Faculty Bibliography

OBJECTIVE:Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. METHODS:We searched PubMed (January 2007-February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS:OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability. CONCLUSIONS:OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.

BACKGROUND: Approximately 50% of nGBMs harbor EGFR-amp. Depatuxizumab mafodotin (depatux-m) is an antibody drug conjugate: a monoclonal antibody that binds activated EGFR (wild-type and EGFRvIII mutant) linked to a microtubule-inhibitor toxin. Pre-clinical and earlier clinical trials suggested efficacy.
METHOD(S): RTOGF 3508/AbbVie M13-813 (INTELLANCE-1, NCT02573324) was a phase 3 academic-industry collaboration (RTOG-Foundation, AbbVie). Eligible adults (KPS >= 70, EGFR-amp nGBM, centrally confirmed histology and biomarkers) were randomized 1:1 to radiotherapy (RT) and temozolomide and either depatux-m (2.0 mg/kg during RT, 1.25 mg/kg thereafter, q 14 days) or placebo, stratified by region of world, RPA class, MGMT methylation, and EGFRvIII mutation. Primary endpoint was overall survival (OS), with 640 patients planned for randomization; 441 events yielded 85% power to detect 25% reduction in hazard of death (HR 0.75), one-sided 2.5% level of significance by stratified weighted log-rank.
RESULT(S): 2229 patients were screened and 639 (median age 60, range 22-84; 394 men, 62%) randomized. Pre-specified interim analysis after 346 events (>= 75% required) found no OS improvement for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.01, 95% CI 0.82-1.25, one-sided p= 0.63). Progression-free survival (PFS) trended toward depatux-m (median 8.0 vs. 6.3 months; HR 0.84, 95% CI 0.70-1.02), particularly among the ~50% with EGFRvIII mutation (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93) but without an OS improvement (median 19.8 vs. 18.2, HR=0.95, 95% CI 0.71-1.27). Ocular side effects (grade >= 1) occurred in 95% of depatux-m treated patients, 61% grade 3-4, causing 12% to discontinue, and were the most common treatment related adverse events.
CONCLUSION(S): Interim analysis demonstrated no OS benefit for treating EGFR-amp nGBM with depatux-m. PFS trended toward favoring depatux-m, particularly in the EGFRvIII harboring subgroup. No new important safety risks were identified. The trial was stopped for futility. Active patients are permitted to continue treatment

BACKGROUND:Psychiatric comorbidity is highly prevalent in general medicine inpatient settings and is associated with increased duration and cost of hospitalization. OBJECTIVE:To evaluate the impact of integrated, proactive psychiatric care on hospital medicine length of stay (LOS), expanding upon methods from earlier studies. METHODS:A full-time psychiatrist was dedicated to a single hospital medicine unit to focus on early case finding and intensified treatment, interdisciplinary communication, and discharge planning. To a pre-post intervention design, we added a simultaneous usual care comparison. We also added adjustments for age, sex, insurance type, and whether the patient was discharged home or to a facility. We included a sensitivity analysis to remove outliers for whom LOS was ≤30 days. RESULTS:Statistically significant differences in LOS occurred on the pilot unit in the pre-post analysis (-1.66 d, P = 0.04) and on the pilot versus control units in the intervention year (-1.91 d, P = 0.003). The differential pre-post change in LOS on the pilot versus control units revealed a positive trend but was not statistically significant (-1.59 d, P = 0.14). This more rigorous test approached statistical significance when patients with LOS >30 days were excluded (-1.15 d, P = 0.07). CONCLUSION/CONCLUSIONS:This analysis strengthens existing evidence that dedicated, proactive psychiatric services integrated into hospital medicine units lower LOS more than does usual psychiatric consultation upon request, particularly in patients with an LOS ≤30 days.

OBJECTIVE:The aim of this study was to identify specific ictal hand postures (HPs) as localizing signs of the epileptogenic zone (EZ) in patients with frontal or temporal lobe epilepsy. METHODS:In this study, we retrospectively analyzed ictal semiology of 489 temporal lobe or frontal lobe seizures recorded over a 6-year period at the Seizure Disorder Center at University of California, Los Angeles in the USA (45 patients) or at the C. Munari Epilepsy Surgery Center at Niguarda Hospital in Milan, Italy (34 patients). Our criterion for EZ localization was at least 2 years of seizure freedom after surgery. We analyzed presence and latency of ictal HP. We then examined whether specific initial HPs are predictive for EZ localization. RESULTS:We found that ictal HPs were present in 72.5% of patients with frontal and 54.5% of patients with temporal lobe seizures. We divided HPs into 6 classes depending on the reciprocal position of the fingers ("fist," "cup," "politician's fist," "pincer," "extended hand," "pointing"). We found a striking correlation between EZ localization and ictal HP. In particular, fist and pointing HPs are strongly predictive of frontal lobe EZ; cup, politician's fist, and pincer are strongly predictive of temporal lobe EZ. INTERPRETATION:Our study offers simple ictal signs that appear to clarify differential diagnosis of temporal versus frontal lobe EZ localization. These results are meant to be used as a novel complementary tool during presurgical evaluation for epilepsy. At the same time, they give us important insight into the neurophysiology of hand movements. ANN NEUROL 2019;86:793-800.

Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DNs) are key structures in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared with healthy controls (HCs) with the aim to expand upon previous findings of DNs in a dataset using advanced, imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and nonmotor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and, in part, replicate previous descriptions of DN RsFc abnormalities in this disorder and reveal correlations between DN-cerebral RsFc and ASD symptom severity.

Application of molecular neuroimaging using positron emission tomographic techniques to assess pediatric neurodegenerative disorders has been limited, unlike in adults where positron emission tomography has contributed to clinical diagnosis, monitoring of neurodegenerative disease progression, and assessment of novel therapeutic approaches. Yet, there is a huge unexplored potential of molecular imaging to improve our understanding of the pathophysiology of neurodegenerative disorders in children and provide radiological biomarkers that can be applied clinically. The obstacles in performing PET scans on children include sedation, radiation exposure, and access but, as will be illustrated, these barriers can be easily overcome. In this review, we summarize findings from PET studies that have been performed over the past three decades on children with various neurodegenerative disorders, including the neuronal ceroid lipofuscinoses, juvenile Huntington disease, Wilson disease, Niemann-Pick disease type C, Dravet syndrome, dystonia, mitochondrial disorders, inborn errors of metabolism, lysosomal storage diseases, dysmyelinating disorders, Rett syndrome, neurotransmitter disorders, glucose transporter Glut 1 deficiency, and Lesch-Nyhan disease. Because positron emission tomographic scans have often been clinically useful and have contributed to the management of these disorders, we suggest that the time has come for glucose metabolism positron emission tomographic scans to be reimbursed by insurance carriers for children with neurodegenerative disorders, and not restricted only to epilepsy surgery evaluation.

Visual neurons respond to static images with specific dynamics: neuronal responses sum sub-additively over time, reduce in amplitude with repeated or sustained stimuli (neuronal adaptation), and are slower at low stimulus contrast. Here, we propose a simple model that predicts these seemingly disparate response patterns observed in a diverse set of measurements-intracranial electrodes in patients, fMRI, and macaque single unit spiking. The model takes a time-varying contrast time course of a stimulus as input, and produces predicted neuronal dynamics as output. Model computation consists of linear filtering, expansive exponentiation, and a divisive gain control. The gain control signal relates to but is slower than the linear signal, and this delay is critical in giving rise to predictions matched to the observed dynamics. Our model is simpler than previously proposed related models, and fitting the model to intracranial EEG data uncovers two regularities across human visual field maps: estimated linear filters (temporal receptive fields) systematically differ across and within visual field maps, and later areas exhibit more rapid and substantial gain control. The model is further generalizable to account for dynamics of contrast-dependent spike rates in macaque V1, and amplitudes of fMRI BOLD in human V1.

This paper updates guidelines for effective treatments of children with specific types of acquired brain injury (ABI) published in 2007 with more recent evidence. A systematic search was conducted for articles published from 2006 to 2017. Full manuscripts describing treatments of children (post-birth to 18) with acquired brain injury were included if study was published in peer-reviewed journals and written in English. Two independent reviewers and a third, if conflicts existed, evaluated the methodological quality of studies with an Individual Study Review Form and a Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Strength of study characteristics was used in development of practice guidelines. Fifty-six peer-reviewed articles, including 27 Class I studies, were included in the final analysis. Established guidelines for writing practice recommendations were used and 22 practice recommendations were written with details of potential treatment limitations. There was strong evidence for family/caregiver-focused interventions, as well as direct interventions to improve attention, memory, executive functioning, and emotional/behavioural functioning. A majority of the practice standards and guidelines provided evidence for the use of technology in delivery of interventions, representing an important trend in the field.Abbreviations: ABI = acquired brain injury, ACRM = American Congress of Rehabilitation Medicine, ACT = Acceptance and Commitment Therapy, Amat-c = Amsterdam Memory and Attention Training for Children, BRIEF = Behaviour Rating Inventory of Executive Function, BRIEF-MI = The Behaviour Rating Inventory of Executive Function Metacognitive Index, CAPS = Counselor Assisted Problem-solving, CBT = cognitive behaviour therapy, COPM = Canadian Occupational Performance Measure, CO-OP = Cognitive Orientation to daily Occupational Performance, CRP = Cognitive Remediation Program, EBR = Evidence-Based Review, FPS = Family Problem-solving, IRC = Internet Resource Comparison, JBI = Joanna Briggs Institute, mTBI = mild traumatic brain injury, SSTP = Stepping Stones Triple P, SMART = Strategic Memory Advanced Reasoning Training, TBI = traumatic brain injury, TOPS = Teen Online Problem-solving, TOPS-TO = Teen Online Problem-solving-Teens Only, WM = Working Memory.

In rodents, waking firing patterns replay in NREM sleep during hippocampal sharpwave-ripples (HC-SWR), correlated with neocortical graphoelements (NC-GE). NC-GE include theta-bursts, spindles, downstates and upstates. In humans, consolidation during sleep is correlated with scalp-recorded spindles and down-upstates, but HC-SWR cannot be recorded non-invasively. Here we show in humans of both sexes that HC-SWR are highly correlated with NC-GE during NREM, with significantly more related HC-SWR/NC-GE for downstates or upstates than theta-bursts or spindles, in N2 than N3, in posterior than anterior HC, in frontal than occipital cortex, and ipsilaterally than contralaterally. The preferences interacted, e.g. frontal spindles co-occurred frequently with posterior HC-SWR in N2. These preferred GE, stages and locations for HC-SWR/NC-GE interactions may index selective consolidation activity, although that was not tested in this study. SWR recorded in different HC regions seldom co-occurred, and were related to GE in different cortical areas, showing that HC-NC interact in multiple transient, widespread but discrete, networks. NC-GE tend to occur with consistent temporal relationships to HC-SWR, and to each other. Cortical theta-bursts usually precede HC-SWR, where they may help define cortical input triggering HC-SWR firing. HC-SWR often follow cortical downstate onsets, surrounded by locally-decreased broadband power, suggesting a mechanism synchronizing cortical, thalamic and hippocampal activities. Widespread cortical upstates and spindles follow HC-SWR, consistent with the hypothesized contribution by hippocampal firing during HC-SWR to cortical firing-patterns during upstates and spindles. Overall, our results describe how hippocampal and cortical oscillations are coordinated in humans during events that are critical for memory consolidation in rodents.SIGNIFICANCE STATEMENTHippocampal sharpwave-ripples, essential for memory consolidation, mark when hippocampal neurons replay waking firing patterns. In rodents, cortical sleep waves coordinate the transfer of temporary hippocampal to permanent cortical memories, but their relationship with human HC-SWR remains unclear. We show that human hippocampal sharpwave-ripples co-occur with all varieties of cortical sleep waves, in all cortical regions, and in all stages of Non-REM sleep but with overall preferences for each of these. We found that sharpwave-ripples in different parts of the hippocampus usually occurred independently of each other, and preferentially interacted with different cortical areas. We found that sharpwave-ripples typically occur after certain types of cortical waves, and before others, suggesting how the cortico-hippocampo-cortical interaction may be organized in time and space.

We studied the relationship between uninstructed, unstructured movements and neural activity in three epilepsy patients with intracranial electroencephalographic (iEEG) recordings. We used a custom system to continuously record high definition video precisely time-aligned to clinical iEEG data. From these video recordings, movement periods were annotated via semi-automatic tracking based on dense optical flow. We found that neural signal features (8--32 Hz and 76--100 Hz power) previously identified from task-based experiments are also modulated before and during a variety of movement behaviors. These movement behaviors are coarsely labeled by time period and movement side (e.g. `Idle' and `Move', `Right' and `Left'); movements within a label can include a wide variety of uninstructed behaviors. A rigorous nested cross-validation framework was used to classify both movement onset and lateralization with statistical significance for all subjects. We demonstrate an evaluation framework to study neural activity related to natural movements not evoked by a task, annotated over hours of video. This work further establishes the feasibility to study neural correlates of unstructured behavior through continuous recording in the epilepsy monitoring unit. The insights gained from such studies may advance our understanding of how the brain naturally controls movement, which may inform the development of more robust and generalizable brain-computer interfaces.