Motor Activity Research Articles

Inhibitory Pedunculopontine Neurons Gate Dopamine-Mediated Motor Actions of Unsigned Valence.

The pedunculopontine nucleus (PPN) maintains a bidirectional connectivity with the basal ganglia that supports their shared roles in the selection and execution of motor actions. Previous studies identified a role for PPN neurons in goal-directed behavior, but the cellular substrates underlying this function have not been elucidated. We recently revealed the existence of a monosynaptic GABAergic input from the PPN that inhibits dopamine neurons of the substantia nigra. Activation of this pathway interferes with the execution of learned motor sequences when the actions are rewarded, even though the inhibition of dopamine neurons did not shift the value of the action, hence suggesting executive control over the gating of behavior. To test the attributes of the inhibition of dopamine neurons by the PPN in the context of goal-directed behavior regardless of whether the outcome is positive or negative. We delivered optogenetic stimulation to PPN GABAergic axon terminals in the substantia nigra during a battery of behavioral tasks with positive and negative valence. Inhibition of dopamine neurons by PPN optogenetic activation during an appetitive task impaired the initiation and overall execution of the behavioral sequence without affecting the consumption of reward. During an active avoidance task, the same activation impaired the ability of mice to avoid a foot shock, but their escape response was unaffected. In addition, responses to potential threats were significantly attenuated. Our results show that PPN GABAergic neurons modulate learned, goal-directed behavior of unsigned valence without affecting overall motor behavior.

The Basal Ganglia Downstream Control of Action - An Evolutionarily Conserved Strategy.

The motor areas of the cortex and the basal ganglia both contribute to determining which motor actions will be recruited at any moment in time, and their functions are intertwined. Here, we review the basal ganglia mechanisms underlying the selection of behavior of the downstream control of motor centers in the midbrain and brainstem and show that the basic organization of the forebrain motor system is evolutionarily conserved throughout vertebrate phylogeny. The output level of the basal ganglia (e.g. substantia nigra pars reticulata) has GABAergic neurons that are spontaneously active at rest and inhibit a number of specific motor centers, each of which can be relieved from inhibition if the inhibitory output neurons themselves become inhibited. The motor areas of the cortex act partially via the dorsolateral striatum (putamen), which has specific modules for the forelimb, hindlimb, trunk, etc. Each module operates in turn through the two types of striatal projection neurons that control the output modules of the basal ganglia and thereby the downstream motor centers. The mechanisms for lateral inhibition in the striatum are reviewed as well as other striatal mechanisms contributing to action selection. The motor cortex also exerts a direct excitatory action on specific motor centers. An overview is given of the basal ganglia control exerted on the different midbrain/brainstem motor centers, and the efference copy information fed back via the thalamus to the striatum and cortex, which is of importance for the planning of future movements.

Remotely Assessing Motor Function and Activity of the Upper Extremity After Stroke: A Systematic Review of Validity and Clinical Utility of Tele-Assessments.

The aim of this systematic review is to identify currently available tele-assessments for motor impairments of the upper extremity in adults after a stroke and to assess their psychometric properties and clinical utility. We searched for studies describing the psychometric properties of tele-assessments for the motor function of the upper extremity. A systematic search was conducted in the Cumulative Index to Nursing and Allied Health Literature, Medline via OVID, Embase, The Cochrane Library, Scopus, Web of Science and Institute of Electrical and Electronics Engineers Xplore from inception until 30 April 2024. The quality assessment for the included studies and the rating of the psychometric properties were performed using the COSMIN Risk of Bias Checklist for systematic reviews of patient-reported outcome measures. A total of 12 studies (N = 3912) describing 11 tele-assessments met the predefined inclusion criteria. The included assessments were heterogeneous in terms of quality and psychometric properties and risk of bias. None of the tele-assessments currently meets the criteria of clinical utility to be recommended for clinical practice without restriction. The quality and clinical utility of tele-assessments varied widely, suggesting a cautious consideration for immediate clinical practice application. There is potential for tele-assessments in clinical practice, but the clinical benefits need to be improved by simplifying the complexity of tele-assessments. CRD42022335035.

Beadex, the Drosophila LIM only protein, is required for the growth of the larval neuromuscular junction.

The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioral studies have identified many molecular candidates and investigated their roles in various neuromuscular processes. In this paper, we show that Beadex (Bx), the Drosophila LIM only (LMO) protein, is required for motor activities and neuromuscular growth of Drosophila. The larvae bearing Bx7, a null allele of Bx, and the RNAi-mediated neuronal-specific knockdown of Bx show drastically reduced crawling behavior, a diminished synaptic span of the neuromuscular junctions (NMJ) and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria, that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show that Highwire (Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulates Bx, as the latter's deficiency was able to rescue the phenotype of the Hiw null mutant, HiwDN. Thus, our data indicates that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology.

Functional Dynamics and Selectivity of Two Parallel Corticocortical Pathways from Motor Cortex to Layer 5 Circuits in Somatosensory Cortex.

In the rodent whisker system, active sensing and sensorimotor integration are mediated in part by the dynamic interactions between the motor cortex (M1) and somatosensory cortex (S1). However, understanding these dynamic interactions requires knowledge about the synapses and how specific neurons respond to their input. Here, we combined optogenetics, retrograde labeling, and electrophysiology to characterize the synaptic connections between M1 and layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons in S1 of mice (both sexes). We found that M1 synapses onto IT cells displayed modest short-term depression, whereas synapses onto PT neurons showed robust short-term facilitation. Despite M1 inputs to IT cells depressing, their slower kinetics resulted in summation and a response that increased during short trains. In contrast, summation was minimal in PT neurons due to the fast time course of their M1 responses. The functional consequences of this reduced summation, however, were outweighed by the strong facilitation at these M1 synapses, resulting in larger response amplitudes in PT neurons than IT cells during repetitive stimulation. To understand the impact of facilitating M1 inputs on PT output, we paired trains of inputs with single backpropagating action potentials, finding that repetitive M1 activation increased the probability of bursts in PT cells without impacting the time dependence of this coupling. Thus, there are two parallel but dynamically distinct systems of M1 synaptic excitation in L5 of S1, each defined by the short-term dynamics of its synapses, the class of postsynaptic neurons, and how the neurons respond to those inputs.

The Neural Correlates of Embodied L2 Learning: Does Embodied L2 Verb Learning Affect Representation and Retention?

We investigated how naturalistic actions in a highly immersive, multimodal, interactive 3D virtual reality (VR) environment may enhance word encoding by recording EEG in a pre/post-test learning paradigm. While behavior data have shown that coupling word encoding with gestures congruent with word meaning enhances learning, the neural underpinnings of this effect have yet to be elucidated. We coupled EEG recording with VR to examine whether embodied learning improves learning and creates linguistic representations that produce greater motor resonance. Participants learned action verbs in an L2 in two different conditions: specific action (observing and performing congruent actions on virtual objects) and pointing (observing actions and pointing to virtual objects). Pre- and post-training participants performed a match-mismatch task as we measured EEG (variation in the N400 response as a function of match between observed actions and auditory verbs) and a passive listening task while we measured motor activation (mu [8-13 Hz] and beta band [13-30 Hz] desynchronization during auditory verb processing) during verb processing. Contrary to our expectations, post-training results revealed neither semantic nor motor effects in either group when considered independently of learning success. Behavioral results showed a great deal of variability in learning success. When considering performance, low performance learners showed no semantic effect and high performance learners exhibited an N400 effect for mismatch versus match trials post-training, independent of the type of learning. Taken as a whole, our results suggest that embodied processes can play an important role in L2 learning.

Applications of Brain Wave Classification for Controlling an Intelligent Wheelchair

The independence and autonomy of both elderly and disabled people have been a growing concern in today’s society. Therefore, wheelchairs have proven to be fundamental for the movement of these people with physical disabilities in the lower limbs, paralysis, or other type of restrictive diseases. Various adapted sensors can be employed in order to facilitate the wheelchair’s driving experience. This work develops the proof concept of a brain–computer interface (BCI), whose ultimate final goal will be to control an intelligent wheelchair. An event-related (de)synchronization neuro-mechanism will be used, since it corresponds to a synchronization, or desynchronization, in the mu and beta brain rhythms, during the execution, preparation, or imagination of motor actions. Two datasets were used for algorithm development: one from the IV competition of BCIs (A), acquired through twenty-two Ag/AgCl electrodes and encompassing motor imagery of the right and left hands, and feet; and the other (B) was obtained in the laboratory using an Emotiv EPOC headset, also with the same motor imaginary. Regarding feature extraction, several approaches were tested: namely, two versions of the signal’s power spectral density, followed by a filter bank version; the use of respective frequency coefficients; and, finally, two versions of the known method filter bank common spatial pattern (FBCSP). Concerning the results from the second version of FBCSP, dataset A presented an F1-score of 0.797 and a rather low false positive rate of 0.150. Moreover, the correspondent average kappa score reached the value of 0.693, which is in the same order of magnitude as 0.57, obtained by the competition. Regarding dataset B, the average value of the F1-score was 0.651, followed by a kappa score of 0.447, and a false positive rate of 0.471. However, it should be noted that some subjects from this dataset presented F1-scores of 0.747 and 0.911, suggesting that the movement imagery (MI) aptness of different users may influence their performance. In conclusion, it is possible to obtain promising results, using an architecture for a real-time application.

Switch-2 determines Mg2+ADP-release kinetics and fine-tunes the duty ratio of Dictyostelium class-1 myosins.

Though myosins share a structurally conserved motor domain, single amino acid variations of active site elements, including the P-loop, switch-1 and switch-2, which act as nucleotide sensors, can substantially determine the kinetic signature of a myosin, i.e., to either perform fast movement or enable long-range transport and tension generation. Switch-2 essentially contributes to the ATP hydrolysis reaction and determines product release. With few exceptions, class-1 myosin harbor a tyrosine in the switch-2 consensus sequence DIYGFE, at a position where class-2 myosins and a selection of myosins from other classes have a substitution. Here, we addressed the role of the tyrosine in switch-2 of class-1 myosins as potential determinant of the duty ratio. We generated constitutively active motor domain constructs of two class-1 myosins from the social amoeba Dictyostelium discoideum, namely, Myo1E, a high duty ratio myosin and Myo1B, a low duty ratio myosin. In Myo1E we introduced mutation Y388F and in Myo1B mutation F387Y. The detailed functional characterization by steady-state and transient kinetic experiments, combined with in vitro motility and landing assays revealed an almost reciprocal relationship of a number of critical kinetic parameters and equilibrium constants between wild-type and mutants that dictate the lifetime of the strongly actin-attached states of myosin. The Y-to-F mutation increased the duty ratio of Moy1B by almost one order of magnitude, while the introduction of the phenylalanine in switch-2 of Myo1E transformed the myosin into a low duty ratio motor. These data together with structural considerations propose a role of switch-2 in fine-tuning ADP release through a mechanism, where the class-specific tyrosine together with surrounding residues contributes to the coordination of Mg2+ and ADP. Our results highlight the importance of conserved switch-2 residues in class-1 myosins for efficient chemo-mechanical coupling, revealing that switch-2 is important to adjust the duty ratio of the amoeboid class-1 myosins for performing movement, transport or gating functions.

Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems.

The classic output pathways of the basal ganglia are known as the direct-D1 and indirect-D2, or "Go/No-Go", pathways. Balance of the activity in these canonical direct-indirect pathways is considered a core requirement for normal movement control, and their imbalance is a major etiologic factor in movement disorders including Parkinson's disease. We present evidence for a conceptually equivalent parallel system of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from the matrix. These striosomal direct (S-D1) and indirect (S-D2) pathways, as a pair, target dopamine-containing neurons of the substantia nigra (SNpc) instead of the motor output nuclei of the basal ganglia. The novel anatomically and functionally distinct indirect-D2 striosomal pathway targets dopaminergic SNpc cells indirectly via a core region of the external pallidum (GPe). We demonstrate that these S-D1 and S-D2 pathways oppositely modulate striatal dopamine release in freely behaving mice under open-field conditions and oppositely modulate locomotor and other movements. These S-D1 and S-D2 pathways further exhibit different, time-dependent responses during performance of a probabilistic decision-making maze task and respond differently to rewarding and aversive stimuli. These contrasts depend on mediolateral and anteroposterior striatal locations of the SPNs as are the classic direct and indirect pathways. The effects of S-D1 and S-D2 stimulation on striatal dopamine release and voluntary locomotion are nearly opposite. The parallelism of the direct-indirect circuit design motifs of the striosomal S-D and S-D2 circuits and canonical matrix M-D1 and M-D2, and their contrasting behavioral effects, call for a major reformulation of the classic direct-indirect pathway model of basal ganglia function. Given that some striosomes receive limbic and association cortical inputs, the S-D1 and S-D2 circuits likely influence motivation for action and behavioral learning, complementing and possibly reorienting the motoric activities of the canonical matrix pathways. At a fundamental level, these findings suggest a unifying framework for aligning two sets of circuits that share the organizational motif of opponent D1 and D2 regulation, but that have different outputs and can even have opposite polarities in their targets and effects, albeit conditioned by striatal topography. Our findings further delineate a potentially therapeutically important set of pathways influencing dopamine, including a D2 receptor-linked S-D2 pathway likely unknowingly targeted by administration of many therapeutic drugs including those for Parkinson's disease. The novel parallel pathway model that we propose here could help to account for the normally integrated modulatory influence of the basal ganglia on motivation for actions as well as the actions themselves.

The effectiveness of core stabilization exercise using ultrasound biofeedback on motor function, balance control, gait speed and activities of daily living in stroke patients.

Patients with hemiparetic stroke experience diminished motor function, dynamic balance, and gait speed, which influence their activities of daily living (ADL). This study aimed to determine the therapeutic effects of ultrasound biofeedback core exercise (UBCE) on Fugl-Meyer assessment (FMA), Time up and go (TUG), 10-meter walking test (10MWT) and functional independent measure (FIM) in participants with stroke. Twenty-four stroke survivors consistently underwent UBCE or abdominal draw-in maneuver (ADIM) for 30 min/session, 3 days a week for 4 weeks. Clinical outcome measurements- the FMA, TUG, 10MWT, and FIM- were observed pre-and post-intervention. We detected significant changes in the FMA-lower extremities, TUG, 10MWT, and FIM scores between the UBCE and ADIM groups. UBCE and ADIM showed significant improvements in FMA-lower extremities, TUG, 10MWT, and FIM scores. However, UBCE showed more favorable results than ADIM in patients with stroke. Our research provides novel therapeutic suggestion of neurorehabilitation in stroke patients.

The effect of constraint-induced movement therapy for children with hemiplegic cerebral palsy in Vietnam

Purpose Pediatric constraint-induced movement therapy (CIMT) is an evidence-based treatment that has a long history of demonstrating efficacy for children with hemiparesis. The purpose of this study is to determine the effectiveness of a culturally responsive CIMT program for children with hemiplegic cerebral palsy (CP) developed for the Vietnam healthcare system. Methods Thirty children with hemiplegic CP (mean age = 2.88 years, age range: 1 to 8 yrs, 60% male) were recruited to a CIMT program (7.5 h/week, 4 weeks) developed for the cultural context of Vietnam. Motor abilities of the affected arm and participation in daily activities were evaluated at 3 time points (one-week prior to CIMT (baseline), one-week before (pre) and after (post) CIMT) using the Quality of Upper Extremity Skill Test (QUEST) and Pediatric Motor Activity Log-Revised (PMAL-R). Individual goals were measured using the Goal Attainment Scale (GAS). Results There were significant increases in the “How often scale” and “How Well” scales of the PMAL-R (0.75 and 0.75, p < 0.00)). Score of Grasp and Dissociated Movement items on the QUEST increased significantly (6.47 and 7.63, p < 0.001). Group GAS T-Scores were 52.19 indicating that children met individual goals. Conclusions A model of CIMT was successfully developed and delivered within the Vietnamese healthcare system. Future studies should explore the optimal model for CIMT in various regions of world where the delivery of rehabilitation services may vary.

The challenge of learning adaptive mental behavior.

Many psychotherapies aim to help people replace maladaptive mental behaviors (such as those leading to unproductive worry) with more adaptive ones (such as those leading to active problem solving). Yet, little is known empirically about how challenging it is to learn adaptive mental behaviors. Mental behaviors entail taking mental operations and thus may be more challenging to perform than motor actions; this challenge may enhance or impair learning. In particular, challenge when learning is often desirable because it improves retention. Yet, it is also plausible that the necessity of carrying out mental operations interferes with learning the expected values of mental actions by impeding credit assignment: the process of updating an action's value after reinforcement. Then, it may be more challenging not only to perform-but also to learn the consequences of-mental (vs. motor) behaviors. We designed a task to assess learning to take adaptive mental versus motor actions via matched probabilistic feedback. In two experiments (N = 300), most participants found it more difficult to learn to select optimal mental (vs. motor) actions, as evident in worse accuracy not only in a learning but also test (retention) phase. Computational modeling traced this impairment to an indicator of worse credit assignment (impaired construction and maintenance of expected values) when learning mental actions, accounting for worse accuracy in the learning and retention phases. The results suggest that people have particular difficulty learning adaptive mental behavior and pave the way for novel interventions to scaffold credit assignment and promote adaptive thinking. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Prevention of stunting with nutrition and reproductive health education of adolescents in west Lombok, West Nusa Tenggara, Indonesia

The problem of stunting in Indonesia is a serious threat that requires appropriate handling. Basic Health Research data in 2018 shows that stunting cases in Indonesia are still relatively high, reaching 30.8%. Behavior change is one of the pillars of efforts to deal with malnutrition and stunting. Adolescent reproductive health is defined as a healthy condition in the system, function, and process of adolescent reproduction physically, mentally, and socio-culturally. The Community Service activities that will be carried out are a Community Partnership Program scheme focusing on service in the health sector which focuses on adolescent reproductive health. The targets of this activity are teachers and students of 1st State Senior High School, Gunungsari, Lombok, West of Nusa Tenggara. This Community Service aims to increase knowledge and implementation regarding strengthening character and leadership spirit and using technology wisely, increasing knowledge and skills about motor activities through the socialization of sports movements, anthropometric measurements related to adolescent reproductive readiness, and breast self-examination. The methods used are seminars, focus group discussions, and training.

Sleep problems and circadian rhythm functioning in autistic children, autism with co-occurring attention deficit hyperactivity disorder, and typically developing children: A comparative study.

Sleep problems are common in autism spectrum disorder (ASD) and different factors can contribute to its occurrence in this population. Misalignment of the biological clock (our circadian system) has been described as one possible explanation. While there is a body of research on sleep problems, relatively less is known about circadian functioning and the specific population of autistic children with co-occurring attention deficit hyperactivity disorder (ADHD). Using an ambulatory circadian monitoring (ACM) system, which resembles a common watch, we gathered sleep parameters and the different rhythms obtained from measuring motor activity, light exposure and distal temperature in 87 autistic children and adolescents, 27 of whom were diagnosed with co-occurring ADHD, and 30 neurotypical children and adolescents as a comparison group. Autistic children and, especially, those with co-occurring ADHD showed greater motor activity during sleep which would be worth studying in future projects which could better define this restless sleep. Of note, we observed an atypical pattern of wrist temperature, with higher values in neurotypical children, followed by autistic children and, ultimately, those with co-occurring ADHD. Temperature is one of the most valuable factors evaluated here as it is closely connected to sleep-wakefulness and the hormone melatonin. Its special pattern during day and nighttime would support the hypothesis of an atypical secretion of melatonin in autistic individuals which would also link with the higher presence of sleep problems in this neurodevelopmental condition.

Anthropometric Influence on Preschool Children's Physical Fitness and Motor Skills: A Systematic Review.

Early childhood is a critical period for physical and motor development with implications for long-term health. This systematic review examined the relationship between anthropometric characteristics and measures of physical fitness and motor skills in preschool-aged children (typically 2-6 years). The search strategy was applied in four databases (PubMed, ProQuest Central, Scopus, and Web of Science) to find articles published before 11 April 2024. The results consistently demonstrated significant associations between anthropometric variables (height, weight, body mass index [BMI], body composition) and physical performance measures. Notably, height and mass were often better predictors of fitness status than BMI alone. Indicators of undernutrition (stunting, wasting) were negatively associated with motor development, emphasizing the importance of adequate nutrition. While some studies reported impaired fitness and motor skills among overweight/obese preschoolers compared to normal-weight peers, others found no differences based on weight status. Relationships between physical activity levels, anthropometrics, and motor outcomes were complex and inconsistent across studies. This review highlights key findings regarding the influence of anthropometric factors on physical capabilities in early childhood. Early identification of children with impaired growth or excessive adiposity may inform tailored interventions to promote optimal motor development and prevent issues like obesity. Creating supportive environments for healthy growth and age-appropriate physical activity opportunities is crucial during this critical developmental window.

Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue

ObjectiveHirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from the failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during...

Boosting Prefrontal Brain Responsiveness by Interoceptive Attentiveness during Synchronized Breathing, Motor, and Cognitive Task

Background: this study explored the prefrontal cortex (PFC) hemodynamic variations produced by the association of an Interoceptive Attentiveness (IA) condition with a simple breath, motor, and cognitive synchronization task. Methods: 18 healthy individuals performed different synchronization activities (breath, motor, and cognitive) under both IA and control conditions, while levels of oxygenated (O2Hb) and deoxygenated hemoglobin were measured using functional Near-Infrared Spectroscopy (fNIRS). Results: findings revealed higher O2Hb levels in the prefrontal brain region during the experimental condition (IA) in contrast to the control condition. Notably, this difference was particularly evident during the cognitive task as opposed to the other tasks (breath and motor). In contrast, no significant differences were found for the PFC lateralization effect. Conclusions: This evidence holds potential for rehabilitation professionals suggesting that the combination of deliberate attention to the breath and a cognitive synchronization task (such as a vocal exercise executed simultaneously) could boost PFC responsiveness.

Familial risk for depression is associated with reduced physical activity in young adults: evidence from a wrist-worn actigraphy study

Depression is characterized by reduced physical activity and sleep-wake cycle disturbances, often considered important features of the disease. While a few studies have suggested that self-reported reduced physical activity and sleep-wake cycle disturbances might both be linked to depression vulnerability, actigraphy-based measures in vulnerable samples remain largely unexplored. This study relied on actigraphy-based parameters to test whether these disturbances characterize depression vulnerability. Seven-day actigraphy data were collected from 20 (13 female) university students with a high vulnerability to depression, which was determined by the presence of a family history of the condition but no current symptoms, and 32 (21 female) controls with neither a family history of depression nor current depressive symptoms. Daily physical activity, namely gross motor activity, was quantified as average daily acceleration and time spent engaging in moderate-vigorous physical activity (MVPA). The sleep-wake cycle and circadian rhythms were assessed as total sleep duration per night (in hours), sleep within sleep period time (in hours), sleep efficiency (%), and relative amplitude (i.e., the difference between the activity during the day and the night, which reflects circadian rhythms amplitude). Results showed that individuals with a familial risk for depression exhibited reduced daily acceleration and time spent in MVPA relative to the control group, particularly on the weekend during their free time away from scheduled activities. On the other hand, the two groups were comparable in terms of sleep estimates. Taken together, reduced physical activity, but not sleep-wake disturbances, seem to be associated with vulnerability to depression and might be a viable target for identification and prevention efforts.

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Non-Invasive Spinal Cord Stimulation for Motor Rehabilitation of Patients with Spinal Muscular Atrophy Treated with Orphan Drugs.

Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in this study. The median duration of drug treatment was over 20 months. The application of tSCS was performed during physical therapy for 20-40 min per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, and forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both type 2 and 3 SMA participants. The magnitude of functional changes was not associated with participant age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation on SMA.