Defining paediatric neurorehabilitation: You cannot improve what you cannot characterize.

Neurorehabilitation is the primary therapy for neurological impairment in children, yet its potential to achieve change remains incompletely understood and probably underestimated. Understanding 'the difference neurorehabilitation can make' against a background of neurological repair and recovery as well as ongoing neurological development is an enormous challenge, exacerbated to no small extent by the lack of a 'common currency' for the description and measurement of the neurorehabilitation services a child is receiving. This review addresses attempts to parse neurorehabilitation treatment content in theoretically and mechanistically valid ways that might help address this challenge.

Evolution of brain MRI lesions in paediatric myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and its relevance to disease course.

BACKGROUND: Lesion resolution is often observed in children with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and asymptomatic lesions are less commonly reported in MOGAD than in multiple sclerosis (MS). OBJECTIVE: We aimed to evaluate brain MRI changes over time in paediatric MOGAD. METHODS: Retrospective study in eight UK paediatric neuroscience centres. Acute brain MRI and available follow-up MRIs were reviewed. Predictors for lesion dynamic were evaluated using multivariable regression and Kaplan-Meier survival analyses were used to predict risk of relapse, disability and MOG-Ab status. RESULTS: 200 children were included (MOGAD 97; MS 103). At first MRI post attack, new symptomatic and asymptomatic lesions were seen more often in MS versus MOGAD (52/103 vs 28/97; p=0.002 and 37/103 vs 11/97; p<0.001); 83% of patients with MOGAD showed at least one lesion's resolution at first follow-up scan, and 23% had normal MRI. Only 1 patient with MS had single lesion resolution; none had normal MRI. Disappearing lesions in MOGAD were seen in 40% after the second attack, 21% after third attack and none after the fourth attack.New lesions at first follow-up scan were associated with increased likelihood of relapse (p=0.02) and persistent MOG-Ab serostatus (p=0.0016) compared with those with no new lesions. Plasma exchange was associated with increased likelihood of lesion resolution (p=0.01). Longer time from symptom onset to steroids was associated with increased likelihood of new lesions; 50% increase at 20 days (p=0.01). CONCLUSIONS: These striking differences in lesion dynamics between MOGAD and MS suggest greater potential to repair. Early treatment with steroids and plasma exchange is associated with reduced likelihood of new lesions.

It's easier to relearn gross motor skills than learn them for the first time after injury: Empirical evidence informing the age at injury debate.

The effect of age at injury on outcomes after brain injury has long been debated. Many have argued that the greater plasticity of the immature brain aids in its recovery from trauma, but others (notably Donald Hebb) have argued that early injury can impair the future ability of the brain to acquire new capabilities. This is difficult to assess empirically due to the presence of many age-dependent confounders. We performed Item Response Theory (IRT) analyses of two datasets of Gross Motor Function Measure (GMFM) observations, one in children with cerebral palsy (CP) and one in children with acquired brain injury (ABI) sustained at later ages. We used IRT to derive independent estimates of test item difficulty in the two populations. Additionally, where comparison between GMFM items and items in the Denver II Developmental Screening Test battery was possible we used the latter to obtain the ages at which these abilities are acquired in typically developing children. Item difficulty estimates for the two populations are highly correlated (adjusted r2=0.89, p<0.0005), but demonstrate significant bias with harder items (typically acquired at later ages) being more readily achieved by children with ABI compared to CP. These results support the Hebbian perspective that (when considering gross motor function) it is easier to maintain or recover previously established functions than to learn them for the first time in an injured brain. This argues for a more cautious outcome prognosis in injury at very young ages.

Early mobilisation and rehabilitation in the PICU: a UK survey.

OBJECTIVE: To understand the context and professional perspectives of delivering early rehabilitation and mobilisation (ERM) within UK paediatric intensive care units (PICUs). DESIGN: A web-based survey administered from May 2019 to August 2019. SETTING: UK PICUs. PARTICIPANTS: A total of 124 staff from 26 PICUs participated, including 22 (18%) doctors, 34 (27%) nurses, 28 (23%) physiotherapists, 19 (15%) occupational therapists and 21 (17%) were other professionals. RESULTS: Key components of participants' definitions of ERM included tailored, multidisciplinary rehabilitation packages focused on promoting recovery. Multidisciplinary involvement in initiating ERM was commonly reported. Over half of respondents favoured delivering ERM after achieving physiological stability (n=69, 56%). All age groups were considered for ERM by relevant health professionals. However, responses differed concerning the timing of initiation. Interventions considered for ERM were more likely to be delivered to patients when PICU length of stay exceeded 28 days and among patients with acquired brain injury or severe developmental delay. The most commonly identified barriers were physiological instability (81%), limited staffing (79%), sedation requirement (73%), insufficient resources and equipment (69%), lack of recognition of patient readiness (67%), patient suitability (63%), inadequate training (61%) and inadequate funding (60%). Respondents ranked reduction in PICU length of stay (74%) and improvement in psychological outcomes (73%) as the most important benefits of ERM. CONCLUSION: ERM is gaining familiarity and endorsement in UK PICUs, but significant barriers to implementation due to limited resources and variation in content and delivery of ERM persist. A standardised protocol that sets out defined ERM interventions, along with implementation support to tackle modifiable barriers, is required to ensure the delivery of high-quality ERM.

Rehabilitation after paediatric acquired brain injury: Longitudinal change in content and effect on recovery.

AIM: To describe cross-sectional and longitudinal variation in neurorehabilitation content provided to young people after severe paediatric acquired brain injury (pABI) and to relate this to observed functional recovery. METHOD: This was an observational study in a cohort of admissions to a residential neurorehabilitation centre. Recovery was described using the Pediatric Evaluation of Disability - Computer Adaptive Testing instrument. Rehabilitation content was measured using the recently described Paediatric Rehabilitation Ingredients Measure (PRISM) and examined using multidimensional scaling. RESULTS: The PRISM reveals wide variation in rehabilitation content between and during admissions primarily reflecting proportions of child active practice, child emotional support, and other management of body structure and function. Rehabilitation content is predicted by pre-admission recovery, suggesting therapist decisions in designing rehabilitation programmes are shaped by their initial expectations of recovery. However, significant correlations persist between plausibly-related aspects of delivered therapy and observed post-admission recovery after adjusting for such effects. INTERPRETATION: The PRISM approach to the analysis of rehabilitation content shows promise in that it demonstrates significant correlations between plausibly-related aspects of delivered therapy and observed recovery that have been hard to identify with other approaches. However, rigorous, causal analysis will be required to truly understand the contributions of rehabilitation to recovery after pABI. WHAT THIS PAPER ADDS: Rehabilitation content varies widely between, and during, admissions for neurorehabilitation after paediatric acquire brain injury. Strong correlations are seen between plausibly-related aspects of rehabilitation content and observed recovery, though careful interpretation is necessary.

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease.

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.

Rasch Properties of the Cognitive and Linguistic Scale and Optimization for Outcome Trajectory Modeling in Pediatric Acquired Brain Injury.

OBJECTIVES: To (1) determine if items on the Cognitive and Linguistic Scale (CALS) follow a Rasch distribution and (2) explore the relationship between Rasch-derived Cognitive Ability Estimates and outcome trajectory parameters using a nonlinear mixed-effects modeling approach. DESIGN: Retrospective study. SETTING: Pediatric inpatient rehabilitation hospital. PARTICIPANTS: A total of 252 children (N=252) aged of 2-21 years (median, 11.8 [IQR, 6.4-15.9] years) consecutively admitted to an inpatient rehabilitation brain injury unit (2008-2014) for a first inpatient admission after acquired brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Rasch-derived Cognitive Ability Estimates from the CALS and associated outcome trajectory parameters. RESULTS: The CALS demonstrates adequate interval-scale properties with removal of scores from the arousal and responsivity items. Rasch-derived Cognitive Ability Estimates were associated with age (ß=0.025, P<.001) such that older age was associated with a faster rate of recovery and more complete ultimate recovery. Slower recovery initiation was associated with a less complete overall cognitive recovery (Spearman ρ=-0.31; P<.001). CONCLUSIONS: The Cognitive Ability Estimates derived from the CALS and associated outcome parameters (eg, rate of recovery) may serve as an ideal outcome measure for clinical trials evaluating interventions for acquired brain injury in a pediatric rehabilitation setting.

Demonstration of functional rehabilitation treatment effects in children and young people after severe acquired brain injury.

PURPOSE: To examine relationships between functional outcomes after pediatric acquired brain injury (ABI) and measures of rehabilitation dose. METHODS: An observational study of children receiving residential neurorehabilitation after severe ABI. RESULTS: Basic total rehabilitation dose shows a paradoxical inverse relationship to global outcome. This is due to confounding by both initial injury severity and length of stay, and variation in treatment content for a given total rehabilitation dose. Content-aware rehabilitation dose measures show robust positive correlations between fractions of rehabilitation treatment received and plausibly related aspects of outcome: specifically, between rates of recovery of gross motor function and the fraction of rehabilitation effort directed to active practice and motor learning. This relationship was robust to adjustment for therapists' expectations of recovery. CONCLUSION: Content-aware measures of rehabilitation dose are robustly causally related to pertinent aspects of outcome. These findings are step toward a goal of comparative effectiveness research in pediatric neurorehabilitation.

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

OBJECTIVES: To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS). METHODS: In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated. RESULTS: Of 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables (p < 0.001) vs 1.6 to 0.3 on newer DMTs (p = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs (p = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank p < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64-89.87, p = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08-7.13, p = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment. CONCLUSION: Newer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS.

Intrathecal baclofen pumps in the management of hypertonia in childhood: a UK and Ireland wide survey.

BACKGROUND: Intrathecal baclofen (ITB) is a useful treatment for hypertonia where non-invasive treatments have been ineffective or poorly tolerated. There is an absence of national guidance on selection criteria and a lack of literature regarding patient characteristics and treatment details for children and young people (CYP) receiving ITB therapy in the UK and Ireland. We aimed to gather patient and treatment characteristics for CYP receiving ITB in the UK and Ireland. METHODS: An electronic survey was sent to all paediatric ITB centres in the UK and Ireland. Anonymised data were returned between December 2019 and April 2020. CYP >16 years and those awaiting ITB pump removal were excluded from the dataset. RESULTS: 176 CYP were identified as receiving ITB therapy across the UK and Ireland. The majority of CYP with ITB pumps were non-ambulant (93%) with a diagnosis of cerebral palsy (79%). Median age of ITB insertion was 9 years; median current age was 14 years. 79% of CYP had significant spasticity, 55% had significant dystonia. The most commonly used ITB dosing modes were continuous (73%) and flexible (23%). CONCLUSIONS: ITB pumps were most frequently used for non-ambulant CYP with cerebral palsy and existence of spasticity and/or dystonia in the UK and Ireland. Most CYP were receiving a continuous dose of ITB. There is significant variation in the number of paediatric ITB pumps across UK and Ireland. There is a need for development of nationally accepted paediatric referral criteria and clinical standards for ITB use.

Imaging Predictors of Neurologic Outcome After Pediatric Arterial Ischemic Stroke.

BACKGROUND AND PURPOSE: To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients. METHODS: We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome. RESULTS: Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome. CONCLUSIONS: In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients.

OBJECTIVE: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). METHODS: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model). RESULTS: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19+B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses. CONCLUSION: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.

Network reorganisation following anterior temporal lobe resection and relation with post-surgery seizure relapse: A longitudinal study.

OBJECTIVE: To characterise temporal lobe epilepsy (TLE) surgery-induced changes in brain network properties, as measured using diffusion weighted MRI, and investigate their association with postoperative seizure-freedom. METHODS: For 48 patients who underwent anterior temporal lobe resection, diffusion weighted MRI was acquired pre-operatively, 3-4 months post-operatively (N = 48), and again 12 months post-operatively (N = 13). Data for 17 controls were also acquired over the same period. After registering all subjects to a common space, we performed two complementary analyses of the subjects' quantitative anisotropy (QA) maps. 1) A connectometry analysis which is sensitive to changes in subsections of fasciculi. 2) A graph theory approach which integrates connectivity information across the wider brain network. RESULTS: We found significant postoperative alterations in QA in patients relative to controls measured over the same period. Reductions were primarily located in the uncinate fasciculus and inferior fronto-occipital fasciculus ipsilaterally for all patients. Larger reductions were associated with postoperative seizure-freedom in left TLE. Increased QA was mainly located in corona radiata and corticopontine tracts. Graph theoretic analysis revealed widespread increases in nodal betweenness centrality, which were not associated with patient outcomes. CONCLUSION: Substantial alterations in QA occur in the months after epilepsy surgery, suggesting Wallerian degeneration and strengthening of specific white matter tracts. Greater reductions in QA were related to postoperative seizure freedom in left TLE.

Investigating Brain Network Changes and Their Association With Cognitive Recovery After Traumatic Brain Injury: A Longitudinal Analysis.

Traumatic brain injury (TBI) can result in acute cognitive deficits and diffuse axonal injury reflected in white matter brain network alterations, which may, or may not, later recover. Our objective is to first characterize the ways in which brain networks change after TBI and, second, investigate if those changes are associated with recovery of cognitive deficits. We aim to make initial progress in discerning the relationships between brain network changes, and their (dys)functional correlates. We analyze longitudinally acquired MRI from 23 TBI patients (two time points: 6 days, 12 months post-injury) and cross-sectional data from 28 controls to construct white matter brain networks. Cognitive assessment was also performed. Graph theory and regression analysis were applied to identify changed brain network metrics after injury that are associated with subsequent improvements in cognitive function. Sixteen brain network metrics were found to be discriminative of different post-injury phases. Eleven of those explain 90% (adjusted R 2) of the variability observed in cognitive recovery following TBI. Brain network metrics that had a high contribution to the explained variance were found in frontal and temporal cortex, additional to the anterior cingulate cortex. Our preliminary study suggests that network reorganization may be related to recovery of impaired cognitive function in the first year after a TBI.

Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy.

Personalized medicine requires that treatments adapt to not only the patient but also changing factors within each individual. Although epilepsy is a dynamic disorder characterized by pathological fluctuations in brain state, surprisingly little is known about whether and how seizures vary in the same patient. We quantitatively compared within-patient seizure network evolutions using intracranial electroencephalographic (iEEG) recordings of over 500 seizures from 31 patients with focal epilepsy (mean 16.5 seizures per patient). In all patients, we found variability in seizure paths through the space of possible network dynamics. Seizures with similar pathways tended to occur closer together in time, and a simple model suggested that seizure pathways change on circadian and/or slower timescales in the majority of patients. These temporal relationships occurred independent of whether the patient underwent antiepileptic medication reduction. Our results suggest that various modulatory processes, operating at different timescales, shape within-patient seizure evolutions, leading to variable seizure pathways that may require tailored treatment approaches.

Complement factor I deficiency: A potentially treatable cause of fulminant cerebral inflammation.

OBJECTIVE: To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation. METHODS: Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature. RESULTS: We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function. CONCLUSIONS: Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role.

Early deviation from normal structural connectivity: A novel intrinsic severity score for mild TBI.

OBJECTIVE: Studies of outcome after traumatic brain injury (TBI) are hampered by the lack of robust injury severity measures that can accommodate spatial-anatomical and mechanistic heterogeneity. In this study we introduce a Mahalanobis distance measure (M) as an intrinsic injury severity measure that combines in a single score the many ways a given injured brain's connectivity can vary from that of healthy controls. Our objective is to test the hypotheses that M is superior to univariate measures in (1) discriminating patients and controls and (2) correlating with cognitive assessment. METHODS: Sixty-five participants (34 with mild TBI, 31 controls) underwent diffusion tensor MRI and extensive neuropsychological testing. Structural connectivity was inferred for all participants for 22 major white matter connections. Twenty-two univariate measures (1 per connection) and 1 multivariate measure (M), capturing and summarizing all connectivity change in a single score, were computed. RESULTS: Our multivariate measure (M) was able to better discriminate between patients and controls (area under the curve 0.81) than any individual univariate measure. M significantly correlated with cognitive outcome (Spearman ρ = 0.31; p < 0.05). No univariate measure showed significant correlation after correction for multiple comparisons. CONCLUSIONS: Heterogeneity in the severity and distribution of injuries after TBI has traditionally complicated the understanding of outcomes after TBI. Our approach provides a single, continuous variable that can fully capture individual heterogeneity. M's ability to distinguish even mildly injured patients from controls and its correlation with cognitive assessment suggest utility as an imaging-based marker of intrinsic injury severity.

Synaptic Scaling Improves the Stability of Neural Mass Models Capable of Simulating Brain Plasticity.

Neural mass models offer a way of studying the development and behavior of large-scale brain networks through computer simulations. Such simulations are currently mainly research tools, but as they improve, they could soon play a role in understanding, predicting, and optimizing patient treatments, particularly in relation to effects and outcomes of brain injury. To bring us closer to this goal, we took an existing state-of-the-art neural mass model capable of simulating connection growth through simulated plasticity processes. We identified and addressed some of the model's limitations by implementing biologically plausible mechanisms. The main limitation of the original model was its instability, which we addressed by incorporating a representation of the mechanism of synaptic scaling and examining the effects of optimizing parameters in the model. We show that the updated model retains all the merits of the original model, while being more stable and capable of generating networks that are in several aspects similar to those found in real brains.