Seeking progress in disease modification in Parkinson disease.

OBJECTIVE: Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. METHODS: The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. RESULTS: Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. CONCLUSIONS: We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

Executive attention deficits after traumatic brain injury reflect impaired recruitment of resources.

Deficits in attention are a common and devastating consequence of traumatic brain injury (TBI), leading to functional impairments, rehabilitation barriers, and long-term disability. While such deficits are well documented, little is known about their underlying pathophysiology hindering development of effective and targeted interventions. Here we evaluate the integrity of brain systems specific to attentional functions using quantitative assessments of electroencephalography recorded during performance of the Attention Network Test (ANT), a behavioral paradigm that separates alerting, orienting, and executive components of attention. We studied 13 patients, at least 6 months post-TBI with cognitive impairments, and 24 control subjects. Based on performance on the ANT, TBI subjects showed selective impairment in executive attention. In TBI subjects, principal component analysis combined with spectral analysis of the EEG after target appearance extracted a pattern of increased frontal midline theta power (2.5-7.5 Hz) and suppression of frontal beta power (12.5-22.5 Hz). Individual expression of this pattern correlated (r = - 0.67, p < 0.001) with executive attention impairment. The grading of this pattern of spatiotemporal dynamics with executive attention deficits reflects impaired recruitment of anterior forebrain resources following TBI; specifically, deafferentation and variable disfacilitation of medial frontal neuronal populations is proposed as the basis of our findings.

A Common Function of Basal Ganglia-Cortical Circuits Subserving Speed in Both Motor and Cognitive Domains.

Distinct regions of the frontal cortex connect with their basal ganglia and thalamic counterparts, constituting largely segregated basal ganglia-thalamo-cortical (BTC) circuits. However, any common role of the BTC circuits in different behavioral domains remains unclear. Indeed, whether dysfunctional motor and cognitive BTC circuits are responsible for motor slowing and cognitive slowing, respectively, in Parkinson's disease (PD) is a matter of debate. Here, we used an effortful behavioral paradigm in which the effects of task rate on accuracy were tested in movement, imagery, and calculation tasks in humans. Using nonlinear fitting, we separated baseline accuracy (Abase ) and "agility" (ability to function quickly) components of performance in healthy participants and then confirmed reduced agility and preserved Abase for the three tasks in PD. Using functional magnetic resonance imaging (fMRI) and diffusion tractography, we explored the neural substrates underlying speeded performance of the three tasks in healthy participants, suggesting the involvement of distinct BTC circuits in cognitive and motor agility. Language and motor BTC circuits were specifically active during speeded performance of the calculation and movement tasks, respectively, whereas premotor BTC circuits revealed activity for speeded performance of all tasks. Finally, PD showed reduced task rate-correlated activity in the language BTC circuits for speeded calculation, in the premotor BTC circuit for speeded imagery, and in the motor BTC circuits for speeded movement, as compared with controls. The present study casts light on the anatomo-functional organization of the BTC circuits and their parallel roles in invigorating movement and cognition through a function of dopamine.

Isolation Syndrome after Cardiac Arrest and Therapeutic Hypothermia.

Here, we present the first description of an isolation syndrome in a patient who suffered prolonged cardiac arrest and underwent a standard therapeutic hypothermia protocol. Two years after the arrest, the patient demonstrated no motor responses to commands, communication capabilities, or visual tracking at the bedside. However, resting neuronal metabolism and electrical activity across the entire anterior forebrain was found to be normal despite severe structural injuries to primary motor, parietal, and occipital cortices. In addition, using quantitative electroencephalography, the patient showed evidence for willful modulation of brain activity in response to auditory commands revealing covert conscious awareness. A possible explanation for this striking dissociation in this patient is that altered neuronal recovery patterns following therapeutic hypothermia may lead to a disproportionate preservation of anterior forebrain cortico-thalamic circuits even in the setting of severe hypoxic injury to other brain areas. Compared to recent reports of other severely brain-injured subjects with such dissociation of clinically observable (overt) and covert behaviors, we propose that this case represents a potentially generalizable mechanism producing an isolation syndrome of blindness, motor paralysis, and retained cognition as a sequela of cardiac arrest and therapeutic hypothermia. Our findings further support that highly-preserved anterior cortico-thalamic integrity is associated with the presence of conscious awareness independent from the degree of injury to other brain areas.

Quantifying Poststroke Apathy With Actimeters.

The authors tested the hypothesis that wrist-worn actimeters can quantify the severity of poststroke apathy. The authors studied 57 patients admitted to an acute rehabilitation unit for ischemic or hemorrhagic stroke. After accounting for motor deficit of the affected arm and accounting for age, each increment of the Apathy Inventory score correlated with 5.6 fewer minutes of moving per hour. The overall statistical model had an R(2) of only 0.34, suggesting unexplained factors for total movement time. Wrist-worn actimeters may serve as an objective, quantifiable measure of poststroke apathy in patients with an intact upper extremity but cannot be used alone to diagnose apathy.

Natural History of Poststroke Apathy During Acute Rehabilitation.

To better understand the natural history of poststroke apathy, the authors tested 96 patients undergoing acute rehabilitation for stroke using the Apathy Inventory. A total of 28% of patients had apathy. Their Apathy Inventory scores improved a mean of 1 point by week 2 and 2 points by week 3, with the majority of patients remaining apathetic at discharge. Apathy severity correlated with aphasia, weakness, and impaired cognition but did not correlate with depression. These findings suggest that acute rehabilitation is an optimal setting for clinical trials for poststroke apathy, because apathy is associated with poor outcomes and shows only a small degree of spontaneous improvement.

Post-stroke apathy and hypersomnia lead to worse outcomes from acute rehabilitation.

Apathy and hypersomnia occur after stroke and, by definition, reduce participation in rehabilitation, but their effect on outcome from acute rehabilitation is not known. We performed a retrospective review of 213 patients admitted to a stroke-specialized acute rehabilitation unit in the United States. All patients had ischemic or hemorrhagic stroke, and no dementia or dependence on others pre-stroke. We diagnosed apathy and hypersomnia using standardized documentation by treating therapists. We used multiple regression analysis to control for overall impairment (combination of strength, cognitive and sensory measures), age, time since stroke, and stroke type (ischemic or hemorrhagic). Forty-four (21%) of the patients had persistent apathy, and 12 (5.6%) had persistent hypersomnia. Both groups were more impaired in cognition, sustained attention, and more likely to be treated for depression. Patients with apathy were 2.4 times more likely to go to a nursing home, and had discharge FIM scores 12 points below the mean. Patients with hypersomnia were ten times more likely to go to a nursing home, and had discharge FIM scores 16 points below the mean. These findings indicate that studies to prospectively define these clinical factors and potential confounds using standardized tools are indicated, and if confirmed, justify studies to identify these patients early and develop targeted interventions.

Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury.

Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6-10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7-0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6-10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001.

Consciousness: its neurobiology and the major classes of impairment.

Human consciousness requires brainstem, basal forebrain, and diencephalic areas to support generalized arousal, and functioning thalamocortical networks to respond to environmental and internal stimuli. Disconnection of these interconnected systems, typically from cardiac arrest and traumatic brain injury, can result in disorders of consciousness. Brain injuries can also result in loss of motor output out of proportion to consciousness, resulting in misdiagnoses. The authors review pathology and imaging studies and derive mechanistic models for each of these conditions. Such models may guide the development of target-based treatment algorithms to enhance recovery of consciousness in many of these patients.

What is the role of brain mechanisms underlying arousal in recovery of motor function after structural brain injuries?

PURPOSE OF REVIEW: Standard neurorehabilitation approaches have limited impact on motor recovery in patients with severe brain injuries. Consideration of the contributions of impaired arousal offers a novel approach to understand and enhance recovery. RECENT FINDINGS: Animal and human neuroimaging studies are elucidating the neuroanatomical bases of arousal and of arousal regulation, the process by which the cerebrum mobilizes resources. Studies of patients with disorders of consciousness have revealed that recovery of these processes is associated with marked improvements in motor performance. Recent studies have also demonstrated that patients with less severe brain injuries also have impaired arousal, manifesting as diminished sustained attention, fatigue, and apathy. In these less severely injured patients, it is difficult to connect disorders of arousal with motor recovery because of a lack of measures of arousal that are independent of motor function. SUMMARY: Arousal impairment is common after brain injury and likely plays a significant role in recovery of motor function. A more detailed understanding of this connection will help to develop new therapeutic strategies applicable for a wide range of patients. This requires new tools that continuously and objectively measure arousal in patients with brain injury, to correlate with detailed measures of motor performance and recovery.

Determination of awareness in patients with severe brain injury using EEG power spectral analysis.

OBJECTIVE: To determine whether EEG spectral analysis could be used to demonstrate awareness in patients with severe brain injury. METHODS: We recorded EEG from healthy controls and three patients with severe brain injury, ranging from minimally conscious state (MCS) to locked-in-state (LIS), while they were asked to imagine motor and spatial navigation tasks. We assessed EEG spectral differences from 4 to 24 Hz with univariate comparisons (individual frequencies) and multivariate comparisons (patterns across the frequency range). RESULTS: In controls, EEG spectral power differed at multiple frequency bands and channels during performance of both tasks compared to a resting baseline. As patterns of signal change were inconsistent between controls, we defined a positive response in patient subjects as consistent spectral changes across task performances. One patient in MCS and one in LIS showed evidence of motor imagery task performance, though with patterns of spectral change different from the controls. CONCLUSIONS: EEG power spectral analysis demonstrates evidence for performance of mental imagery tasks in healthy controls and patients with severe brain injury. SIGNIFICANCE: EEG power spectral analysis can be used as a flexible bedside tool to demonstrate awareness in brain-injured patients who are otherwise unable to communicate.