Implications of the consciousness state on decannulation in patients with a prolonged Disorder of Consciousness.

OBJECTIVE: to prospectively investigate the evolution of the consciousness state and the cannula-weaning progression in patients with prolonged Disorders of Consciousness (pDoC). DESIGN: non-concurrent cohort study SETTING: rehabilitation unit of the Fondazione Don Gnocchi, Florence PARTICIPANTS: adult patients, with a pDoC following a sABI admitted between 06.2020 and 09.2022 INTERVENTIONS: not applicable MAIN OUTCOME MEASURES: consciousness state was assessed by repeated Coma Recovery Scale-Revised (CRS-R) administration at admission, and weekly afterwards. The dates of the first improvement of consciousness state and the achievement of decannulation were recorded. Decannulation followed an internal protocol of multi-professional rehabilitation. RESULTS: 144 patients were included: age: 69 years, 64 (44.4%) with hemorrhagic etiology, time post-onset: 40 days, CRS-R at admission: 9, median length of stay: 90 days. Seventy-three (50.7%) patients were decannulated. They showed a significantly higher CRS-R (p<0.001) and states of consciousness (p<0.001) at admission, at the first improvement of the consciousness state (p=0.003), and discharge (p<0.001), a lower severity in the Cumulative Illness Rating Scale at admission (p=0.01), and a lower rate of pulmonary infections with recurrence (p=0.021), compared to non-decannulated patients. Almost all decannulated patients (97.3%) improved their consciousness before decannulation. Consciousness states at decannulation were: Unresponsive wakefulness Syndrome: 0 (0%), Minimally conscious state (MCS) minus: 4 (5.5%), MCS plus: 7 (9.6%), Emergence from MCS: 62 (84.9%). Kaplan-Meier analysis showed a significant divergence between the curves with a higher probability of decannulation in patients who improved consciousness (p<0.001). CONCLUSION: This study showed that the presence of signs of consciousness, even subtle, is a necessary condition for decannulation, suggesting that consciousness may influence some of the components implied in the decannulation process.

Low-density EEG-based Functional Connectivity Discriminates Minimally Conscious State plus from minus.

OBJECTIVE: Within the continuum of consciousness, patients in a Minimally Conscious State (MCS) may exhibit high-level behavioral responses (MCS+) or may not (MCS-). The evaluation of residual consciousness and related classification is crucial to propose tailored rehabilitation and pharmacological treatments, considering the inherent differences among groups in diagnosis and prognosis. Currently, differential diagnosis relies on behavioral assessments posing a relevant risk of misdiagnosis. In this context, EEG offers a non-invasive approach to model the brain as a complex network. The search for discriminating features could reveal whether behavioral responses in post-comatose patients have a defined physiological background. Additionally, it is essential to determine whether the standard behavioral assessment for quantifying responsiveness holds physiological significance. METHODS: In this prospective observational study, we investigated whether low-density EEG-based graph metrics could discriminate MCS+/- patients by enrolling 57 MCS patients (MCS-: 30; males: 28). At admission to intensive rehabilitation, 30 min resting-state closed-eyes EEG recordings were performed together with consciousness diagnosis following international guidelines. After EEG preprocessing, graphs' metrics were estimated using different connectivity measures, at multiple connection densities and frequency bands (α,θ,δ). Metrics were also provided to cross-validated Machine Learning (ML) models with outcome MCS+/-. RESULTS: A lower level of brain activity integration was found in the MCS- group in the α band. Instead, in the δ band MCS- group presented an higher level of clustering (weighted clustering coefficient) respect to MCS+. The best-performing solution in discriminating MCS+/- through the use of ML was an Elastic-Net regularized logistic regression with a cross-validation accuracy of 79% (sensitivity and specificity of 74% and 85% respectively). CONCLUSION: Despite tackling the MCS+/- differential diagnosis is highly challenging, a daily-routine low-density EEG might allow to differentiate across these differently responsive brain networks. SIGNIFICANCE: Graph-theoretical features are shown to discriminate between these two neurophysiologically similar conditions, and may thus support the clinical diagnosis.

Brain microstate spatio-temporal dynamics as a candidate endotype of consciousness.

Consciousness can be defined as a phenomenological experience continuously evolving. Current research showed how conscious mental activity can be subdivided into a series of atomic brain states converging to a discrete spatiotemporal pattern of global neuronal firing. Using the high temporal resolution of EEG recordings in patients with a severe Acquired Brain Injury (sABI) admitted to an Intensive Rehabilitation Unit (IRU), we detected a novel endotype of consciousness from the spatiotemporal brain dynamics identified via microstate analysis. Also, we investigated whether microstate features were associated with common neurophysiological alterations. Finally, the prognostic information comprised in such descriptors was analysed in a sub-cohort of patients with prolonged Disorder of Consciousness (pDoC). Occurrence of frontally-oriented microstates (C microstate), likelihood of maintaining such brain state or transitioning to the C topography and complexity were found to be indicators of consciousness presence and levels. Features of left-right asymmetric microstates and transitions toward them were found to be negatively correlated with antero-posterior brain reorganization and EEG symmetry. Substantial differences in microstates' sequence complexity and presence of C topography were found between groups of patients with alpha dominant background, cortical reactivity and antero-posterior gradient. Also, transitioning from left-right to antero-posterior microstates was found to be an independent predictor of consciousness recovery, stronger than consciousness levels at IRU's admission. In conclusions, global brain dynamics measured with scale-free estimators can be considered an indicator of consciousness presence and a candidate marker of short-term recovery in patients with a pDoC.

Relationship between Nutritional Risk, Clinical and Demographic Characteristics, and Pressure Ulcers in Patients with Severe Acquired Brain Injuries Attending a Rehabilitative Program.

Preliminary evidence in the literature suggests a high prevalence of malnutrition (undernutrition) in patients with severe acquired brain injuries (sABI), with an expected negative impact on clinical outcomes and pressure ulcers (PUs) in particular. In a retrospective cohort study on patients discharged from intensive care units (ICU) and admitted to an intensive rehabilitation unit (IRU), the risk of malnutrition was systematically assessed, in addition to standard clinical procedures (including PUs evaluation), using two different tools: the Malnutrition Universal Screening Tool (MUST) and the Controlling Nutritional Status (CONUT) tool. Eighty-eight patients were included in the analysis. A high proportion (79.5%) of patients with sABI suffered from PUs, being older and more frequently men, with a longer ICU stay between the event and admission to IRU, and a greater MUST score. At discharge, when compared to patients whose PUs had healed, those with persisting PUs were more often men and had the worst cognitive performance at admission. As for nutritional risk, the baseline CONUT score was identified as an independent negative predictor of PUs at discharge by the logistic regression model. In conclusion, the assessment of nutritional risk using simple standard tools may be useful in the clinical evaluation of sABI patients with PUs.

Neural coding of autonomic functions in different states of consciousness.

Detecting signs of residual neural activity in patients with altered states of consciousness is a crucial issue for the customization of neurorehabilitation treatments and clinical decision-making. With this large observational prospective study, we propose an innovative approach to detect residual signs of consciousness via the assessment of the amount of autonomic information coded within the brain. The latter was estimated by computing the mutual information (MI) between preprocessed EEG and ECG signals, to be then compared across consciousness groups, together with the absolute power and an international qualitative labeling. One-hundred seventy-four patients (73 females, 42%) were included in the study (median age of 65 years [IQR = 20], MCS +: 29, MCS -: 23, UWS: 29). Electroencephalography (EEG) information content was found to be mostly related to the coding of electrocardiography (ECG) activity, i.e., with higher MI (p < 0.05), in Unresponsive Wakefulness Syndrome and Minimally Consciousness State minus (MCS -). EEG-ECG MI, besides clearly discriminating patients in an MCS - and +, significantly differed between lesioned areas (sides) in a subgroup of unilateral hemorrhagic patients. Crucially, such an accessible and non-invasive measure of residual consciousness signs was robust across electrodes and patient groups. Consequently, exiting from a strictly neuro-centric consciousness detection approach may be the key to provide complementary insights for the objective assessment of patients' consciousness levels and for the patient-specific planning of rehabilitative interventions.

EEG fractal dimensions predict high-level behavioral responses in minimally conscious patients.

Objective.Brain-injured patients may enter a state of minimal or inconsistent awareness termed minimally conscious state (MCS). Such patient may (MCS+) or may not (MCS-) exhibit high-level behavioral responses, and the two groups retain two inherently different rehabilitative paths and expected outcomes. We hypothesized that brain complexity may be treated as a proxy of high-level cognition and thus could be used as a neural correlate of consciousness.Approach.In this prospective observational study, 68 MCS patients (MCS-: 30; women: 31) were included (median [IQR] age 69 [20]; time post-onset 83 [28]). At admission to intensive rehabilitation, 30 min resting-state closed-eyes recordings were performed together with consciousness diagnosis following international guidelines. The width of the multifractal singularity spectrum (MSS) was computed for each channel time series and entered nested cross-validated interpretable machine learning models targeting the differential diagnosis of MCS±.Main results.Frontal MSS widths (p< 0.05), as well as the ones deriving from the left centro-temporal network (C3:p= 0.018, T3:p= 0.017; T5:p= 0.003) were found to be significantly higher in the MCS+ cohort. The best performing solution was found to be the K-nearest neighbor model with an aggregated test accuracy of 75.5% (median [IQR] AuROC for 100 executions 0.88 [0.02]). Coherently, the electrodes with highest Shapley values were found to be Fz and Cz, with four out the first five ranked features belonging to the fronto-central network.Significance.MCS+ is a frequent condition associated with a notably better prognosis than the MCS-. High fractality in the left centro-temporal network results coherent with neurological networks involved in the language function, proper of MCS+ patients. Using EEG-based interpretable algorithm to complement differential diagnosis of consciousness may improve rehabilitation pathways and communications with caregivers.

Cognitive reserve index and long-term disability in patients with severe traumatic brain injury discharged from the intensive rehabilitation unit.

Objectives: The "cognitive reserve" (CR) theory posits that higher premorbid cognitive activities can mitigate the effects of brain damage. This study aimed to investigate the association between CR and long-term functional autonomy in patients surviving a severe traumatic brain injury (sTBI). Setting: Data were collected from the database of inpatients with severe acquired brain injury in a rehabilitation unit admitted from August 2012 to May 2020. Participants: Patients that had incurred an sTBI, aged 18+ years, completing the phone Glasgow Outcome Scale-Expanded at follow-up (pGOS-E) in absence of previous brain trauma or neurological disease, or cognitive disorders were included. Patients with severe brain injury from non-traumatic etiologies were not included in the study. Design: In this longitudinal study, all patients underwent a multidimensional assessment including the cognitive reserve index questionnaire (CRIq), the coma recovery scale-revised, the level of cognitive functioning, the Disability Rating Scale (DRS), and the Galveston Orientation and Amnesia Test at admission. At discharge, functional scales were administered again together with the Glasgow Outcome Scale. The pGOS-E was assessed at follow-up. Main measures: pGOS-E. Results: A total of 106 patients/caregivers underwent the pGOS-E after 5.8 [3.6] years from the event. Among them, 46 (43.4%) died after discharge, and 60 patients [men: 48 (80%); median age: 54 years; median time post-onset: 37 days; median education level: 10 years; median CRIq total score: 91] were included in the analysis exploring the association between pGOS-E and demographic data, cognitive reserve surrogates, and clinical variables at admission and discharge from the rehabilitation unit. A younger age (B = -0.035, p = 0.004) and a lower DRS category at discharge (B = -0.392, p = 0.029) were significantly related to a higher long-term functional autonomy in the multivariate analysis. Conclusion: Long-term functional autonomy was not influenced by CR as assessed through the educational level and the CRIq.

The Impact of Cerebral Amyloid Angiopathy on Functional Outcome of Patients Affected by Spontaneous Intracerebral Hemorrhage Discharged from Intensive Inpatient Rehabilitation: A Cohort Study.

Background: Sporadic CAA is recognized as a major cause of sICH and sABI. Even if intensive rehabilitation is recommended to maximize functional recovery after sICH, no data are available on whether CAA may affect rehabilitation outcomes. In this observational prospective study, to explore the impact of CAA on rehabilitation results, functional outcomes after intensive rehabilitation have been compared between patients affected by sICH with and without a diagnosis of CAA. Methods: All adults affected by sABI due to sICH and admitted to the IRU of IRCCS-Don-Gnocchi-Foundation were consecutively enrolled for 12 months. Demographic and clinical data were recorded upon admission and discharge. Results: Among 102 sICH patients (age: 66 (IQR = 16), 53% female), 13% were diagnosed as probable/possible-CAA. TPO and functional assessment were comparable upon admission, but CAA patients were significantly older (p = 0.001). After a comparable LOS, CAA patients presented higher care burden (ERBI: p = 0.025), poorer functional recovery (FIM: p = 0.02) and lower levels of global independence (GOSE > 4: p = 0.03). In multivariate analysis, CAA was significantly correlated with a lower FIM (p = 0.019) and a lower likelihood of reaching GOS-E > 4, (p = 0.041) at discharge, independently from age. Conclusions: CAA seems to be independently associated with poorer rehabilitation outcomes, suggesting the importance of improving knowledge about CAA to better predict rehabilitation outcomes.

Clinical, Neurophysiological, and Genetic Predictors of Recovery in Patients With Severe Acquired Brain Injuries (PRABI): A Study Protocol for a Longitudinal Observational Study.

Background: Due to continuous advances in intensive care technology and neurosurgical procedures, the number of survivors from severe acquired brain injuries (sABIs) has increased considerably, raising several delicate ethical issues. The heterogeneity and complex nature of the neurological damage of sABIs make the detection of predictive factors of a better outcome very challenging. Identifying the profile of those patients with better prospects of recovery will facilitate clinical and family choices and allow to personalize rehabilitation. This paper describes a multicenter prospective study protocol, to investigate outcomes and baseline predictors or biomarkers of functional recovery, on a large Italian cohort of sABI survivors undergoing postacute rehabilitation. Methods: All patients with a diagnosis of sABI admitted to four intensive rehabilitation units (IRUs) within 4 months from the acute event, aged above 18, and providing informed consent, will be enrolled. No additional exclusion criteria will be considered. Measures will be taken at admission (T0), at three (T1) and 6 months (T2) from T0, and follow-up at 12 and 24 months from onset, including clinical and functional data, neurophysiological results, and analysis of neurogenetic biomarkers. Statistics: Advanced machine learning algorithms will be cross validated to achieve data-driven prediction models. To assess the clinical applicability of the solutions obtained, the prediction of recovery milestones will be compared to the evaluation of a multiprofessional, interdisciplinary rehabilitation team, performed within 2 weeks from admission. Discussion: Identifying the profiles of patients with a favorable prognosis would allow customization of rehabilitation strategies, to provide accurate information to the caregivers and, possibly, to optimize rehabilitation outcomes. Conclusions: The application and validation of machine learning algorithms on a comprehensive pool of clinical, genetic, and neurophysiological data can pave the way toward the implementation of tools in support of the clinical prognosis for the rehabilitation pathways of patients after sABI.

Critical Illness Polyneuropathy and Myopathy and Clinical Detection of the Recovery of Consciousness in Severe Acquired Brain Injury Patients with Disorders of Consciousness after Rehabilitation.

BACKGROUND: Disorders of consciousness (DoCs) include unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). Critical illness polyneuropathy and myopathy (CIPNM) is frequent in severe acquired brain injuries and impacts functional outcomes at discharge from the intensive rehabilitation unit (IRU). We investigated the prevalence of CIPNM in DoCs and its relationship with the consciousness assessment. METHODS: Patients with DoCs were retrospectively selected from the database including patients admitted to the IRU of the IRCCS Don Gnocchi Foundation, Florence, from August 2012 to May 2020. Electroneurography/electromyography was performed at admission. Consciousness was assessed using the Coma Recovery Scale-Revised (CRS-R) at admission and discharge. Patients transitioning from a lower consciousness state to a higher one were classified as improved responsiveness (IR). RESULTS: A total of 177 patients were included (UWS: 81 (45.8%); MCS: 96 (54.2%); 78 (44.1%) women; 67 years (IQR: 20). At admission, 108 (61.0%) patients had CIPNM. At discharge, 117 (66.1%) patients presented an IR. In the multivariate analysis, CRS-R at admission (p = 0.006; OR: 1.462) and CIPNM (p = 0.039; OR: -1.252) remained significantly associated with IR only for the UWS patients. CONCLUSIONS: CIPNM is frequent in DoCs and needs to be considered during the clinical consciousness assessment, especially in patients with UWS.

Multicenter prospective study on predictors of short-term outcome in disorders of consciousness.

OBJECTIVE: This international multicenter, prospective, observational study aimed at identifying predictors of short-term clinical outcome in patients with prolonged disorders of consciousness (DoC) due to acquired severe brain injury. METHODS: Patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in minimally conscious state (MCS) were enrolled within 3 months from their brain injury in 12 specialized medical institutions. Demographic, anamnestic, clinical, and neurophysiologic data were collected at study entry. Patients were then followed up for assessing the primary outcome, that is, clinical diagnosis according to standardized criteria at 6 months postinjury. RESULTS: We enrolled 147 patients (44 women; mean age 49.4 [95% confidence interval 46.1-52.6] years; VS/UWS 71, MCS 76; traumatic 55, vascular 56, anoxic 36; mean time postinjury 59.6 [55.4-63.6] days). The 6-month follow-up was complete for 143 patients (VS/UWS 70; MCS 73). With respect to study entry, the clinical diagnosis improved in 72 patients (VS/UWS 27; MCS 45). Younger age, shorter time postinjury, higher Coma Recovery Scale-Revised total score, and presence of EEG reactivity to eye opening at study entry predicted better outcome, whereas etiology, clinical diagnosis, Disability Rating Scale score, EEG background activity, acoustic reactivity, and P300 on event-related potentials were not associated with outcome. CONCLUSIONS: Multimodal assessment could identify patients with higher likelihood of clinical improvement in order to help clinicians, families, and funding sources with various aspects of decision-making. This multicenter, international study aims to stimulate further research that drives international consensus regarding standardization of prognostic procedures for patients with DoC.

Prognostic value of post-acute EEG in severe disorders of consciousness, using American Clinical Neurophysiology Society terminology.

OBJECTIVE: To evaluate whether electroencephalographic (EEG) features recorded during the post-acute stage in patients with severe disorders of consciousness (DoC) after acute brain injury (ABI), contribute to neurological outcome prediction of these patients at discharge from the intensive rehabilitation unit (IRU). METHODS: We retrospectively evaluated all patients consecutively admitted to the IRU from August 2012 to December 2016. Inclusion criteria were: 1) age >18years, 2) patients with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), and 3) EEG and a coma recovery scale-revised (CRS-R) score available within the first week after admission. Clinical evaluation was performed using the Italian version of the CRS-R score. EEGs were classified according to American Clinical Neurophysiology Society (ACNS) terminology. Clinical state at final discharge was evaluated using the CRS-R score. RESULTS: In total, 102 patients were included in the analysis. After a mean of five months of IRU stay, among the 61 UWS subjects, 19 transitioned to MCS and 11 recovered to exit-MCS (E-MCS); twenty-three of the 41 subjects in MCS progressed to E-MCS. Using logistic regression, consciousness level (UWS/MCS-OR=13.4), CRS-R score at admission (OR=1.33) and use of activating drugs (OR=4.7) were significant predictors of clinical improvement. Multivariable analysis showed that specific EEG patterns were independent predictors of improved consciousness at discharge in UWS patients. DISCUSSION: EEG performed within the first week after IRU admission, classified according to ACNS-terminology in patients with UWS at admission, can provide useful prognostic contribution.

Score on Coma Recovery Scale-Revised at admission predicts outcome at discharge in intensive rehabilitation after severe brain injury.

OBJECTIVE: To assess the prognostic utility of the Coma Recovery Scale-Revised (CRS-R) in rehabilitation of patients surviving from severe brain injury. METHODS: In this prospective cohort study, all patients consecutively admitted to an Italian Intensive Rehabilitation Unit, with a diagnosis of unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS) due to acquired brain injury, underwent clinical evaluations using the Italian version of the CRS-R. At discharge, patients transitioning from UWS to MCS or emergence from MCS (E-MCS) and from MCS to E-MCS were classified as improved responsiveness (IR). Score on the Glasgow Outcome Scale (GOS) at discharge was recorded. RESULTS: In total, 137 (66 UWS, 71 MCS) subjects were enrolled. After a mean hospital stay of 5.3 ± 2.9 months, 81 (59.1%) patients achieved an IR. In the multivariable analysis, IR was associated with higher CRS-R score at admission (p = 0.002) and younger age at injury (p = 0.010). Moreover, higher GOS scores at discharge were related to younger age at injury (p = 0.018), shorter time post-onset (p = 0.003) and higher CRS-R score at admission (p < 0.001). CONCLUSIONS: Higher CRS-R scores at admission in intensive rehabilitation unit can help differentiate patients with better outcome at discharge, providing information for rehabilitation planning and communication with patients and their caregivers.

Improvement on the Coma Recovery Scale-Revised During the First Four Weeks of Hospital Stay Predicts Outcome at Discharge in Intensive Rehabilitation After Severe Brain Injury.

OBJECTIVES: To evaluate the prognostic utility of serial assessment on the Coma Recovery Scale-Revised (CRS-R) during the first 4 weeks of intensive rehabilitation in patients surviving a severe brain injury. DESIGN: Prospective cohort study. SETTING: An intensive rehabilitation unit. PARTICIPANTS: Patients (N=110) consecutively admitted to the intensive rehabilitation unit. Inclusion criteria were (1) a diagnosis of unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS) caused by an acquired brain injury, and (2) aged >18 years. INTERVENTIONS: All patients underwent clinical evaluations using the Italian version of the CRS-R during the first month of hospital stay. MAIN OUTCOME MEASURES: Behavioral classification on the CRS-R and the score on the Glasgow Outcome Scale (GOS) at final discharge. Patients transitioning from UWS to MCS or emergence from MCS (E-MCS), and from MCS to E-MCS were classified as patients with improved responsiveness (IR). RESULTS: After a mean ± SD hospital stay of 5.3±2.7 months, 59 of 110 patients (53.6%) achieved IR. In the multivariable analysis, a higher CRS-R score change at week 4 (odds ratio =1.99; 95% confidence interval [CI], 1.49-2.66; P<.001) was the only significant predictor of IR at discharge. Fifty-three patients (48.2%) were classified as severely impaired at discharge (GOS=3). In the multivariable analysis, higher GOS scores were related to a higher CRS-R score at admission (B=.051; 95% CI, .027-.074; P<.001), a higher CRS-R score change at week 4 (B=.087; 95% CI, .064-.110; P<.001), and an absence of severe infections (B=-.477; 95% CI, -.778 to -.176; P=.002). CONCLUSIONS: An improvement on the total CRS-R score and on different subscales across the first 4 weeks of inpatient rehabilitation discriminates patients who will have a better outcome at discharge, providing information for rehabilitation planning and for communication with patients and their caregivers.

Fetal striatal grafting slows motor and cognitive decline of Huntington's disease.

OBJECTIVE: To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntington's disease (HD). METHODS: We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. RESULTS: Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post-transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post-transplantation [(18)F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [(123)I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. CONCLUSIONS: Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival.

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation.

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.