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The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.

Introduction: While well-established risk factors for cervical artery dissection include trauma and connective tissue disorders, many cases are considered “spontaneous.” Although the incidence of cervical artery dissection is greatest in the young, the prevalence increases with age, suggesting a potential role of vascular disease. In this study, we hypothesized that atherosclerosis may be a risk factor for cervical artery dissection. Methods: We performed a retrospective cohort study using administrative claims data from a 5% sample of Medicare beneficiaries between 2008 and 2018. The exposures of interest were vascular risk factors potentially associated with atherosclerosis including coronary artery disease, hyperlipidemia, hypertension, diabetes mellitus, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, atrial fibrillation, tobacco use, and alcohol abuse. The primary outcome was a new diagnosis of cervical artery dissection. Marginal structural Cox models were used to characterize the association between the exposures and outcomes, adjusted for time-dependent confounding, age, sex, race/ethnicity, and prior stroke. Results: Among 2,256,826 eligible Medicare beneficiaries, 1,527 (0.07%) developed cervical artery dissection, with a mean age of 70.8, compared to 71.5 in those without cervical artery dissection. The following exposures were found to be significantly associated with the development of cervical artery dissection: coronary artery disease (1.81 [1.63-2.01]), hyperlipidemia (1.84 [1.61-2.11]), hypertension (2.04 [1.76-2.37]), diabetes mellitus (1.34 [1.21-1.49]), heart failure (1.44 [1.25-1.67]), chronic kidney disease (1.38 [1.20-1.59]), chronic obstructive pulmonary disease (1.3 [1.16-1.46]), valvular heart disease (1.81 [1.60-2.04]), atrial fibrillation (HR 1.75 [95% CI 1.54-1.98]), tobacco use (1.84 [1.57-2.15]), and alcohol abuse (1.84 [1.56-2.16]). Conclusion: In a large population-based cohort of older people, atherosclerotic risk factors were associated with subsequent cervical artery dissection. Further studies exploring the role of atherosclerosis in the development of cervical artery dissection are required.

Cerebrovascular complications among critically ill patients with COVID-19 have yet to be fully characterized. In this retrospective case series from a single academic tertiary care referral center in New York City, we present 12 patients with ischemic or hemorrhagic strokes that were found on imaging after a period of prolonged sedation in the setting of COVID-19 pneumonia. This series demonstrates a pattern of cerebrovascular events clinically masked by deep sedation required for management of COVID-19 related acute respiratory distress syndrome (ARDS). Of the 12 patients included, 10 had ischemic stroke, 4 of which had hemorrhagic conversion, and 2 had primary intracerebral hemorrhage. Ten patients were on therapeutic anticoagulation prior to discovery of their stroke, and the remainder received intermediate dose anticoagulation (in a range between prophylactic and therapeutic levels). Additional studies are needed to further characterize the counterbalancing risks of ischemic and hemorrhagic stroke, as well as the optimal management of this patient population.

BackgroundIdiopathic intracranial hypertension is a disease of raised intra-cranial pressure of unknown etiology. Lateral cerebral venous sinus stenosis (VSS) has been increasingly reported in these patients, and stenting has emerged as an alternative treatment for medically refractory symptoms. Treatment efficacy on meta-analysis appears promising, but identifying which patients are likely to benefit most, and which are likely to require repeat procedures, is currently unclear.MethodsWe retrospectively reviewed a prospectively collected database of 79 patients treated with venous sinus stenting at a single academic center with minimum follow-up of 18 months. We extracted baseline clinical data, as well as manometry at lumbar puncture and during angiography, and used logistic regression to identify parameters that could predict stent failure.ResultsRetreatment rate after successful VSS was 13.9%. Lumbar puncture opening pressure (OP) was shown to significantly predict treatment failure (ß=0.06; OR=1.064 (1.003–1.135); P=0.039). This effect remained significant when age, sex and body mass index were added to the model (ß=0.06; OR=1.066 (1.002–1.140); P=0.043). OP was correlated with venous sinus manometry readings in the superior sagittal and transverse sinus pre-stent placement, as well trans-stenotic gradient (PConclusionsHigher lumbar puncture OP was associated with an increased risk of stent failure in transverse sinus stenting for idiopathic intracranial hypertension, although the performance of this model as a linear discriminator was poor. Further studies are required to better assess which patients are at greatest risk of treatment failure.

Coronavirus disease (COVID-19) has a number of emerging neurological manifestations in addition to pneumonia and respiratory distress. In what follows, we describe a case of a previously healthy young man with severe COVID-19 who subsequently developed an acute flaccid paralysis. Work up revealed a lesion in his cervical spinal cord concerning for spinal infarction or transverse myelitis. He received empiric pulsed steroids without improvement. Taken together, we felt his presentation was most consistent with spinal cord infarction in the setting of critical illness with COVID-19. We believe this is a rare case of spinal cord stroke associated with COVID-19.

Neurologic complications of COVID-19 are not well described. We report 2 patients who were diagnosed with COVID-19 after presenting with diplopia and ophthalmoparesis.

Importance It is uncertain whether coronavirus disease 2019 (COVID-19) is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection. Objective To compare the rate of ischemic stroke between patients with COVID-19 and patients with influenza, a respiratory viral illness previously associated with stroke. Design, Setting, and Participants This retrospective cohort study was conducted at 2 academic hospitals in New York City, New York, and included adult patients with emergency department visits or hospitalizations with COVID-19 from March 4, 2020, through May 2, 2020. The comparison cohort included adults with emergency department visits or hospitalizations with influenza A/B from January 1, 2016, through May 31, 2018 (spanning moderate and severe influenza seasons). Exposures COVID-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 in the nasopharynx by polymerase chain reaction and laboratory-confirmed influenza A/B. Main Outcomes and Measures A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, mechanisms, and outcomes. We used logistic regression to compare the proportion of patients with COVID-19 with ischemic stroke vs the proportion among patients with influenza. Results Among 1916 patients with emergency department visits or hospitalizations with COVID-19, 31 (1.6%; 95% CI, 1.1%-2.3%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78 years); 18 (58%) were men. Stroke was the reason for hospital presentation in 8 cases (26%). In comparison, 3 of 1486 patients with influenza (0.2%; 95% CI, 0.0%-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was higher with COVID-19 infection than with influenza infection (odds ratio, 7.6; 95% CI, 2.3-25.2). The association persisted across sensitivity analyses adjusting for vascular risk factors, viral symptomatology, and intensive care unit admission. Conclusions and Relevance In this retrospective cohort study from 2 New York City academic hospitals, approximately 1.6% of adults with COVID-19 who visited the emergency department or were hospitalized experienced ischemic stroke, a higher rate of stroke compared with a cohort of patients with influenza. Additional studies are needed to confirm these findings and to investigate possible thrombotic mechanisms associated with COVID-19.

Key Points Question How does the risk of acute ischemic stroke compare between patients with Covid-19 and patients with influenza (a respiratory virus previously linked to stroke)? Findings In this large retrospective cohort study conducted at two academic hospitals in New York City, patients with emergency department visits and hospitalizations with Covid-19 were approximately seven times as likely to have an acute ischemic stroke as compared to patients with emergency department visits or hospitalizations with influenza. Meaning Patients with Covid-19 are at heightened risk for acute ischemic stroke as compared to patients with influenza. Importance Case series without control groups suggest that Covid-19 may cause ischemic stroke, but whether Covid-19 is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection is uncertain. Objective To compare the rate of ischemic stroke between patients with Covid-19 and patients with influenza, a respiratory viral illness previously linked to stroke. Design A retrospective cohort study. Setting Two academic hospitals in New York City. Participants We included adult patients with emergency department visits or hospitalizations with Covid-19 from March 4, 2020 through May 2, 2020. Our comparison cohort included adult patients with emergency department visits or hospitalizations with influenza A or B from January 1, 2016 through May 31, 2018 (calendar years spanning moderate and severe influenza seasons). Exposures Covid-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the nasopharynx by polymerase chain reaction, and laboratory-confirmed influenza A or B. Main Outcomes and Measures A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, etiological mechanisms, and outcomes. We used logistic regression to compare the proportion of Covid-19 patients with ischemic stroke versus the proportion among patients with influenza. Results Among 2,132 patients with emergency department visits or hospitalizations with Covid-19, 31 patients (1.5%; 95% confidence interval [CI], 1.0%-2.1%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78) and 58% were men. Stroke was the reason for hospital presentation in 8 (26%) cases. For our comparison cohort, we identified 1,516 patients with influenza, of whom 0.2% (95% CI, 0.0-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was significantly higher with Covid-19 than with influenza infection (odds ratio, 7.5; 95% CI, 2.3-24.9). Conclusions and Relevance Approximately 1.5% of patients with emergency department visits or hospitalizations with Covid-19 experienced ischemic stroke, a rate 7.5-fold higher than in patients with influenza. Future studies should investigate the thrombotic mechanisms in Covid-19 in order to determine optimal strategies to prevent disabling complications like ischemic stroke.

Titus Andronicus scares me. It scares me because it presents a world so far from what I hope our world is, but so close to what I fear our world is. It is a world of cruelty, of a perverse and violent logic driven by insatiable revenge. The challenge of the production was to create a clear and cruel world that forced the audience to deal with the reality of the horror of the events of the play. We sought to create a space where there was nowhere to hide, a harsh and unflattering lighting design that exposed rather than pleased the eye, a sound design that instilled a feeling of creeping horror. Through the style of acting, we strove to eliminate self-pity and lament from the emotional language of the play. Only in its final moments is the audience granted a kind of catharsis, when the young woman playing Young Lucius removes her boy's wig to reveal the actor, alone, weeping at the tragedy and the cruelty of the world that surrounds her. At my advisor's urging to challenge myself, I chose to take on a play that is largely devoid of the redemptive qualities of life. The world of Titus Andronicus is replete with cruelty and violence. It is a profane world, one driven by a perverse logic that perpetuates its hatred and barbarism

Background Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias. Objective To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks. Methods We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI. Results Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network. Conclusion Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks. Trial registration number NCT02263937.

Subthalamic nucleus deep brain stimulation is an effective treatment for advanced Parkinson's disease; however, its therapeutic mechanism is unclear. Previous modelling of functional MRI data has suggested that deep brain stimulation has modulatory effects on a number of basal ganglia pathways. This work uses an enhanced data collection protocol to collect rare functional MRI data in patients with subthalamic nucleus deep brain stimulation. Eleven patients with Parkinson's disease and subthalamic nucleus deep brain stimulation underwent functional MRI at rest and during a movement task; once with active deep brain stimulation, and once with deep brain stimulation switched off. Dynamic causal modelling and Bayesian model selection were first used to compare a series of plausible biophysical models of the cortico-basal ganglia circuit that could explain the functional MRI activity at rest in an attempt to reproduce and extend the findings from our previous work. General linear modelling of the movement task functional MRI data revealed deep brain stimulation-associated signal increases in the primary motor and cerebellar cortices. Given the significance of the cerebellum in voluntary movement, we then built a more complete model of the motor system by including cerebellar-basal ganglia interactions, and compared the modulatory effects deep brain stimulation had on different circuit components during the movement task and again using the resting state data. Consistent with previous results from our independent cohort, model comparison found that the rest data were best explained by deep brain stimulation-induced increased (effective) connectivity of the cortico-striatal, thalamo-cortical and direct pathway and reduced coupling of subthalamic nucleus afferent and efferent connections. No changes in cerebellar connectivity were identified at rest. In contrast, during the movement task, there was functional recruitment of subcortical-cerebellar pathways, which were additionally modulated by deep brain stimulation, as well as modulation of local (intrinsic) cortical and cerebellar circuits. This work provides in vivo evidence for the modulatory effects of subthalamic nucleus deep brain stimulation on effective connectivity within the cortico-basal ganglia loops at rest, as well as further modulations in the cortico-cerebellar motor system during voluntary movement. We propose that deep brain stimulation has both behaviour-independent effects on basal ganglia connectivity, as well as behaviour-dependent modulatory effects.

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC-visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context.

We appreciate Dr. Machado's insightful comments regarding our case series1 describing cranial neuropathies in 2 patients with COVID-19. The triad of progressive ophthalmoplegia, ataxia, and areflexia in our first case suggested Miller Fisher syndrome (MFS), despite the negative ganglioside panel, although we were surprised by the short interval of 4 days between respiratory and neurologic symptoms. However, in 2 cases of COVID-19-associated MFS, latencies were similar (5 and 3 days),2 suggesting that the postinfectious interval is shorter for COVID-19 than for other infections. In fact, in a recent case of Guillain-Barre syndrome associated with COVID-19, neurologic symptoms preceded the respiratory symptoms by 1 week.3 The authors noted that lymphopenia was present on admission, indicating the presence of COVID-19 long before systemic symptoms began. This is in line with recent observations that 10/13 nursing home residents only developed symptoms 7 days after testing positive.4 Our second case may reflect direct viral invasion because there were no signs of MFS. Transfer of the virus through the olfactory bulbs is supported by recent evidence of olfactory bulb edema5 and hyperintensity of the adjacent gyrus rectus6 in patients with COVID-19-associated anosmia, although our patient never developed anosmia. The rapid recovery of anosmia observed in most COVID-19 cases argues for olfactory epithelial dysfunction as opposed to olfactory nerve damage, and we agree with Dr. Machado that hematogenous spread of virus may also play a role in CNS disease.

Deep brain stimulation (DBS) for Parkinson's disease is a highly effective treatment in controlling otherwise debilitating symptoms. Yet the underlying brain mechanisms are currently not well understood. Whole-brain computational modeling was used to disclose the effects of DBS during resting-state functional Magnetic Resonance Imaging in ten patients with Parkinson's disease. Specifically, we explored the local and global impact that DBS has in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts global brain dynamics of patients towards a Healthy regime. This effect was more pronounced in very specific brain areas such as the thalamus, globus pallidus and orbitofrontal regions of the right hemisphere (with the left hemisphere not analyzed given artifacts arising from the electrode lead). Global aspects of integration and synchronization were also rebalanced. Empirically, we found higher communicability and coherence brain measures during DBS-ON compared to DBS-OFF. Finally, using our model as a framework, artificial in silico DBS was applied to find potential alternative target areas for stimulation and whole-brain rebalancing. These results offer important insights into the underlying large-scale effects of DBS as well as in finding novel stimulation targets, which may offer a route to more efficacious treatments, In this work, Gustavo Deco is supported by the ERC Advanced Grant: DYSTRUCTURE (n. 295129), by the Spanish Research Project PSI2016-75688-P and by the the European Union's Horizon 2020 research and innovation programme under grant agreement n. 720270 (HBP SGA1). Morten Kringelbach is supported by the ERC Consolidator Grant CAREGIVING (n. 615539) and the Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). Victor M Saenger is supported by the Research Personnel Training program PSI2013-42091-P funded by the Spanish Ministry of Economy and Competitiveness., info:eu-repo/semantics/publishedVersion

Dementia is a major cause of disability amongst the elderly and represents a serious global health issue. Current treatments for dementia are limited; at best they provide inadequate symptomatic relief. In contrast, there are a plethora of approaches that provide symptomatic relief for abnormalities of movement including surgical approaches. Deep brain stimulation has been used successfully to directly alter processing in neural networks and thereby improve movement functions. Here we describe the anatomy, intrinsic organization and connectivity of the cholinergic nucleus basalis of Meynert, a basal forebrain structure implicated in cognitive functions including memory, attention, arousal and perception. A significant body of evidence suggests that degeneration of the nucleus and its cortical projections underlies the cognitive decline seen in dementia. We review this evidence and postulate that deep brain stimulation to this nucleus may be able to improve specific cognitive functions. This could represent a novel treatment strategy for some dementias in carefully selected individuals. Controlled trials of deep brain stimulation of the nucleus basalis of Meynert for Parkinson's disease dementia and Alzheimer's disease are required to evaluate potential efficacy and the mechanisms of possible cognitive changes.

The Parkinson's disease research field is a rapidly moving one, as many of the relevant processes underlying PD neurodegeneration are being deciphered, enabling novel approaches to treatment to be assessed both in the laboratory and in the clinic. This review aims to highlight the most relevant updates in the PD field, with emphasis on research that may help lead towards an improvement in the treatment of this condition.

Deep brain stimulation (DBS) for Parkinson's disease is a highly effective treatment in controlling otherwise debilitating symptoms yet the underlying brain mechanisms are currently not well understood. We used whole-brain computational modeling to disclose the effects of DBS ON and OFF during collection of resting state fMRI in ten Parkinson's Disease patients. Specifically, we explored the local and global impact of DBS in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts the global brain dynamics of patients nearer to that of healthy people by significantly changing the bifurcation parameters in brain regions implicated in Parkinson's Disease. We also found higher communicability and coherence brain measures during DBS ON compared to DBS OFF. Finally, by modeling stimulation we identified possible novel DBS targets. These results offer important insights into the underlying effects of DBS, which may in time offer a route to more efficacious treatments.

Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus-deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single-photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus-deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus-deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus-deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation.

Importance Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia. Objective To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia. Design, Setting, and Participants A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant. Interventions After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks. Main Outcomes and Measures The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging. Results Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, −8 to 5.5 points; P = .69). Conclusions and Relevance Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms. Trial Registration clinicaltrials.gov Identifier:NCT01701544

Recently, there has been a lot of interest in characterising the connectivity of resting state brain networks. Most of the literature uses functional connectivity to examine these intrinsic brain networks. Functional connectivity has well documented limitations because of its inherent inability to identify causal interactions. Dynamic causal modelling (DCM) is a framework that allows for the identification of the causal (directed) connections among neuronal systems — known as effective connectivity. This technical note addresses the validity of a recently proposed DCM for resting state fMRI – as measured in terms of their complex cross spectral density – referred to as spectral DCM. Spectral DCM differs from (the alternative) stochastic DCM by parameterising neuronal fluctuations using scale free (i.e., power law) forms, rendering the stochastic model of neuronal activity deterministic. Spectral DCM not only furnishes an efficient estimation of model parameters but also enables the detection of group differences in effective connectivity, the form and amplitude of the neuronal fluctuations or both. We compare and contrast spectral and stochastic DCM models with endogenous fluctuations or state noise on hidden states. We used simulated data to first establish the face validity of both schemes and show that they can recover the model (and its parameters) that generated the data. We then used Monte Carlo simulations to assess the accuracy of both schemes in terms of their root mean square error. We also simulated group differences and compared the ability of spectral and stochastic DCMs to identify these differences. We show that spectral DCM was not only more accurate but also more sensitive to group differences. Finally, we performed a comparative evaluation using real resting state fMRI data (from an open access resource) to study the functional integration within default mode network using spectral and stochastic DCMs., Highlights • This paper provides construct validation of spectral DCM against stochastic DCM. • Spectral DCM is shown to be more accurate than stochastic DCM in terms of root mean square error. • Spectral DCM is shown to be more sensitive at identifying group differences.

Data from an open label randomised controlled trial have suggested possible advantages on both motor and non-motor measures in patients with Parkinson's disease following 12 months exposure to exenatide.Continued follow up of these same patients was performed to investigate whether these possible advantages persisted in the prolonged absence of this medication.All participants from an open label, randomised controlled trial of exenatide as a treatment for Parkinson's disease, were invited for a further follow up assessment at the UCL Institute of Neurology. This visit included all 20 individuals who had previously completed twelve months exposure to exenatide 10ug bd and the 24 individuals who had acted as randomised controls. Motor severity of PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the MDS-UPDRS, together with several non-motor tests. This assessment was thus 24 months after their original baseline visit, i.e. 12 months after cessation of exenatide.Compared to the control group of patients, patients previously exposed to exenatide had an advantage of 5.6 points (95% CI, 2.2-9.0; p = 0.002) using blinded video rating of the MDS-UPDRS part 3 motor subscale. There was also a difference of 5.3 points; (95% CI, 9.3-1.4; p = 0.006) between the 2 groups on the Mattis Dementia Rating scale.While these data must still not be interpreted as evidence of neuroprotection, they nevertheless provide strong encouragement for the further study of this drug as a potential disease modifying agent in Parkinson's disease.

Deep brain stimulation is an established therapy for Parkinson’s disease, although its mechanism of action remains unclear. Kahan et al. use resting state fMRI and dynamic causal modelling to study changes in ‘effective’ connectivity within the basal ganglia. Analyses implicate subthalamic afferents and the direct pathway in the clinical response., Depleted of dopamine, the dynamics of the parkinsonian brain impact on both ‘action’ and ‘resting’ motor behaviour. Deep brain stimulation has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Non-invasive characterizations of induced brain responses, and the effective connectivity underlying them, generally appeals to dynamic causal modelling of neuroimaging data. When the brain is at rest, however, this sort of characterization has been limited to correlations (functional connectivity). In this work, we model the ‘effective’ connectivity underlying low frequency blood oxygen level-dependent fluctuations in the resting Parkinsonian motor network—disclosing the distributed effects of deep brain stimulation on cortico-subcortical connections. Specifically, we show that subthalamic nucleus deep brain stimulation modulates all the major components of the motor cortico-striato-thalamo-cortical loop, including the cortico-striatal, thalamo-cortical, direct and indirect basal ganglia pathways, and the hyperdirect subthalamic nucleus projections. The strength of effective subthalamic nucleus afferents and efferents were reduced by stimulation, whereas cortico-striatal, thalamo-cortical and direct pathways were strengthened. Remarkably, regression analysis revealed that the hyperdirect, direct, and basal ganglia afferents to the subthalamic nucleus predicted clinical status and therapeutic response to deep brain stimulation; however, suppression of the sensitivity of the subthalamic nucleus to its hyperdirect afferents by deep brain stimulation may subvert the clinical efficacy of deep brain stimulation. Our findings highlight the distributed effects of stimulation on the resting motor network and provide a framework for analysing effective connectivity in resting state functional MRI with strong a priori hypotheses.

Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus-deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single-photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus-deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus-deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus-deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation.

Myoclonic jerks are sudden shock–like involuntary movements, either manifesting as a brief contraction of a group of muscles (positive) or cessation of muscle activity (negative), driven by aberrant activity in one of the cortex, subcortical regions, brainstem or spinal cord. Its aetiology is variable and can occur physiologically, in a primary myoclonic syndrome (myoclonus–dystonia), or as part of an epilepsy (Progressive myoclonic epilepsy) or neurodegenerative syndrome (Alzheimer9s disease, multiple systems atrophy). Myoclonus can also occur secondary to hypoxic brain injury either in an acute (myoclonic status epilepticus) or a chronic form, eponymously titled Lance–Adams syndrome (LAS). LAS is characterised by a non–progressive generalised myoclonus with added seizures and ataxia. There is no curative management strategy, only symptomatic relief. A multidisciplinary approach involving medical, physiotherapy, speech and occupational therapy achieves the best holistic outcomes for patients. Case studies suggest certain antiepileptic agents may alleviate symptoms, but combinations are often required, and the most effective options have sedative side effects. A subset of cases have marked alcohol responsiveness that can lead to dependence. A number of experimental treatment options have been proposed including deep brain stimulation (DBS) and sodium oxybate, a sodium salt of gamma–Hydroxybutyrate. In what follows, a patient with an eleven year history of the LAS is presented and the experimental therapeutics explored, concluding with a recent trial of sodium oxybate. Sodium oxybate was well tolerated and produced improvements in the patient9s symptoms and perceived disability. This case highlights the difficulties of managing chronic myoclonic conditions and suggests sodium oxybate may be a useful treatment option in these patients.