Exploring the Significance of Cognitive Motor Dissociation on Patient Outcome in Acute Disorders of Consciousness.

Cognitive motor dissociation (CMD) is characterized by a dissociation between volitional brain responses and motor control, detectable only through techniques such as electroencephalography (EEG) and functional magnetic resonance imaging. Hence, it has recently emerged as a major challenge in the assessment of patients with disorders of consciousness. Specifically, this review focuses on the prognostic implications of CMD detection during the acute stage of brain injury. CMD patients were identified in each diagnostic category (coma, unresponsive wakefulness syndrome/vegetative state, minimally conscious state minus) with a relatively similar prevalence of around 20%. Current knowledge tends to indicate that the diagnosis of CMD in the acute phase often predicts a more favorable clinical outcome compared with other unresponsive non-CMD patients. Nevertheless, the review underscores the limited research in this domain, probably at least partially explained by its nascent nature and the lack of uniformity in the nomenclature for CMD-related disorders, hindering the impact of the literature in the field.

A protocol for a multicenter randomized and personalized controlled trial using rTMS in patients with disorders of consciousness.

Background: Improving the functional recovery of patients with DoC remains one of the greatest challenges of the field. Different theories exist about the role of the anterior (prefrontal areas) versus posterior (parietal areas) parts of the brain as hotspots for the recovery of consciousness. Repetitive transcranial magnetic stimulation (rTMS) is a powerful non-invasive brain stimulation technique for the treatment of DoC. However, a direct comparison of the effect of TMS treatment on the front versus the back of the brain has yet to be performed. In this study, we aim to assess the short- and long-term effects of frontal and parietal rTMS on DoC recovery and characterize responders phenotypically. Methods/design: Ninety patients with subacute and prolonged DoC will be included in a two-part multicenter prospective study. In the first phase (randomized controlled trial, RCT), patients will undergo four rTMS sessions in a crossover design over 10 days, targeting (i) the left dorsolateral prefrontal cortex (DLPFC) and (ii) the left angular gyrus (AG), as well as (iii & iv) their sham alternatives. In the second phase (longitudinal personalized trial), patients will receive personalized stimulations for 20 working days targeting the brain area that showed the best results in the RCT and will be randomly assigned to either active or sham intervention. The effects of rTMS on neurobehavioral and neurophysiological functioning in patients with DoC will be evaluated using clinical biomarkers of responsiveness (i.e., the Coma Recovery Scale-Revised; CRS-R), and electrophysiological biomarkers (e.g., power spectra, functional and effective connectivity, perturbational complexity index before and after intervention). Functional long-term outcomes will be assessed at 3 and 6 months post-intervention. Adverse events will be recorded during the treatment phase. Discussion: This study seeks to identify which brain region (front or back) is best to stimulate for the treatment of patients with DoC using rTMS, and to characterize the neural correlates of its action regarding recovery of consciousness and functional outcome. In addition, we will define the responders' profile based on patients' characteristics and functional impairments; and develop biomarkers of responsiveness using EEG analysis according to the clinical responsiveness to the treatment. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04401319, Clinicaltrials.gov, n° NCT04401319.

Cerebral electrometabolic coupling in disordered and normal states of consciousness.

We assess cerebral integrity with cortical and subcortical FDG-PET and cortical electroencephalography (EEG) within the mesocircuit model framework in patients with disorders of consciousness (DoCs). The mesocircuit hypothesis proposes that subcortical activation facilitates cortical function. We find that the metabolic balance of subcortical mesocircuit areas is informative for diagnosis and is associated with four EEG-based power spectral density patterns, cortical metabolism, and α power in healthy controls and patients with a DoC. Last, regional electrometabolic coupling at the cortical level can be identified in the θ and α ranges, showing positive and negative relations with glucose uptake, respectively. This relation is inverted in patients with a DoC, potentially related to altered orchestration of neural activity, and may underlie suboptimal excitability states in patients with a DoC. By understanding the neurobiological basis of the pathophysiology underlying DoCs, we foresee translational value for diagnosis and treatment of patients with a DoC.

Transcutaneous vagal nerve stimulation to treat disorders of consciousness: Protocol for a double-blind randomized controlled trial

Background: Patients with disorders of consciousness (DoC) are a challenging population prone to misdiagnosis with limited effective treatment options. Among neuromodulation techniques, transcutaneous auricular vagal nerve stimulation (taVNS) may act through a bottom-up manner to modulate thalamo-cortical connectivity and promote patients’ recovery. In this clinical trial, we aim to (1) assess the therapeutic clinical effects of taVNS in patients with DoC; (2) investigate the neural mechanisms underlying the effects of its action; (3) assess the feasibility and safety of the procedure in this challenging population; (4) define the phenotype of clinical responders; and (5) assess the long-term efficacy of taVNS in terms of functional outcomes. Methods: We will conduct a prospective parallel randomized controlled double-blind clinical trial investigating the effects of taVNS as a treatment in DoC patients. Forty-four patients in the early period post-injury (7 to 90 days following the injury) will randomly receive 5 days of either active bilateral vagal stimulation (45 min duration with 30s alternative episodes of active/rest periods; 3mA; 200-300μs current width, 25Hz.) or sham stimulation. Behavioural (i.e., Coma Recovery Scale-Revised, CRS-R) and neurophysiological (i.e., high-density electroencephalography, hd-EEG) measures will be collected at baseline and at the end of the 5-day treatment. Analyses will seek for changes in the CRS-R and the EEG metrics (e.g., alpha band power spectrum, functional connectivity) at the group and individual (i.e., responders) levels. Discussion: These results will allow us to investigate the vagal afferent network and will contribute towards a definition of the role of taVNS for the treatment of patients with DoC. We aim to identify the neural correlates of its action and pave the way to novel targeted therapeutic strategies. (AU)

Transcutaneous vagal nerve stimulation to treat disorders of consciousness: Protocol for a double-blind randomized controlled trial.

Background: Patients with disorders of consciousness (DoC) are a challenging population prone to misdiagnosis with limited effective treatment options. Among neuromodulation techniques, transcutaneous auricular vagal nerve stimulation (taVNS) may act through a bottom-up manner to modulate thalamo-cortical connectivity and promote patients' recovery. In this clinical trial, we aim to (1) assess the therapeutic clinical effects of taVNS in patients with DoC; (2) investigate the neural mechanisms underlying the effects of its action; (3) assess the feasibility and safety of the procedure in this challenging population; (4) define the phenotype of clinical responders; and (5) assess the long-term efficacy of taVNS in terms of functional outcomes. Methods: We will conduct a prospective parallel randomized controlled double-blind clinical trial investigating the effects of taVNS as a treatment in DoC patients. Forty-four patients in the early period post-injury (7 to 90 days following the injury) will randomly receive 5 days of either active bilateral vagal stimulation (45 min duration with 30s alternative episodes of active/rest periods; 3mA; 200-300µs current width, 25Hz.) or sham stimulation. Behavioural (i.e., Coma Recovery Scale-Revised, CRS-R) and neurophysiological (i.e., high-density electroencephalography, hd-EEG) measures will be collected at baseline and at the end of the 5-day treatment. Analyses will seek for changes in the CRS-R and the EEG metrics (e.g., alpha band power spectrum, functional connectivity) at the group and individual (i.e., responders) levels. Discussion: These results will allow us to investigate the vagal afferent network and will contribute towards a definition of the role of taVNS for the treatment of patients with DoC. We aim to identify the neural correlates of its action and pave the way to novel targeted therapeutic strategies. Clinical trial registration: Clinicaltrials.gov n° NCT04065386.

Neuroimaging and neurophysiological diagnosis and prognosis in paediatric disorders of consciousness.

The diagnosis and prognosis of disorders of consciousness (DOC) such as coma, unresponsive wakefulness syndrome, or minimally conscious state are especially challenging in children. In some paediatric patients with severe acquired brain injury, medical comorbidities or developmental factors may obscure the detection of signs of consciousness via clinical assessments, thus leading to misdiagnosis. To circumvent these biases, patients benefit from multimodal assessments that combine behavioural, neuroimaging, and neurophysiological measures. In this review, we provide original data for such diagnostic procedures in children. Neuroimaging is largely underdocumented in children and most neurophysiological research consists of a cohort study design aimed at providing prognostic markers for clinical outcomes. The scarcity of available data on complementary diagnostic approaches in children makes it difficult to establish clear paediatric guidelines. Although there is preliminary evidence for the applicability of paradigms involving event-related potentials as support for diagnosis in children, more well-designed studies need to be conducted to promote evidence-based practices in paediatric DOC.

The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons.

Although several ionic mechanisms are known to control rate and regularity of the slow pacemaker in dopamine (DA) neurons, the core mechanism of pacing is controversial. Here we tested the hypothesis that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidinium (XG), an established blocker of gating pore currents, selectively inhibits pacemaking of DA neurons. The compound inhibited all slow pacemaking DA neurons that were tested, both in the substantia nigra pars compacta, and in the ventral tegmental area. Interestingly, bursting behavior was not affected by XG. Furthermore, the drug did not affect fast pacemaking of GABAergic neurons from substantia nigra pars reticulata neurons or slow pacemaking of noradrenergic neurons. In DA neurons, current-clamp analysis revealed that XG did not appear to affect ion channels involved in the action potential. Its inhibitory effect persisted during blockade of all ion channels previously suggested to contribute to pacemaking. RNA sequencing and voltage-clamp recordings yielded no evidence for a gating pore current to underlie the conductance. However, we could isolate a small subthreshold XG-sensitive current, which was carried by both Na+ and Cl- ions. Although the molecular target of XG remains to be defined, these observations represent a step towards understanding pacemaking in DA neurons.

Beyond current guidelines: reduction in minimum administered radiopharmaceutical activity with preserved diagnostic image quality in pediatric hepatobiliary scintigraphy.

PURPOSE: To determine if the minimum administered radiopharmaceutical activity for hepatobiliary scintigraphy can be reduced while preserving diagnostic image quality using enhanced planar processing (EPP). METHODS: A total of 40 infants between 10 and 270 days old (body mass 2.2 - 6.5 kg) had hepatobiliary scintigraphy during the period 2004 - 2010 following the intravenous administration of either (99m)Tc-mebrofenin (18 patients) or (99m)Tc-disofenin (22 patients). Due to the small size of these patients, they all received the minimum administered activity of 18.5 MBq consistent with the North American Consensus Guidelines. Six nuclear medicine physicians subjectively graded the acceptability of the image quality for clinical interpretation using a four-point scale (not acceptable, fair, good, excellent). Each physician independently graded seven image sets including the original study (full activity) and simulated reduced activity studies using binomial subsampling (50% of full activity, 25% of full activity and activity reduced by weight), with and without EPP. RESULTS: For full-activity studies, 98% were deemed acceptable by the six physicians for clinical interpretation. The percentages of acceptable 50% reduced activity studies with and without EPP were not significantly different from the percentage of acceptable full-activity studies (P = 0.193 and P = 0.998, respectively). The percentage of acceptable 25% reduced activity studies without EPP was significantly different from the percentage of acceptable full-activity studies (P < 0.001); however, this difference vanished when EPP was applied (P = 0.482). The activity reduced by weight ranged from 1.85 to 4.81 MBq (10% to 26% of full dose) and the percentages of acceptable studies with and without EPP were significantly different from the percentage of acceptable full-activity studies (P < 0.001 and P = 0.02, respectively). CONCLUSION: Clinically interpretable hepatobiliary scintigraphy images can be obtained in infants when the minimum administered activity is substantially reduced. Without EPP, clinically acceptable images may be produced with a reduction of 50%, and with EPP, a reduction of 75% or more may be possible.

Policies to promote use of generic medicines in low and middle income countries: a review of published literature, 2000-2010.

OBJECTIVE: Review the literature on the impact of policies designed to enhance uptake of generic medicines in low and middle income countries (LMICs). METHODS: We searched for publications related to generic medicines policies (January 2000-March 2010) and did a bibliometric, descriptive analysis of the dataset in addition to an analysis of studies evaluating the impact of pro-generic policies. We repeated a subset of this larger search in January 2012. RESULTS: Of the 4994 articles screened, 315 (6.3%) full-text publications were related to generic medicines policies. Of these 315, 236 (75%) dealt with generic medicine policies in high-income countries, and 79 (25%) with policies in LMICs. In total, we found only 10 evaluation studies looking at the impact of competition, trade, pricing and prescribing policies on generic medicine price and/or volume. Key barriers to implementing generic medicine policies in LMICs are negative perceptions of stakeholders (e.g., generics are of lower quality) plus perverse private sector financial incentives to sell products with the highest profit margin. Other relevant barriers are legal/regulatory, such as the absence of generic substitution regulations. There also exists a general difficulty in promoting generics due to a lack of transparency in the pharmaceutical supply and distribution system, for example, a lack of price information provided by health care provider organizations to physicians. CONCLUSION: There is little policy evaluation to determine which pro-generic policies increase generic medicines utilization in LMICs. Ensuring a functioning medicines regulation authority, creating a reasonably robust market of generic medicines and aligning incentives for physicians, consumers and drug sellers are necessary prerequisites for increasing the uptake and use of generic medicines.

Local production of medical technologies and its effect on access in low and middle income countries: a systematic review of the literature.

OBJECTIVES: The objective of this study was to assess the existing theoretical and empirical literature examining the link between "local production" of pharmaceuticals and medical devices and increased local access to these products. Our preliminary hypothesis is that studies showing a robust relationship between local production and access to medical products are sparse, at best. METHODS: An extensive literature search was conducted using a wide variety of databases and search terms intending to capture as many different aspects of this issue as possible. The results of the search were reviewed and categorized according to their relevance to the research question. The literature was also reviewed to determine the rigor used to examine the effects of local production and what implications these experiences hold for other developing countries. RESULTS: Literature addressing the benefits of local production and the link between it and access to medical products is sparse, mainly descriptive and lacking empirical evidence. Of the literature we reviewed that addressed comparative economics and strategic planning of multinational and domestic firms, there are few dealing with emerging markets and lower-middle income countries and even fewer that compare local biomedical producers with multinational corporations in terms of a reasonable metric. What comparisons exist mainly relate to prices of local versus foreign/multinational produced medicines. CONCLUSIONS: An assessment of the existing theoretical and empirical literature examining the link between "local production" of pharmaceuticals and medical devices and increased local access to these products reveals a paucity of literature explicitly dealing with this issue. Of the literature that does exist, methods used to date are insufficient to prove a robust relationship between local production of medical products and access to these products. There are mixed messages from various studies, and although the studies may correctly depict specific situations in specific countries with reference to specific products, such evidence cannot be generalized. Our review strongly supports the need for further research in understanding the dynamic link between local production and access to medical products.