Lecanemab Questions.

The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer disease, quickly led to approval by the FDA and widespread acceptance of lecanemab treatment. However, there are a number of matters that deserve further consideration. The success of blinding was not assessed, even as infusion reactions and the cerebral pathology underlying amyloid-related imaging abnormalities could have signaled to many participants that they were on drug, potentially exerting a potent placebo effect. The value of the outcome to participants is not defined in the absolute terms necessary for clinical decision-making, and the difference attributable to lecanemab was between 18% and 46% of estimates of the minimal clinically important difference on the Clinical Dementia Rating Scale Sum of Boxes. The attenuation of change on the Alzheimer's Disease Assessment Scale-Cognitive 14 achieved by lecanemab at 18 months was 50% of that achieved by donepezil at 6 months. Lecanemab treatment imposes a high treatment burden. The fact that the burden commences at the initiation of lecanemab treatment, whereas the benefit accrues years later requires us to take into account value discounting over time, which would significantly reduce the benefit/burden ratio. Finally, treatment with monoclonal antibodies to cerebral amyloid has consistently been associated with progressive cerebral atrophy. At the least, these issues should be raised in treatment discussions with patients. They also suggest a need to very seriously reconsider how we evaluate clinical trial results preparatory to translating them into clinical practice. Some suggestions are provided.

Management of chronic non-cancer pain: a framework.

Aim: Since publication of the CDC 2016 Guideline, opioid-related mortality in the USA has doubled and a crisis has developed among the 15-20 million Americans with chronic, moderate-to-severe, noncancer pain. Our aim was to develop a comprehensive alternative approach to management of chronic pain. Methods: Analytic review of the clinical literature. Results: Published science provides a solid framework for the management of chronic non-cancer pain, detailed here, even as it leaves many knowledge gaps, which we fill with insights from clinical experience. Conclusion: There is a sufficient basis in science and in clinical experience to achieve adequate control of chronic pain in nearly all patients in a way that adequately balances benefits and potential harms.

Opioid-related mortality in the USA continues to increase rapidly despite the decline in opioid prescriptions achieved by the CDC 2016 Guideline. This Guideline has also created a crisis among the 15­20 million Americans with chronic, moderate-to-severe, noncancer pain. We offer a detailed framework for an alternative approach to management of chronic pain. We also offer some suggestions for solving the problem of illicit drug use, which now accounts for 84% of opioid-related deaths. To the extent possible, we have relied upon published science. However, we also identify many knowledge gaps that we address with insights from clinical experience and thousands of interactions with patients. These knowledge gaps will ultimately need to be addressed by further research.

The Challenge of Achieving Greater Generalization in Phonological Treatment of Aphasia.

Background: Stimulus selection is important to anomia treatment because similarity between trained and untrained words in the mental lexicon may influence treatment generalization. We focused on phonological similarity between trained and untrained words from a clinical trial of Phonomotor Treatment (PMT) that showed gains in confrontation naming accuracy of untrained words post-treatment. One way to capture the amount of similarity between the trained and untrained words is to consider the phonological network path distance between words. We posited that the distance between trained and untrained words in a phonological network could account for the improvement in confrontation naming accuracy post-treatment. Aim: To define the phonological network distance between trained and untrained words that influences change in confrontation naming accuracy post-treatment. Methods and procedures: We retrospectively analyzed data from 28 people with aphasia who received PMT as part of a clinical trial. Participants completed confrontation naming (baseline, post-treatment, and 3-months post-treatment) of words varying in phonological distance to the treatment stimuli. We used a phonological network to calculate the average shortest path length (ASPL), defined by number of phoneme differences, between an untrained word and all trained words. We used mixed effects regression models to predict change in confrontation naming accuracy of untrained words post-treatment from ASPL. Several post-hoc analyses were also conducted. Outcomes and results: We found no effect of ASPL on change in confrontation naming accuracy of untrained words immediately post- and 3-months post-treatment. However, post-hoc analyses indicated significant subject heterogeneity and limitations in observable path distance between trained and untrained words. Conclusion: Despite the clinical trial report that confrontation naming of untrained words improved after PMT, we found no overall effect of ASPL on the amount of improvement. We discuss further investigation of the entire domain of phonological sequence knowledge (the phonological sequence knowledge landscape) and its influence on treatment generalization, and the potential importance of identifying predictors of treatment response to enhance the effects of treatment generalization.

Emotional and Neuropsychiatric Disorders Associated with Alzheimer's Disease.

Alzheimer's disease is associated with impairments in emotional communication including comprehension and production of facial emotional expressions, comprehension of affective prosody, and alexithymia. It is also associated with disorders of emotional experience including mood disorders (depression and anxiety), agitation/aggression, and psychosis. Agitation/aggression and psychosis are particularly disruptive, are associated with earlier institutionalization, and pose a major challenge to institutional management. Treatment of disorders of emotional experience has been primarily pharmacologic (reviewed here in detail) and has relied heavily on antipsychotic medications despite the small effect sizes demonstrated in a large number of randomized controlled trials and the prevalence of serious side effects associated with these drugs. Recent studies suggest that treatment with pimavanserin, an antipsychotic without activity at dopamine receptors, may represent an important advance for treatment of psychotic manifestations, even as the drug appears to pose significant risk. Dextromethorphan/quinidine may represent an important advance in the treatment of agitation/aggression. There is also compelling evidence that sleep disorders, which are common among patients with Alzheimer's disease and are readily treatable, may potentiate psychotic manifestations and agitation/aggression, but further studies are needed.

Language and Aphasias.

PURPOSE OF REVIEW: This article reveals how it is possible for a brain composed of 100 billion highly interconnected, lipid-encased, reticular electrochemical devices to support complex functions such as language and how language disorders can be understood as a reflection of degradation of one or more domains of knowledge. RECENT FINDINGS: Ongoing research, building on landmark work regarding parallel distributed processing (PDP), provides the basis for understanding cognitive functions as a manifestation of the activity of populations of millions or billions of neurons in various highly interconnected networks. Population encoding networks have the following intrinsic properties that provide an orderly explanation for normal and degraded language: (1) a capacity for settling into stable "attractor" states; (2) processing occurs in and knowledge (long-term memories) is stored in exactly the same network; (3) a capacity for incorporating statistical regularities of experience, frequency, and age of acquisition; (4) support of content-addressable memory; and (5) graceful degradation, such that lesions increase the probability of errors but do not fundamentally transform network operations. Knowledge in parallel distributed processing networks resides in the strength of connections between units (synapses in the brain). Aphasia, whether stemming from stroke or dementing disorders, can be understood in terms of the degradation of one or more domains of knowledge. SUMMARY: Understanding the brain as a population encoding machine incorporating vast interconnectivity provides an orderly explanation for language function, both normal and abnormal.

Treatment of disorders of emotional comprehension, expression, and emotional semantics.

Neurological disease can impair emotional communication by several means: damaging the networks important in understanding the meaning of emotional stimuli (emotional semantics); damaging networks important in the perceptual recognition and production of emotional stimuli, and damaging the connections between networks supporting emotional semantics and recognition/production networks. Disorders of emotional expression, comprehension, and emotional semantics may improve with pharmacological or behavioral treatments. Pharmacological treatments can be used to redress naturally occurring or disease-related alterations in the computational properties of target neural systems. No drug treatment can replace a loss of cerebral knowledge related to the pathological loss of neural connectivity. Behavioral treatments that benefit either comprehension or expression of specific emotions may be of value if these emotions are particularly important in enabling human social interaction. However, behavioral treatments that achieve generalization, that is, improve performance with untrained exemplars and in daily life, are much to be preferred, even as they pose the greatest methodological challenges. This chapter will discuss possible mechanisms of generalization and then review what is known about the treatment of expressive and receptive affective aprosodia, deficits in recognition of facial emotions, and pseudobulbar affect. The final section of the chapter is devoted to a discussion of three disorders of emotional semantics, apathy, alexithymia, and impaired empathy.

Neural mechanisms of emotions, alexithymia, and depression.

This chapter brings the powerful conceptual tools of the science of parallel distributed processing (PDP) to bear on the cognitive neuroscience of emotions discussed in this book. Cerebral representations are encoded as patterns of activity involving billions of neurons. PDP across these neuronal populations provides the basis for a number of emergent properties: (1) processing occurs and knowledge (long term memories) is stored (as synaptic connection strengths) in exactly the same networks; (2) networks have the capacity for setting into stable attractor states corresponding to concepts, symbols, implicit rules, or data transformations; (3) networks provide the scaffold for the acquisition of knowledge, but knowledge is acquired through experience; (4) PDP networks are adept at incorporating the statistical regularities of experience as well as frequency and age of acquisition effects; (5) networks enable content-addressable memory; (6) because knowledge is distributed throughout networks, they exhibit the property of graceful degradation; (7) networks intrinsically provide the capacity for inference. With this perspective, I propose a new model of emotional function that reasonably accounts for the effects of focal lesions at various points (insula, orbitofrontal cortex, convexity cortex, and intervening white matter) due to stroke, trauma, surgery, and degenerative disease, as reflected in disorders of affective prosody, facial emotional comprehension and expression, emotional behavior, and personality. I consider a modification of the James Lange theory that takes into account the role of a lifetime of subjective knowledge acquisition by the orbitofrontal cortex. Alexithymia is conceptualized as a disorder of the insula/orbitofrontal cortex/dorsolateral prefrontal cortex (DL-PFC) system, the function of which can be disrupted by degradation of knowledge at a number of different locations. Finally, I consider the possibility that depression reflects pathological learning involving the medial and lateral orbitofrontal cortices such that there is a pathologic engagement of the two regions, as suggested by Rolls. I conclude with a consideration of the peculiar responsivity of depression to serotonergic and noradrenergic agents, as well as to surgical orbitofrontal undercutting, and what that might be telling us about the mechanisms of depression and its treatment.

Basal Ganglia and Thalamic Contributions to Language Function: Insights from A Parallel Distributed Processing Perspective.

Cerebral representations are encoded as patterns of activity involving billions of neurons. Parallel distributed processing (PDP) across these neuronal populations provides the basis for a number of emergent properties: 1) processing occurs and knowledge (long term memories) is stored (as synaptic connection strengths) in exactly the same networks; 2) networks have the capacity for setting into stable attractor states corresponding to concepts, symbols, implicit rules, or data transformations; 3) networks provide the scaffold for the acquisition of knowledge but knowledge is acquired through experience; 4) PDP networks are adept at incorporating the statistical regularities of experience as well as frequency and age of acquisition effects; 5) networks enable content-addressable memory; 6) because knowledge is distributed throughout networks, they exhibit the property of graceful degradation; 7) networks intrinsically provide the capacity for inference. This paper details the features of the basal ganglia and thalamic systems (recurrent and distributed connectivity) that support PDP. The PDP lens and an understanding of the attractor trench dynamics of the basal ganglia provide a natural explanation for the peculiar dysfunctions of Parkinson's disease and the mechanisms by which dopamine deficiency is causal. The PDP lens, coupled with the fact that the basal ganglia of humans bears strong homology to the basal ganglia of lampreys and the central complex of arthropods, reveals that the fundamental function of the basal ganglia is computational and involves the reduction of the vast dimensionality of a complex multi-dimensional array of sensorimotor input into the optimal choice from a small repertoire of behavioral options - the essence of reactive intention (automatic responses to sensory input). There is strong evidence that the sensorimotor basal ganglia make no contributions to cognitive or motor function in humans but can cause serious dysfunction when pathological. It appears that humans, through the course of evolution, have developed cortical capacities (working memory and volitional and reactive attention) for managing sensory input, however complex, that obviate the need for the basal ganglia. The functions of the dorsal tier thalamus, however, even viewed with an understanding of the properties of population encoded representations, remain somewhat more obscure. Possibilities include the enabling of attractor state constellations that optimize function by taking advantage of simultaneous input from multiple cortical areas; selective engagement of cortical representations; and support of the gamma frequency synchrony that enables binding of the multiple network representations that comprise a full concept representation.

Opioids and Chronic Pain: An Analytic Review of the Clinical Evidence.

We conducted an analytic review of the clinical scientific literature bearing on the use of opioids for treatment of chronic non-cancer pain in the United States. There is substantial, albeit not definitive, scientific evidence of the effectiveness of opioids in treating pain and of high variability in opioid dose requirements and side effects. The estimated risk of death from opioid treatment involving doses above 100 MMED is ~0.25%/year. Multiple large studies refute the concept that short-term use of opioids to treat acute pain predisposes to development of opioid use disorder. The prevalence of opioid use disorder associated with prescription opioids is likely <3%. Morbidity, mortality, and financial costs of inadequate treatment of the 18 million Americans with moderate to severe chronic pain are high. Because of the absence of comparative effectiveness studies, there are no scientific grounds for considering alternative non-pharmacologic treatments as an adequate substitute for opioid therapy but these treatments might serve to augment opioid therapy, thereby reducing dosage. There are reasons to question the ostensible risks of co-prescription of opioids and benzodiazepines. As the causes of the opioid crisis have come into focus, it has become clear that the crisis resides predominantly in the streets and that efforts to curtail it by constraining opioid treatment in the clinic are unlikely to succeed.

Neural Population Dynamics and Cognitive Function.

Representations in the brain are encoded as patterns of activity of large populations of neurons. The science of population encoded representations, also known as parallel distributed processing (PDP), achieves neurological verisimilitude and has been able to account for a large number of cognitive phenomena in normal people, including reaction times (and reading latencies), stimulus recognition, the effect of stimulus salience on attention, perceptual invariance, simultaneous egocentric and allocentric visual processing, top-down/bottom-up processing, language errors, the effect of statistical regularities of experience, frequency, and age of acquisition, instantiation of rules and symbols, content addressable memory and the capacity for pattern completion, preservation of function in the face of noisy or distorted input, inference, parallel constraint satisfaction, the binding problem and gamma coherence, principles of hippocampal function, the location of knowledge in the brain, limitations in the scope and depth of knowledge acquired through experience, and Piagetian stages of cognitive development. PDP studies have been able to provide a coherent account for impairment in a variety of language functions resulting from stroke or dementia in a large number of languages and the phenomenon of graceful degradation observed in such studies. They have also made important contributions to our understanding of attention (including hemispatial neglect), emotional function, executive function, motor planning, visual processing, decision making, and neuroeconomics. The relationship of neural network population dynamics to electroencephalographic rhythms is starting to emerge. Nevertheless, PDP approaches have scarcely penetrated major areas of study of cognition, including neuropsychology and cognitive neuropsychology, as well as much of cognitive psychology. This article attempts to provide an overview of PDP principles and applications that addresses a broader audience.

Phonomotor Versus Semantic Feature Analysis Treatment for Anomia in 58 Persons With Aphasia: A Randomized Controlled Trial.

Purpose The ultimate goal of anomia treatment should be to achieve gains in exemplars trained in the therapy session, as well as generalization to untrained exemplars and contexts. The purpose of this study was to test the efficacy of phonomotor treatment, a treatment focusing on enhancement of phonological sequence knowledge, against semantic feature analysis (SFA), a lexical-semantic therapy that focuses on enhancement of semantic knowledge and is well known and commonly used to treat anomia in aphasia. Method In a between-groups randomized controlled trial, 58 persons with aphasia characterized by anomia and phonological dysfunction were randomized to receive 56-60 hr of intensively delivered treatment over 6 weeks with testing pretreatment, posttreatment, and 3 months posttreatment termination. Results There was no significant between-groups difference on the primary outcome measure (untrained nouns phonologically and semantically unrelated to each treatment) at 3 months posttreatment. Significant within-group immediately posttreatment acquisition effects for confrontation naming and response latency were observed for both groups. Treatment-specific generalization effects for confrontation naming were observed for both groups immediately and 3 months posttreatment; a significant decrease in response latency was observed at both time points for the SFA group only. Finally, significant within-group differences on the Comprehensive Aphasia Test-Disability Questionnaire (Swinburn, Porter, & Howard, 2004) were observed both immediately and 3 months posttreatment for the SFA group, and significant within-group differences on the Functional Outcome Questionnaire (Glueckauf et al., 2003) were found for both treatment groups 3 months posttreatment. Discussion Our results are consistent with those of prior studies that have shown that SFA treatment and phonomotor treatment generalize to untrained words that share features (semantic or phonological sequence, respectively) with the training set. However, they show that there is no significant generalization to untrained words that do not share semantic features or phonological sequence features.

Locomotor Training and Strength and Balance Exercises for Walking Recovery After Stroke: Response to Number of Training Sessions.

BACKGROUND: Evidence-based guidelines are needed to inform rehabilitation practice, including the effect of number of exercise training sessions on recovery of walking ability after stroke. OBJECTIVE: The objective of this study was to determine the response to increasing number of training sessions of 2 interventions-locomotor training and strength and balance exercises-on poststroke walking recovery. DESIGN: This is a secondary analysis of the Locomotor Experience Applied Post-Stroke (LEAPS) randomized controlled trial. SETTING: Six rehabilitation sites in California and Florida and participants' homes were used. PARTICIPANTS: Participants were adults who dwelled in the community (N=347), had had a stroke, were able to walk at least 3 m (10 ft) with assistance, and had completed the required number of intervention sessions. INTERVENTION: Participants received 36 sessions (3 times per week for 12 weeks), 90 minutes in duration, of locomotor training (gait training on a treadmill with body-weight support and overground training) or strength and balance training. MEASUREMENTS: Talking speed, as measured by the 10-Meter Walk Test, and 6-minute walking distance were assessed before training and following 12, 24, and 36 intervention sessions. RESULTS: Participants at 2 and 6 months after stroke gained in gait speed and walking endurance after up to 36 sessions of treatment, but the rate of gain diminished steadily and, on average, was very low during the 25- to 36-session epoch, regardless of treatment type or severity of impairment. LIMITATIONS: Results may not generalize to people who are unable to initiate a step at 2 months after stroke or people with severe cardiac disease. CONCLUSIONS: In general, people who dwelled in the community showed improvements in gait speed and walking distance with up to 36 sessions of locomotor training or strength and balance exercises at both 2 and 6 months after stroke. However, gains beyond 24 sessions tended to be very modest. The tracking of individual response trajectories is imperative in planning treatment.

Using Radiological Data to Estimate Ischemic Stroke Severity.

BACKGROUND: Risk-adjusted poststroke mortality has been proposed for use as a measure of stroke care quality. Although valid measures of stroke severity (e.g., the National Institutes of Health Stroke Scale [NIHSS]) are not typically available in administrative datasets, radiology reports are often available within electronic health records. We sought to examine whether admission head computed tomography data could be used to estimate stroke severity. MATERIALS AND METHODS: Using chart review data from a cohort of acute ischemic stroke patients (1998-2003), we developed a radiographic measure ([BIS]) of stroke severity in a two-third development set and assessed in a one-third validation set. The retrospective NIHSS was dichotomized as mild/moderate (<10) and severe (≥10). We compared the association of this radiographic score with NIHSS and in-hospital mortality at the patient level. RESULTS: Among 1348 stroke patients, 86.5% had abnormal findings on initial head computed tomography. The c-statistic for the BIS for modeling severe stroke (development, .581; validation, .579) and in-hospital mortality (development, .623; validation, .678) were generated. CONCLUSIONS: Although the c-statistics were only moderate, the BIS provided significant risk stratification information with a 2-variable score. Until administrative data routinely includes a valid measure of stroke severity, radiographic data may provide information for use in risk adjustment.

The Effects of Stroke Type, Locus, and Extent on Long-Term Outcome of Gait Rehabilitation: The LEAPS Experience.

Background Paresis in stroke is largely a result of damage to descending corticospinal and corticobulbar pathways. Recovery of paresis predominantly reflects the impact on the neural consequences of this white matter lesion by reactive neuroplasticity (mechanisms involved in spontaneous recovery) and experience-dependent neuroplasticity, driven by therapy and daily experience. However, both theoretical considerations and empirical data suggest that type of stroke (large vessel distribution/lacunar infarction, hemorrhage), locus and extent of infarction (basal ganglia, right-hemisphere cerebral cortex), and the presence of leukoaraiosis or prior stroke might influence long-term recovery of walking ability. In this secondary analysis based on the 408 participants in the Locomotor Experience Applied Post-Stroke (LEAPS) study database, we seek to address these possibilities. Methods Lesion type, locus, and extent were characterized by the 2 neurologists in the LEAPS trial on the basis of clinical computed tomography and magnetic resonance imaging scans. A series of regression models was used to test our hypotheses regarding the effects of lesion type, locus, extent, and laterality on 2- to 12-month change in gait speed, controlling for baseline gait speed, age, and Berg Balance Scale score. Results Gait speed change at 1 year was significantly reduced in participants with basal ganglia involvement and prior stroke. There was a trend toward reduction of gait speed change in participants with lacunar infarctions. The presence of right-hemisphere cortical involvement had no significant impact on outcome. Conclusions Type, locus, and extent of lesion, and the loss of substrate for neuroplastic effect as a result of prior stroke may affect long-term outcome of rehabilitation of hemiparetic gait.

Considerations for the Optimization of Induced White Matter Injury Preclinical Models.

White matter (WM) injury in relation to acute neurologic conditions, especially stroke, has remained obscure until recently. Current advances in imaging technologies in the field of stroke have confirmed that WM injury plays an important role in the prognosis of stroke and suggest that WM protection is essential for functional recovery and post-stroke rehabilitation. However, due to the lack of a reproducible animal model of WM injury, the pathophysiology and mechanisms of this injury are not well studied. Moreover, producing selective WM injury in animals, especially in rodents, has proven to be challenging. Problems associated with inducing selective WM ischemic injury in the rodent derive from differences in the architecture of the brain, most particularly, the ratio of WM to gray matter in rodents compared to humans, the agents used to induce the injury, and the location of the injury. Aging, gender differences, and comorbidities further add to this complexity. This review provides a brief account of the techniques commonly used to induce general WM injury in animal models (stroke and non-stroke related) and highlights relevance, optimization issues, and translational potentials associated with this particular form of injury.

Cognitive-motor dysfunction after severe traumatic brain injury: A cerebral interhemispheric disconnection syndrome.

BACKGROUND/OBJECTIVES: In most right-handed people, the left hemisphere is dominant for programming the temporal and spatial "how" (praxis) aspects of purposeful skilled movements, and the right hemisphere is dominant for control of the intentional "when" aspects of actions that mediate initiation, persistence, termination, and inhibition. Since the interhemispheric axons of the corpus callosum are especially susceptible to shearing from torsional forces during traumatic brain injury (TBI), the goal of this study was to learn whether participants with a history of severe traumatic brain injury demonstrate three types of cognitive-motor impairments that may result from callosal injury: ideomotor apraxia of the left hand, limb kinetic apraxia of the left hand, and hypokinesia of the right hand in response to left hemispatial stimuli. METHOD: Nine participants with severe TBI and nine healthy control participants were studied for the presence of ideomotor apraxia, limb kinetic apraxia, and hypokinesia. RESULTS: When compared to the control participants, the participants with TBI revealed ideomotor apraxia and limb kinetic apraxia of the left hand and hypokinesia in response to left-sided visual stimuli when tested with the right hand. CONCLUSIONS: TBI appears to cause unilateral disorders of cognitive-motor functions. Future research is needed to understand how these cognitive-motor disorders are related to interhemispheric disconnection most likely induced by injury to the corpus callosum.

Opioids for chronic noncancer pain: To prescribe or not to prescribe-What is the question?

The recent American Academy of Neurology position paper by Franklin, "Opioids for chronic noncancer pain," suggests that the benefits of opioid treatment are very likely to be substantially outweighed by the risks and recommends avoidance of doses above 80-120 mg/day morphine equivalent. However, close reading of the primary literature supports a different conclusion: opioids have been shown in randomized controlled trials (RCTs) to be highly effective in the treatment of chronic nonmalignant pain; long-term follow-up studies have shown that this effectiveness can be maintained; and effectiveness has been limited in many clinical trials by failure to take into account high variability in dose requirements, failure to adequately treat depression, and use of suboptimal outcome measures. Frequency of side effects in many RCTs has been inflated by overly rapid dose titration and failure to appreciate the high interindividual variability in side effect profiles. The recent marked increase in incidence of opioid overdose is of grave concern, but there is good reason to believe that it has been somewhat exaggerated. Potential causes of overdose include inadequately treated depression; inadequately treated pain, particularly when compounded by hopelessness; inadvertent overdose; concurrent use of alcohol; and insufficient practitioner expertise. Effective treatment of pain can enable large numbers of patients to lead productive lives and improve quality of life. Effective alleviation of suffering associated with pain falls squarely within the physician's professional obligation. Existing scientific studies provide the basis for many improvements in pain management that can increase effectiveness and reduce risk. Many potentially useful areas of further research can be identified.