activation patterns in the contralateral hemisphere. The presence of ipsilateral neural reorganization, especially around the foot motor area, suggests that careful mapping of the hand and foot in both contralateral and ipsilateral hemispheres prior to surgery might minimize postoperative deficits.

Robot-Assisted Passive Exercise for Ankle Hypertonia in Individuals with Chronic Spinal Cord Injury

Hypertonia is one of the major causes of movement disorders in individuals with central nervous system lesions. Robot-assisted therapy can minimize the immobilization side-effect such as severe hypertonia by providing repetitive motor practice with minimal labor assistance. The purpose of this study was to design a robot-assisted passive exercise device and establish optimal parameter settings for reducing both reflexive and non-reflexive muscle tone. A custom-made device with a built-in force transducer was developed to provide ankle cyclic passive exercise at various speeds and measure the total resistance during stretching. Ten individuals with spinal cord injury received 8 min of low-speed passive exercise (20 cycles/min), 8 min of high-speed (50 cycles/min) passive exercise, and repeated contractions elicited by electrical stimulation (ES), in randomized order over 3 consecutive weeks. Maximum ES-elicited isometric torque, M waves, H reflexes, and total resistance during stretching were measured before and after each of the treatments. The results show that the H reflex was reduced after passive exercise at both speeds but not after repeated ES-elicited contractions. The reduction of the total resistance during stretching was speed-dependent. Significant fatigue was induced only after repeated ES-elicited contractions. This study successfully developed a robot-assisted passive exercise device, evaluated parameter settings, and provided evidence of the reduction of both reflexive excitability and total muscle tone in hypertonia muscles.

The Adult Repetitive Behaviours Questionnaire-2 (RBQ-2A): A Self-Report Measure of Restricted and Repetitive Behaviours.

In two studies we developed and tested a new self-report measure of restricted and repetitive behaviours (RRB) suitable for adults. In Study 1, The Repetitive Behaviours Questionnaire-2 for adults (RBQ-2A) was completed by a sample of 163 neurotypical adults. Principal components analysis revealed two components: Repetitive Motor Behaviours and Insistence on Sameness. In Study 2, the mean RBQ-2A scores of a group of adults with autism spectrum disorder (ASD; N = 29) were compared to an adult neurotypical group (N = 37). The ASD sample had significantly higher total and subscale scores. These results indicate that the RBQ-2A has utility as a self-report questionnaire measure of RRBs suitable for adults, with potential clinical application.

Effects of Anxiety on Spontaneous Ritualized Behavior

Environmental uncertainty and uncontrollability cause psycho-physiological distress to organisms, often impeding normal functioning. A common response involves ritualization, that is, the limitation of behavioral expressions to predictable stereotypic and repetitive motor patterns. In humans, such behaviors are also symptomatic of psychopathologies like obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASDs). Although these reactions might be mediated by different neural pathways, they serve to regain a sense of control over an uncertain situation by engaging in behavioral patterns characterized by redundancy (superfluous actions that exceed the functional requirements of a goal), repetitiveness (recurrent behaviors or utterances), and rigidity (emphasis on fidelity and invariance). We examined whether ritualized behavior will manifest spontaneously as a dominant behavioral strategy in anxiogenic situations. Manipulating anxiety, we used motion-capture technology to quantify various characteristics of hand movements. We found that induced anxiety led to an increase in repetitiveness and rigidity, but not redundancy. However, examination of both psychological and physiological pathways revealed that repetitiveness and rigidity were predicted by an increase in heart rate, while self-perceived anxiety was a marginally significant predictor of redundancy. We suggest that these findings are in accordance with an entropy model of uncertainty, in which anxiety motivates organisms to return to familiar low-entropy states in order to regain a sense of control. Our results might inform a better understanding of ritual behavior and psychiatric disorders whose symptoms include over-ritualization.

Motor imagery modality in expert dancers: an investigation of hip and pelvis kinematics in demi-plié and sauté.

Elite dancers often engage in mental practice during training, but little is known about the effects of discrete, repetitive motor imagery on dance movement performance. This study compared the effects of two motor imagery modalities, third-person visual imagery and kinesthetic imagery, on hip and pelvis kinematics during two technical dance movements, plié and sauté. Twenty-four female dancers (mean age: 26.04; mean years of training: 19.63) were randomly assigned to a type of imagery practice: visual imagery (VI), kinesthetic imagery (KI), or a mental arithmetic task control condition (MAT). No statistically significant effects of imagery group or task type were found for external hip rotation, sagittal pelvic excursion, or a ratio relating hip to pelvic movement, suggesting that imagery practice did not affect either temporal or kinematic characteristics of the plié or sauté.

Developmental trajectories as autism phenotypes.

Numerous studies of Autism Spectrum Disorder have attempted to link behavioral phenotypes to genetic findings. Reliance on cross-sectional behavioral data in samples that span wide age ranges may have limited this endeavor because ASD behaviors are not static within individuals across development. This study uses quantitative methods to describe specific aspects of changes in autism-related and more general behaviors in order to yield trajectories that could be used in place of single time-point data as behavioral phenotypes in neurobiological studies of both Autism Spectrum Disorders and overlapping conditions. Building on previous analyses, we examined trajectories of parent-reported social-communication deficits, social adaptive functioning, and two types of repetitive behaviors, repetitive sensory motor (RSM) behaviors and insistence on sameness (IS) behaviors, in a relatively large sample of participants referred for possible autism at age 2 years and followed into young adulthood (n=85). A strength of this sample was the diverse range of outcomes, including young adults with intellectual disability and persistent autism related difficulties, those with IQs in the borderline or average range who continued to experience functional impairment related to Autism Spectrum Disorders, and a small group of young adults (n=8) with IQs in the average range who were judged to be functioning socially and adaptively at age-appropriate levels at age 19 years, despite a previous childhood diagnosis of autism.

Perseveration in a guessing task by laying hens selected for high or low levels of feather pecking does not support classification of feather pecking as a stereotypy

Feather pecking is a behaviour by which birds damage or destroy the feathers of themselves (self-pecking) or other birds (allo feather pecking), in some cases even plucking out feathers and eating these. The self-pecking is rarely seen in domestic laying hens but is not uncommon in parrots. Feather pecking in laying hens has been described as being stereotypic, i.e. a repetitive invariant motor pattern without an obvious function, and indeed the amount of self-pecking in parrots was found to correlate positively with the amount of recurrent perseveration (RP), the tendency to repeat responses inappropriately, which in humans and other animals was found to correlate with stereotypic behaviour. In the present experiment we set out to investigate the correlation between allo feather pecking and RP in laying hens. We used birds (N=92) from the 10th and 11th generation (G10 and G11) of lines selectively bred for high feather pecking (HFP) and low feather pecking (LFP), and from an unselected control line (CON) with intermediate levels of feather pecking. We hypothesised that levels of RP would be higher, and the time taken (standardised latency) to repeat a response lower, in HFP compared to LFP hens, with CON hens in between. Using a two-choice guessing task, we found that lines differed significantly in their levels of RP, with HFP unexpectedly showing lower levels of RP than CON and LFP. Latency to make a repeat did not differ between lines. Latency to make a switch differed between lines with a shorter latency in HFP compared to LFP (in G10), or CON (in G11). Latency to peck for repeats vs. latency to peck for switches did not differ between lines. Total time to complete the test was significantly shorter in HFP compared to CON and LFP. Thus, our hypotheses were not supported by the data. In contrast, selection for feather pecking seems to induce the opposite effects than would be expected from stereotyping animals: pecking was less sequenced and reaction to make a switch and to complete the test was lower in HFP. This supports the hyperactivity-model of feather pecking, suggesting that feather pecking is related to a higher general activity, possibly due to changes in the dopaminergic system.

Focal dystonia in musicians: Phenomenology and musical triggering factors

Dystonias are defined as a joint sustained and involuntary contraction of agonist and antagonist muscles, which can cause torsion, repetitive abnormal involuntary movements, and/or abnormal postures. One special group of dystonias are those known as occupational, which include dystonia disorders triggered by a repetitive motor activity associated with a specific professional activity or task. Musicians are a population particularly vulnerable to these types of dystonia, which are presented as a loss of coordination and voluntary motor control movements highly trained in musical interpretation. Our aim is to describe a clinical series of focal dystonias in musicians evaluated and treated in our centre. Patients and methodsData are presented on a clinical series of 12 musicians with occupational dystonia. Their history and phenomenology are described, as well as well as their outcome after therapy. ResultsDemographic details: Mean age 34.8±11.8 years, 10 males (83.3%) and 2 females (16.7%). Clinical history: History of trauma in dystonic segment, 6 patients (50%); family history of neurological diseases in first-degree relatives, 6 patients (50%). Occupational history according to music category: 8 patients (66.6%) were classical musicians and 4 patients (33.3%) were popular musicians. PhenomenologyDystonia syndrome was characterised by having a mean age of onset of 28.2±11.3 years (range 18–57 years). The segment affected was the hand (91.7%) in 11 patients. Of all the musicians seen in the clinic, 9 of them (75%) received therapy. The majority of patients appeared to have triggering factors specific to musical execution and linked to the requirement of fine motor control. It should be mentioned that 50% of the musicians treated maintained their professional activity or position in the orchestra to which they belonged. ConclusionsThe majority of our phenomenological findings are consistent with those reported in the current literature. However, it is worth mentioning the presence of triggering factors attributed to the specific requirements of performing music, linked to the participation of fine motor control.

Pulse and entrainment to non-isochronous auditory stimuli: the case of north Indian alap.

Pulse is often understood as a feature of a (quasi-) isochronous event sequence that is picked up by an entrained subject. However, entrainment does not only occur between quasi-periodic rhythms. This paper demonstrates the expression of pulse by subjects listening to non-periodic musical stimuli and investigates the processes behind this behaviour. The stimuli are extracts from the introductory sections of North Indian (Hindustani) classical music performances (alap, jor and jhala). The first of three experiments demonstrates regular motor responses to both irregular alap and more regular jor sections: responses to alap appear related to individual spontaneous tempi, while for jor they relate to the stimulus event rate. A second experiment investigated whether subjects respond to average periodicities of the alap section, and whether their responses show phase alignment to the musical events. In the third experiment we investigated responses to a broader sample of performances, testing their relationship to spontaneous tempo, and the effect of prior experience with this music. Our results suggest an entrainment model in which pulse is understood as the experience of one’s internal periodicity: it is not necessarily linked to temporally regular, structured sensory input streams; it can arise spontaneously through the performance of repetitive motor actions, or on exposure to event sequences with rather irregular temporal structures. Greater regularity in the external event sequence leads to entrainment between motor responses and stimulus sequence, modifying subjects’ internal periodicities in such a way that they are either identical or harmonically related to each other. This can be considered as the basis for shared (rhythmic) experience and may be an important process supporting ‘social’ effects of temporally regular music.

The Effects of Motor and Vocal Response Interruption and Redirection on Vocal Stereotypy and Appropriate Vocalizations

Stereotypy has been defined as repetitive vocal or motor behaviors that are noncontextual with invariant topographies. One intervention to reduce vocal stereotypy and increase appropriate vocalizations is response interruption and redirection (RIRD). Previous research has suggested that RIRD's behavioral mechanism consists of punishment. The purpose of this study was to extend this research by comparing two procedures, namely, vocal and motor RIRD contingent upon the occurrence of vocal stereotypy and to evaluate concomitant increases in appropriate vocalizations. A multiple treatment reversal design was used to compare the effectiveness of both interventions on five children diagnosed with an Autism Spectrum Disorder. Results suggested that both demand topographies were equally effective in reducing vocal stereotypy and increasing appropriate vocalizations. This research replicates previous findings that have suggested that RIRD is a punishment procedure. Copyright © 2015 John Wiley &amp; Sons, Ltd.

The Effect of the Task-Oriented Upper Extremity Motor Task on Upper Extremity Function and Activities of Daily Living Performance in the Stroke Patients

The purpose of this study was to investigate of the effect of the task-oriented upper motor task on upper extremity function and activities of daily living performance of stroke patients. The objects of this study were 30 stroke patients and each 15 patients were randomly assigned in two groups, control group performing repetitive extremity motor treatment and experimental group performing task-oriented upper motor tasks. Evaluation of the upper extremity function and activities of daily living was performed before intervention, after 4 weeks using Fugl-Meyer Assessment Scale and(FMA), Manual Functional Test(MFT), Korean Modified Barthel Index(K-MBI). The result as follows: Both groups showed the improved upper extremity function and activities of daily living. The experimental group was statistically increase more than thecontrol group in FMA, MFT, K-MBI. However FMA, MFT, K-MBI mean score showed no significant differences between the two group. Consequently, both the task-oriented upper motor tasks and repetitive extremity motor treatment lead improvement of upper extremity function, activities of daily living ability.

Structural and Functional Neuroimaging of Restricted and Repetitive Behavior in Autism Spectrum Disorder

A prominent symptom of Autism Spectrum Disorder includes restricted and repetitive behaviours. This symptom has been divided into three subtypes: repetitive motor behaviour, insistence on sameness and circumscribed interests. In the past, the neural correlates of these behaviours have been largely understudied. More recently, neuroimaging studies have pointed to a number of neural networks that may underlay these behaviours. However, results from this work have been varied and remain difficult to integrate. The purpose of this review is to summarize recent neuroimaging studies on restricted and repetitive behaviours in autism, and to provide an organized framework that will permit a clearer understanding of the neural correlates of these behaviours. Using a developmental perspective, this review will identify that there are distinct and overlapping neural networks that are associated with repetitive motor behaviour, insistence on sameness and circumscribed interests. In addition, this review will identify a series of executive and affective function tasks that have proven efficacious in the study of repetitive behaviour.

Distal motor deficit contributions to postural instability and gait disorder in Parkinson's disease

Clinical subtypes in Parkinson's disease (PD) are often based on the presence of clustered motor symptoms. In contrast to the tremor dominant (TD) subtype, the postural instability and gait disorder (PIGD) subtype is characterized by predominantly axial motor involvement and increased cognitive impairment. It is, however, unclear if subtypes represent distinct underlying neuropathological mechanisms or reflect more severe disease progression. We aimed to clarify the validity of PD subtypes by investigating behavioral outcomes at multiple levels. Therefore, spatiotemporal kinematics of gait, upper and lower limb repetitive movements in combination with a balance and cognitive assessment were recorded in 73 patients with PD. We classified patients as PIGD (n=43), TD (n=22) or indeterminate (n=8) while ‘off’ medication and recruited 20 age-matched controls. Surprisingly, differences between PIGD and TD were more prominent during repetitive distal motor tasks than during gait. Gait impairment in PIGD was only shown by reduced step length and gait speed. However, motor scaling and coordination of distal movements were more affected in PIGD than in TD patients. PIGD patients also had impaired postural control compared to TD patients as shown by lower mini-BESTest scores. There were no cognitive differences between patient subgroups. Distal movement was not significantly different in TD patients from controls, except for greater movement asymmetry. The results indicate a widespread impairment within PIGD with more pronounced distal than axial motor deficits. This suggests involvement of different neurotransmitter systems in the neuropathology of PD subtypes, which are at least partially independent of disease progression.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.