Looking toward predicting functional recovery in disorders of consciousness: can sensorimotor integration help us?

PRIMARY OBJECTIVE: Only a few objective prognostic markers are available for patients with disorders of consciousness (DoC). We assessed whether the magnitude of short-latency afferent inhibition (SAI) might be a useful predictor of responsiveness recovery and functional outcome in patients with DoC. RESEARCH DESIGN: We enrolled 40 patients with prolonged Minimally Conscious State (MCS) and Unresponsive Wakefulness Syndrome (UWS) in a longitudinal, observational study. METHODS AND PROCEDURES: Clinical features (including Coma Recovery Scale-Revised, CRS-R, and Glasgow Outcome Scale, GOS) and SAI were collected at the study entry and after 18 months from study inclusion, to assess a correlation between SAI and the clinical outcome. MAIN OUTCOMES AND RESULTS: At the follow-up, 19 patients remained in their baseline condition, whereas 7 UWS evolved into MCS or emerged-from-MCS (EMCS), eight MCS evolved into EMCS, and two MCS- evolved into MCS+. Two UWS and one MCS+ died for cardiopulmonary complications. The patients who showed the highest GOS, the highest CRS-R and the lowest SAI strength at study entry, improved at the follow-up. CONCLUSIONS: Our findings suggest that an objective and simple neurophysiologic measure as SAI strength could provide useful information to predict the outcome and the behavioral responsiveness of patients with DoC.

Paving the way for a better understanding of the pathophysiology of gait impairment in myotonic dystrophy: a pilot study focusing on muscle networks.

BACKGROUND: A proper rehabilitation program targeting gait is mandatory to maintain the quality of life of patients with Myotonic dystrophy type 1 (DM1). Assuming that gait and balance impairment simply depend on the degree of muscle weakness is potentially misleading. In fact, the involvement of the Central Nervous System (CNS) in DM1 pathophysiology calls into account the deterioration of muscle coordination in gait impairment. Our study aimed at demonstrating the presence and role of muscle connectivity deterioration in patients with DM1 by a CNS perspective by investigating signal synergies using a time-frequency spectral coherence and multivariate analyses on lower limb muscles while walking upright. Further, we sought at determining whether muscle networks were abnormal secondarily to the muscle impairment or primarily to CNS damage (as DM1 is a multi-system disorder also involving the CNS). In other words, muscle network deterioration may depend on a weakening in signal synergies (that express the neural drive to muscles deduced from surface electromyography data). METHODS: Such an innovative approach to estimate muscle networks and signal synergies was carried out in seven patients with DM1 and ten healthy controls (HC). RESULTS: Patients with DM1 showed a commingling of low and high frequencies among muscle at both within- and between-limbs level, a weak direct neural coupling concerning inter-limb coordination, a modest network segregation, high integrative network properties, and an impoverishment in the available signal synergies, as compared to HCs. These network abnormalities were independent from muscle weakness and myotonia. CONCLUSIONS: Our results suggest that gait impairment in patients with DM1 depends also on a muscle network deterioration that is secondary to signal synergy deterioration (related to CNS impairment). This suggests that muscle network deterioration may be a primary trait of DM1 rather than a maladaptive mechanism to muscle degeneration. This information may be useful concerning the implementation of proper rehabilitative strategies in patients with DM1. It will be indeed necessary not only addressing muscle weakness but also gait-related muscle connectivity to improve functional ambulation in such patients.

Bridging the Gap Towards Awareness Detection in Disorders of Consciousness: An Experimental Study on the Mirror Neuron System.

Advanced functional neuroimaging approaches dealing with motor imagery have disclosed covert cognitive processes in patients with disorders of consciousness (DoC). However, motor impairment and cognitive-motor dissociation can bias such approaches. Fourteen patients with post-traumatic DoC and ten healthy controls (HC) were provided with three motor tasks related to mirror neuron system (MNS) activation (movement observation, movement execution, and passive motor imagery of a movement) while recording electroencephalographic (EEG) metrics [EEG power and Granger Casualty Index (GCI)] to detect residual signs of conscious awareness. The most relevant finding was that all HCs, all patients with Minimally Conscious State and one with Unresponsive Wakefulness Syndrome demonstrated an event-related synchronization in the gamma range over left frontal regions, with high GCI values, in the passive motor imagery condition. These data significantly correlated with the level of behavioral responsiveness measured by the Coma Recovery Scale-Revised. Thus, our findings may indicate that motor tasks related to MNS can activate frontoparietal networks, although leading to different conscious processes. Hence, MNS assessment can be usefully employed to differentiate among patients with DoC.

The role of virtual reality in improving motor performance as revealed by EEG: a randomized clinical trial.

BACKGROUND: Many studies have demonstrated the usefulness of repetitive task practice by using robotic-assisted gait training (RAGT) devices, including Lokomat, for the treatment of lower limb paresis. Virtual reality (VR) has proved to be a valuable tool to improve neurorehabilitation training. The aim of our pilot randomized clinical trial was to understand the neurophysiological basis of motor function recovery induced by the association between RAGT (by using Lokomat device) and VR (an animated avatar in a 2D VR) by studying electroencephalographic (EEG) oscillations. METHODS: Twenty-four patients suffering from a first unilateral ischemic stroke in the chronic phase were randomized into two groups. One group performed 40 sessions of Lokomat with VR (RAGT + VR), whereas the other group underwent Lokomat without VR (RAGT-VR). The outcomes (clinical, kinematic, and EEG) were measured before and after the robotic intervention. RESULTS: As compared to the RAGT-VR group, all the patients of the RAGT + VR group improved in the Rivermead Mobility Index and Tinetti Performance Oriented Mobility Assessment. Moreover, they showed stronger event-related spectral perturbations in the high-γ and ß bands and larger fronto-central cortical activations in the affected hemisphere. CONCLUSIONS: The robotic-based rehabilitation combined with VR in patients with chronic hemiparesis induced an improvement in gait and balance. EEG data suggest that the use of VR may entrain several brain areas (probably encompassing the mirror neuron system) involved in motor planning and learning, thus leading to an enhanced motor performance. TRIAL REGISTRATION: Retrospectively registered in Clinical Trials on 21-11-2016, n. NCT02971371 .

Could autonomic system assessment be helpful in disorders of consciousness diagnosis? A neurophysiological study.

Although patients with chronic disorders of consciousness (DOC), including unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), show a limited repertoire of awareness signs, owing to a large-scale cortico-thalamo-cortical functional disconnectivity, an activation of some cortical areas in response to relevant stimuli has been described by means of electrophysiological and functional neuroimaging approaches. In addition, cognitive processes associated with autonomic nervous system (ANS) responses elicited by nociceptive stimuli have been identified in some DOC patients. In an attempt to identify ANS functionality markers that could be useful in differentiating UWS and MCS individuals, we measured the amplitude, latency and γ-band power (γPOW) of ultra-late laser-evoked potentials (CLEPs) and skin reflex (SR), which both express some aspects of cognitive processes related to ANS functionality, besides other ANS parameters either during a 24(hh)-polygraphy or following a solid-state laser repetitive nociceptive stimulation. MCS showed physiological modification of vital signs (O2 saturation, hearth rate, hearth rate variability) throughout the night and a preservation of SR-γPOW, whereas UWS did not show significant variations. Following repetitive nociceptive stimulation, MCS patients had a significant increase in CLEP-γPOW, O2 saturation, hearth rate, and hearth rate variability, whereas UWS individuals did not show any significant change (but two patients, who reached high Coma Recovery Scale-Revised scores). Hence, our work suggests that a wide-spectrum electrophysiological evaluation of ANS functionality may support DOC differential diagnosis. Interestingly, the two above-mentioned UWS patients showed MCS-like vital sign modifications and electrophysiological pain responsiveness. It is therefore hypothesizable that our approach could be helpful in identifying residual aware autonomic system-related cognitive processes even in some UWS patients. Such issue draws the attention to either DOC clinical diagnosis or adequate pain treatment in DOC patients.

Transcranial Alternating Current Stimulation in Patients with Chronic Disorder of Consciousness: A Possible Way to Cut the Diagnostic Gordian Knot?

Unresponsive wakefulness syndrome (UWS) is a chronic disorder of consciousness (DOC) characterized by a lack of awareness and purposeful motor behaviors, owing to an extensive brain connectivity impairment. Nevertheless, some UWS patients may retain residual brain connectivity patterns, which may sustain a covert awareness, namely functional locked-in syndrome (fLIS). We evaluated the possibility of bringing to light such residual neural networks using a non-invasive neurostimulation protocol. To this end, we enrolled 15 healthy individuals and 26 DOC patients (minimally conscious state-MCS- and UWS), who underwent a γ-band transcranial alternating current stimulation (tACS) over the right dorsolateral prefrontal cortex. We measured the effects of tACS on power and partial-directed coherence within local and long-range cortical networks, before and after the protocol application. tACS was able to specifically modulate large-scale cortical effective connectivity and excitability in all the MCS participants and some UWS patients, who could be, therefore, considered as suffering from fLIS. Hence, tACS could be a useful approach in supporting a DOC differential diagnosis, depending on the level of preservation of the cortical large-scale effective connectivity.

Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

OBJECTIVE: The aim of our study was to better investigate the role of Sativex(®) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment. SETTING: Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. SUBJECTS AND METHODS: We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. RESULTS: One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength. CONCLUSIONS: Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.

Robotic gait rehabilitation and substitution devices in neurological disorders: where are we now?

Gait abnormalities following neurological disorders are often disabling, negatively affecting patients' quality of life. Therefore, regaining of walking is considered one of the primary objectives of the rehabilitation process. To overcome problems related to conventional physical therapy, in the last years there has been an intense technological development of robotic devices, and robotic rehabilitation has proved to play a major role in improving one's ability to walk. The robotic rehabilitation systems can be classified into stationary and overground walking systems, and several studies have demonstrated their usefulness in patients after severe acquired brain injury, spinal cord injury and other neurological diseases, including Parkinson's disease, multiple sclerosis and cerebral palsy. In this review, we want to highlight which are the most widely used devices today for gait neurological rehabilitation, focusing on their functioning, effectiveness and challenges. Novel and promising rehabilitation tools, including the use of virtual reality, are also discussed.

Tele-health-care in the elderly living in nursing home: the first Sicilian multimodal approach.

BACKGROUND: The continued aging of the population is affecting the health of the industrialized countries, with an increasing burden for the healthcare system. Thus, during the last decade, we assisted to relevant progress in the medical treatment and rehabilitation techniques and devices, including the development of telemedicine for geriatric care. AIM: To demonstrate the effectiveness of a novel tele-health-care model allowing a better management of elderly living in nursing homes. METHODS: Fifty-nine elderly patients (19 males and 40 females; mean age 79.1 (±9.2), were randomly divided into two groups: the experimental group that performed a proper telemonitoring with a multimodal approach (including monitoring of the vital signs and neurological/psychological counseling), and the control group, which underwent standard in-home nursing care. Neurobehavioral symptoms and quality of life were assessed in both the groups at baseline, and after the telecare protocol's end. RESULTS: The experimental group had a statistically significant reduction in Geriatric Depression Scale (p < 0.01) and Brief Psychiatric Rating Scale (p < 0.05) scores, and an improvement in their quality of life. Moreover, mean blood pressure and heart rate were lower in the experimental than in the control group (p < 0.05), and admission to health care services was higher in the control than in the experimental group (p < 0.05). CONCLUSIONS: Telemedicine can be considered as an important tool in improving health and quality of life in the elderly living in nursing homes, and potentially reducing healthcare service access, hospitalization, and costs.

Could combined sleep and pain evaluation be useful in the diagnosis of disorders of consciousness (DOC)? Preliminary findings.

BACKGROUND: The diagnosis of Disorders of Consciousness (DOC) is still challenging. Indeed, ~ 40% of patients in vegetative state (VS) are misdiagnosed, suggesting the need of more appropriate diagnostic tools. Emerging data are showing that EEG, including sleep structure evaluation and multimodal evoked potential recording could be helpful in DOC diagnosis. Moreover, pain perception evaluation could further increase diagnosis accuracy in such individuals. METHODS: Fourteen individuals with DOC, due to severe brain injury, were enrolled and admitted to the Intensive Neurorehabilitation Unit of the Research Institute. All patients were evaluated by means of the Coma Recovery Scale-Revised, a 24(hh)-polysomnography and a Laser Evoked Potential (LEP) paradigm. RESULTS: Clinically-defined patients in Minimally Consciousness State showed a more preserved sleep structure, physiologic hypnic figures and preserved REM/NREM sleep distribution than subjects in VS. LEP showed increased latencies and reduced amplitudes and were also detectable in patients with more structured sleep. CONCLUSIONS: The data support previous findings concerning the importance of sleep study in DOC diagnosis, with more specific neurophysiological paradigms. Interestingly, the findings shed some light on the possible correlations among global brain connectivity, sleep structure and pain perception, which are related to the activity of the wide thalamo-cortical and cortico-cortical networks underlying consciousness.

Repetitive transcranial magnetic stimulation induced slow wave activity modification: A possible role in disorder of consciousness differential diagnosis?

Slow wave activity (SWA) generation depends on cortico-thalamo-cortical loops that are disrupted in patients with chronic Disorders of Consciousness (DOC), including the Unresponsive Wakefulness Syndrome (UWS) and the Minimally Conscious State (MCS). We hypothesized that the modulation of SWA by means of a repetitive transcranial magnetic stimulation (rTMS) could reveal residual patterns of connectivity, thus supporting the DOC clinical differential diagnosis. We enrolled 10 DOC individuals who underwent a 24hh polysomnography followed by a real or sham 5Hz-rTMS over left primary motor area, and a second polysomnographic recording. A preserved sleep-wake cycle, a standard temporal progression of sleep stages, and a SWA perturbation were found in all of the MCS patients and in none of the UWS individuals, only following the real-rTMS. In conclusion, our combined approach may improve the differential diagnosis between MCS patients, who show a partial preservation of cortical plasticity, and UWS individuals, who lack such properties.

Lokomat training in vascular dementia: motor improvement and beyond!

Vascular dementia (VaD) is a general term describing problems with reasoning, planning, judgment, memory, and other thought processes caused by brain damage from impaired blood flow to the brain. Cognitive rehabilitation and physical therapy are the mainstays of dementia treatment, although often ineffective because of the scarce collaboration of the patients. However, emerging data suggest that physical activity may reduce the risk of cognitive impairment, mainly VaD, in older people living independently. Herein, we describe a 72-year-old male affected by VaD, in which traditional cognitive training in addition to intensive gait robotic rehabilitation (by using Lokomat device) led to a significant improvement in the motor and cognitive function. This promising finding may be related either to the intensive and repetitive aerobic exercises or to the task-oriented training with computerized visual feedback, which can be considered as a relevant tool to increase patients' motor output, involvement, and motivation during robotic training.

Audiomotor Integration in Minimally Conscious State: Proof of Concept!

Patients suffering from chronic disorders of consciousness (DOC) are characterized by profound unawareness and an impairment of large-scale cortical and subcortical connectivity. In this study, we applied an electrophysiological approach aimed at identifying the residual audiomotor connectivity patterns that are thought to be linked to awareness. We measured some markers of audiomotor integration (AMI) in 20 patients affected by DOC, before and after the application of a repetitive transcranial magnetic stimulation protocol (rTMS) delivered over the left primary motor area (M1), paired to a transauricular alternating current stimulation. Our protocol induced potentiating of the electrophysiological markers of AMI and M1 excitability, paired to a clinical improvement, in all of the patients with minimally conscious state (MCS) but in none of those suffering from unresponsive wakefulness syndrome (UWS). Our protocol could be a promising approach to potentiate the functional connectivity within large-scale audiomotor networks, thus allowing clinicians to differentiate patients affected by MCS from UWS, besides the clinical assessment.

Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation.

Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, and Hmax/Mmax ratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability.

Sexual dysfunction induced by intrathecal baclofen administration: is this the price to pay for severe spasticity management?

INTRODUCTION: Intrathecal administration of baclofen (ITB) is widely recognized as an effective treatment for severe spasticity of both spinal and supraspinal origin with fewer side effects. The lower drug dosages used for spinal intrathecal administration, acting directly on the receptor sites, result in greater therapeutic efficacy with less systemic toxicity than with oral preparations. AIM: This study aims to prospectively evaluate the effects of ITB on erectile function in male patients affected by severe spasticity. METHODS: Twenty adult male patients, with a 34.85 ± 10.27 mean age, affected by severe spasticity mainly due to spinal cord lesions (10 traumatic, three vascular, six degenerative, and one congenital in origin) and treated with ITB, were enrolled in the study. All participants underwent specific clinical scales to evaluate force, muscle tone, cognition and mood, and specific sexual questionnaires, including an accurate semi-structured interview. MAIN OUTCOME MEASURE: The International Index of Erectile Function (IIEF) was used to evaluate sexual function before and after pump implantation. RESULTS: A comparative analysis of the neurological scales and psychometric scores at T1 (baseline) and T2 (follow-up) showed statistically significant differences before and after pump implantation. In particular, we noted a significant decrease in the IIEF median scores (from 0.42 ± 0.07 to 0.14 ± 0.02, P value < 0.0001) and a correlation between ITB dosage and IIEF scores (ρ = -0.60; P < 0.05). CONCLUSIONS: This study supports previous findings on a possible negative effect of ITB on sexual function, with regard to erection. Patients who are considering ITB for treatment of severe spasticity should be informed about possible but reversible sexual side effects, especially at higher dosage. Future studies with larger samples should be fostered to confirm these findings for a better management of these, often young, patients.

Pudendal nerve stimulation: a potential tool for neurogenic bowel dysfunction!

Neurogenic bowel disease occurs after damage to the spinal cord, which affects the bowel's extrinsic innervation resulting in a lack of control of the colon with incontinence or constipation. To avoid more invasive procedures, sacral and pudendal nerve stimulation (PNS) have been recently considered as emerging treatment for patients with intractable constipation. In particular, PNS effects are thought to be secondary to interactions between the somatic and autonomic pathways within both the spinal cord and higher centers. Thus, PNS may be considered a potential tool in the treatment of neurogenic bowel dysfunction, even after a complete spinal cord damage.

Sexual dysfunction in male patients with multiple sclerosis: a need for counseling!

Sexuality and sexual health are significant factors in determining the quality of life (QoL). Multiple sclerosis (MS) is one of the most serious causes of neurological disability in young adults, therefore it can considerably reduce sexuality. Physical and cognitive symptoms of MS as well as mental and psycho-social issues can directly affect sexual life and body representation, causing reduced libido and self-esteem. Male patients with MS frequently develop sexual dysfunction (SD) as a result of their neurological impairment: in fact physical, psychological and neuropsychological changes indirectly interfere in the sexual response. Thus, MS physicians' greater concern on SD has led to the enhancement of diagnostic and therapeutic diagnoses on neurogenic SD. Given the increasing number of people coping with MS, a more effective focus on MS-related problems, including SD, is absolutely essential to provide the patients and their partner with the necessary information to achieve a better sexual health and consequently improve their QoL. This review aims to investigate the epidemiology and pathophysiology of SD in male patients, provide an insight into multidisciplinary diagnostic and therapeutic approaches, and focus on the need of proper counseling.

Estimation of the anaerobic threshold from heart rate variability in an incremental swimming test.

This study aimed to evaluate, in swimming, the agreement between the anaerobic threshold (AT) as determined from the analysis of blood lactate concentration ([La]) and from a new method based on the heart rate (HR) variability (HRV). Fourteen high-level swimmers completed an incremental 7 × 200-m front crawl test, during which the HRV was measured continuously and [La] was collected after each step. To individuate the AT, the trends of the high-frequency HRV spectral power (HFPOW) and of the fraction of HFPOW relative to the respiratory sinus arrhythmia (HFPOW-RSA) were analyzed. In all the subjects, an abrupt increase of both HFPOW and HFPOW-RSA was observed and associated with the AT. The AT parameters determined, respectively, from [La] and HFPOW-RSA were similar (p > 0.05) and highly correlated (HR: 182.0 ± 8.1 vs. 181.1 ± 8.2 b·min, r = 0.93, 95% limits of agreement [LoA]: -6.7 to 4.9 b·min; velocity: 1.47 ± 0.11 vs. 1.47 ± 0.11 m·s, r = 0.98, 95% LoA: -0.05 to 0.05 m·s). Instead, the AT HR and velocity obtained from HFPOW (179.2 ± 8.4 b·min; 1.45 ± 0.11 m·s) were correlated to the corresponding parameters determined from [La] (HR: r = 0.84; velocity: r = 0.94) but underestimated them slightly (95% LoA: -11.9 to 6.3 b·min and -0.11 to 0.05 m·s). These results demonstrate that the AT can be assessed from the HRV in swimming, providing an important testing tool for coaches. Furthermore, using the actual respiratory spectral component, rather than the total HF spectral power, allows us to obtain a more accurate estimate of AT parameters.

Multiplex and Multilayer Network EEG Analyses: A Novel Strategy in the Differential Diagnosis of Patients with Chronic Disorders of Consciousness.

The deterioration of specific topological network measures that quantify different features of whole-brain functional network organization can be considered a marker for awareness impairment. Such topological measures reflect the functional interactions of multiple brain structures, which support the integration of different sensorimotor information subtending awareness. However, conventional, single-layer, graph theoretical analysis (GTA)-based approaches cannot always reliably differentiate patients with Disorders of Consciousness (DoC). Using multiplex and multilayer network analyses of frequency-specific and area-specific networks, we investigated functional connectivity during resting-state EEG in 17 patients with Unresponsive Wakefulness Syndrome (UWS) and 15 with Minimally Conscious State (MCS). Multiplex and multilayer network metrics indicated the deterioration and heterogeneity of functional networks and, particularly, the frontal-parietal (FP), as the discriminant between patients with MCS and UWS. These data were not appreciable when considering each individual frequency-specific network. The distinctive properties of multiplex/multilayer network metrics and individual frequency-specific network metrics further suggest the value of integrating the networks as opposed to analyzing frequency-specific network metrics one at a time. The hub vulnerability of these regions was positively correlated with the behavioral responsiveness, thus strengthening the clinically-based differential diagnosis. Therefore, it may be beneficial to adopt both multiplex and multilayer network analyses when expanding the conventional GTA-based analyses in the differential diagnosis of patients with DoC. Multiplex analysis differentiated patients at a group level, whereas the multilayer analysis offered complementary information to differentiate patients with DoC individually. Although further studies are necessary to confirm our preliminary findings, these results contribute to the issue of DoC differential diagnosis and may help in guiding patient-tailored management.