The Neuroanatomy of Speech Processing: A Large-scale Lesion Study.

The neural basis of language has been studied for centuries, yet the networks critically involved in simply identifying or understanding a spoken word remain elusive. Several functional-anatomical models of critical neural substrates of receptive speech have been proposed, including (1) auditory-related regions in the left mid-posterior superior temporal lobe, (2) motor-related regions in the left frontal lobe (in normal and/or noisy conditions), (3) the left anterior superior temporal lobe, or (4) bilateral mid-posterior superior temporal areas. One difficulty in comparing these models is that they often focus on different aspects of the sound-to-meaning pathway and are supported by different types of stimuli and tasks. Two auditory tasks that are typically used in separate studies-syllable discrimination and word comprehension-often yield different conclusions. We assessed syllable discrimination (words and nonwords) and word comprehension (clear speech and with a noise masker) in 158 individuals with focal brain damage: left (n = 113) or right (n = 19) hemisphere stroke, left (n = 18) or right (n = 8) anterior temporal lobectomy, and 26 neurologically intact controls. Discrimination and comprehension tasks are doubly dissociable both behaviorally and neurologically. In support of a bilateral model, clear speech comprehension was near ceiling in 95% of left stroke cases and right temporal damage impaired syllable discrimination. Lesion-symptom mapping analyses for the syllable discrimination and noisy word comprehension tasks each implicated most of the left superior temporal gyrus. Comprehension but not discrimination tasks also implicated the left posterior middle temporal gyrus, whereas discrimination but not comprehension tasks also implicated more dorsal sensorimotor regions in posterior perisylvian cortex.

The Neurobiology of Agrammatic Sentence Comprehension: A Lesion Study.

Broca's area has long been implicated in sentence comprehension. Damage to this region is thought to be the central source of "agrammatic comprehension" in which performance is substantially worse (and near chance) on sentences with noncanonical word orders compared with canonical word order sentences (in English). This claim is supported by functional neuroimaging studies demonstrating greater activation in Broca's area for noncanonical versus canonical sentences. However, functional neuroimaging studies also have frequently implicated the anterior temporal lobe (ATL) in sentence processing more broadly, and recent lesion-symptom mapping studies have implicated the ATL and mid temporal regions in agrammatic comprehension. This study investigates these seemingly conflicting findings in 66 left-hemisphere patients with chronic focal cerebral damage. Patients completed two sentence comprehension measures, sentence-picture matching and plausibility judgments. Patients with damage including Broca's area (but excluding the temporal lobe; n = 11) on average did not exhibit the expected agrammatic comprehension pattern-for example, their performance was >80% on noncanonical sentences in the sentence-picture matching task. Patients with ATL damage ( n = 18) also did not exhibit an agrammatic comprehension pattern. Across our entire patient sample, the lesions of patients with agrammatic comprehension patterns in either task had maximal overlap in posterior superior temporal and inferior parietal regions. Using voxel-based lesion-symptom mapping, we find that lower performances on canonical and noncanonical sentences in each task are both associated with damage to a large left superior temporal-inferior parietal network including portions of the ATL, but not Broca's area. Notably, however, response bias in plausibility judgments was significantly associated with damage to inferior frontal cortex, including gray and white matter in Broca's area, suggesting that the contribution of Broca's area to sentence comprehension may be related to task-related cognitive demands.

Startle Habituation and Midfrontal Theta Activity in Parkinson Disease.

The ability to adapt to aversive stimuli is critical for mental health. Here, we investigate the relationship between habituation to startling stimuli and startle-related activity in medial frontal cortex as measured by EEG in both healthy control participants and patients with Parkinson disease (PD). We report three findings. First, patients with PD exhibited normal initial startle responses but reduced startle habituation relative to demographically matched controls. Second, control participants had midfrontal EEG theta activity in response to startling stimuli, and this activity was attenuated in patients with PD. Finally, startle-related midfrontal theta activity was correlated with the rate of startle habituation. These data indicate that impaired startle habituation in PD is a result of attenuated midfrontal cognitive control signals. Our findings could provide insight into the frontal regulation of startle habituation.

Arrested development: early prefrontal lesions impair the maturation of moral judgement.

Learning to make moral judgements based on considerations beyond self-interest is a fundamental aspect of moral development. A deficit in such learning is associated with poor socialization and criminal behaviour. The neural systems required for the acquisition and maturation of moral competency are not well understood. Here we show in a unique sample of neurological patients that focal lesions involving ventromedial prefrontal cortex, acquired during development, result in an abnormally egocentric pattern of moral judgement. In response to simple hypothetical moral scenarios, the patients were more likely than comparison participants to endorse self-interested actions that involved breaking moral rules or physically harming others in order to benefit themselves. This pattern (which we also found in subjects with psychopathy) differs from that of patients with adult-onset ventromedial prefrontal cortex lesions--the latter group showed normal rejection of egocentric rule violations. This novel contrast of patients with ventromedial prefrontal cortex lesions acquired during development versus during adulthood yields new evidence suggesting that the ventromedial prefrontal cortex is a critical neural substrate for the acquisition and maturation of moral competency that goes beyond self-interest to consider the welfare of others. Disruption to this affective neural system early in life interrupts moral development.

Does brain damage caused by stroke versus trauma have different neuropsychological outcomes? A lesion-matched multiple case study.

Traumatic brain injury (TBI) and stroke both have the potential to cause significant damage to the brain, with resultant neuropsychological impairments. How these different mechanisms of injury influence cognitive and behavioral changes associated with brain damage, however, is not well understood. Moreover, previous research directly comparing TBI and stroke has not accounted carefully for lesion location and size. Here, using a detailed lesion-matching approach that was used previously to compare neuropsychological outcomes in stroke versus tumor, we compared the neuropsychological profiles of 14 patients with focal lesions caused by TBI to those of 27 lesion-matched patients with stroke. Each patient with TBI was matched to two patients with stroke, based on lesion location and size (except 1 TBI case where only 1 stroke match was available). Demographic attributes (age, gender, handedness, education) were also matched in the TBI: stroke triplets, as much as possible. The patients with TBI versus stroke had similar performances across all cognitive and behavioral measures, with no significant or clinically meaningful differences. A supplemental analysis on developmental- versus adult-onset TBI cases (with their respective stroke matches) also yielded non-significant results, with TBI and stroke groups being statistically indistinguishable. Our results suggest that focal lesions caused by TBI versus stroke have similar neuropsychological outcomes in the chronic recovery phase, when location and size of lesion are comparable across TBI versus stroke mechanisms of injury.

Lesions in different prefrontal sectors are associated with different types of acquired personality disturbances.

"Frontal lobe syndrome" is a term often used to describe a diverse array of personality disturbances following frontal lobe damage. This study's guiding premise was that greater neuroanatomical specificity could be achieved by evaluating specific types of personality disturbances following acquired frontal lobe lesions. We hypothesized that three acquired personality disturbances would be associated with lesion involvement of distinct sectors of the prefrontal cortex (PFC): 1) emotional-social disturbance and ventromedial PFC, 2) hypoemotional disturbance and dorsomedial PFC, and 3) dysexecutive and dorsolateral PFC. In addition, we hypothesized that distressed personality disturbance would not be associated with focal PFC lesions in any sector. Each hypothesis was pre-registered and tested in 182 participants with adult-onset, chronic, focal brain lesions studied with an observational, cross-sectional design. Pre- and postmorbid personality was assessed by informant-rating with the Iowa Scales of Personality Change, completed by a spouse or family member. Two complementary analytic approaches were employed: 1) a hypothesis-driven region-of-interest (ROI) regression analysis examining the associations of lesions in specific PFC sectors with acquired personality disturbances; 2) a data-driven multivariate lesion-behavior mapping analysis, which was not limited to pre-specified regions. Each hypothesis received some support: (i) Emotional/social personality disturbance was most strongly associated with ventromedial PFC lesions in both statistical approaches. (ii) Hypoemotional disturbance was associated with dorsomedial PFC lesions in the ROI analyses, without any significant lesion-symptom mapping associations. (iii) Dysexecutive personality disturbance was associated with bilateral dorsolateral PFC lesions and ventromedial PFC lesions; lesion-symptom mapping showed maximal association of executive dysfunction with damage of the right middle frontal gyrus within the dorsolateral PFC. (iv) Distressed personality disturbance was not associated with lesions in any PFC sector. Altogether, the findings can be interpreted to indicate that damage to different prefrontal sectors may disrupt different anatomical-functional systems and result in distinct personality disturbances.

Behavioral effects of congenital ventromedial prefrontal cortex malformation.

BACKGROUND: A detailed behavioral profile associated with focal congenital malformation of the ventromedial prefrontal cortex (vmPFC) has not been reported previously. Here we describe a 14 year-old boy, B.W., with neurological and psychiatric sequelae stemming from focal cortical malformation of the left vmPFC. CASE PRESENTATION: B.W.'s behavior has been characterized through extensive review Patience of clinical and personal records along with behavioral and neuropsychological testing. A central feature of the behavioral profile is severe antisocial behavior. He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance. CONCLUSIONS: The vmPFC has a profound contribution to the development of human prosocial behavior. B.W. demonstrates how a congenital lesion to this cortical region severely disrupts this process.

Are mirror neurons the basis of speech perception? Evidence from five cases with damage to the purported human mirror system.

The discovery of mirror neurons in macaque has led to a resurrection of motor theories of speech perception. Although the majority of lesion and functional imaging studies have associated perception with the temporal lobes, it has also been proposed that the 'human mirror system', which prominently includes Broca's area, is the neurophysiological substrate of speech perception. Although numerous studies have demonstrated a tight link between sensory and motor speech processes, few have directly assessed the critical prediction of mirror neuron theories of speech perception, namely that damage to the human mirror system should cause severe deficits in speech perception. The present study measured speech perception abilities of patients with lesions involving motor regions in the left posterior frontal lobe and/or inferior parietal lobule (i.e., the proposed human 'mirror system'). Performance was at or near ceiling in patients with fronto-parietal lesions. It is only when the lesion encroaches on auditory regions in the temporal lobe that perceptual deficits are evident. This suggests that 'mirror system' damage does not disrupt speech perception, but rather that auditory systems are the primary substrate for speech perception.

Prediction of driving ability with neuropsychological tests: demographic adjustments diminish accuracy.

Demographically adjusted norms generally enhance accuracy of inferences based on neuropsychological assessment. However, we hypothesized that demographic corrections diminish predictive accuracy for real-world activities with absolute cognitive demands. Driving ability was assessed with a 45-minute drive along a standardized on-road route in participants aged 65+ (24 healthy elderly, 26 probable Alzheimer's disease, 33 Parkinson's disease). Neuropsychological measures included: Trail-Making A and B, Complex Figure, Benton Visual Retention, and Block Design tests. A multiple regression model with raw neuropsychological scores was significantly predictive of driving errors (R2 = .199, p = .005); a model with demographically adjusted scores was not (R2 = .113, p = .107). Raw scores were more highly correlated with driving errors than were adjusted scores for each neuropsychological measure, and among healthy elderly and Parkinson's patients. When predicting real-world activities that depend on absolute levels of cognitive abilities regardless of demographic considerations, predictive accuracy is diminished by demographic corrections.

Approach to Cognitive Impairment in Parkinson's Disease.

Cognitive dysfunction is common in Parkinson's disease (PD) and predicts poor clinical outcomes. It is associated primarily with pathologic involvement of basal forebrain cholinergic and prefrontal dopaminergic systems. Impairments in executive functions, attention, and visuospatial abilities are its hallmark features with eventual involvement of memory and other domains. Subtle symptoms in the premotor and early phases of PD progress to mild cognitive impairment (MCI) which may be present at the time of diagnosis. Eventually, a large majority of PD patients develop dementia with advancing age and longer disease duration, which is usually accompanied by immobility, hallucinations/psychosis, and dysautonomia. Dopaminergic medications and deep brain stimulation help motor dysfunction, but may have potential cognitive side effects. Central acetylcholinesterase inhibitors, and possibly memantine, provide modest and temporary symptomatic relief for dementia, although there is no evidence-based treatment for MCI. There is no proven disease-modifying treatment for cognitive impairment in PD. The symptomatic and disease-modifying role of physical exercise, cognitive training, and neuromodulation on cognitive impairment in PD is under investigation. Multidisciplinary approaches to cognitive impairment with effective treatment of comorbidities, proper rehabilitation, and maintenance of good support systems in addition to pharmaceutical treatment may improve the quality of life of the patients and caregivers.

Right anterior cingulate: a neuroanatomical correlate of aggression and defiance in boys.

Variation in emotional processes may contribute to aggressive and defiant behavior. This study assessed these problem behaviors in a large sample of children and adolescents in relation to the volume of two cortical regions with prominent roles in emotion processing, the anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC). One hundred seventeen participants (61 boys, 56 girls), ages 7-17, were recruited from the community. Aggressive and defiant behavior was measured using the parent- and teacher-reported Pediatric Behavior Scale and volumetric measures were generated using structural MRI. Regression analyses indicated a significant sex X ACC volume interaction in predicting aggressive and defiant behavior, without significant results for the vmPFC. Follow-up analyses showed that aggressive and defiant behavior is associated with decreased right ACC volume in boys and a nonsignificant reduction in left ACC volume in girls. These results are consistent with the notion that the right ACC acts as a neuroanatomical correlate of aggression and defiance in boys. The authors discuss this finding in light of its implications for understanding the neural correlates of antisocial behavior.

Impaired navigation in drivers with Parkinson's disease.

Navigating a new route during automobile driving uses the driver's cognitive resources and has the potential to impair driving ability in people with Parkinson's disease (PD). Our aim was to assess navigation and safety errors during a route following task (RFT) in drivers with the illness. Seventy-seven subjects with mild-moderate PD (median Hoehn-Yahr stage = 2.0) and 152 neurologically normal elderly adults, all active and licensed drivers, were tested with a battery of visual, cognitive and motor tests of abilities. Each driver also performed a RFT administered on the road in an instrumented vehicle. Main outcome variables included: number of incorrect turns, times lost and at-fault safety errors. All group comparisons were adjusted for age, gender, education and familiarity with the region. Drivers with PD performed significantly worse on cognitive, visual and motor tests compared to controls, and took longer to finish the RFT. Higher proportions of these drivers made incorrect turns {53.9% in PD versus 21.1% in controls, Odds Ratio (OR) [95% Confidence Interval (CI)] = 2.8 [1.4, 5.7], P = 0.006}, got lost (15.8% versus 2.0%, OR [95%CI] = 4.7 [1.1, 20.0], P = 0.037), or committed at-fault safety errors (84.2% versus 46.7%, OR [95%CI] = 7.5 [3.3, 17.0], P < 0.001). Within the patient group, the navigational and safety errors were predicted by poor performances on cognitive and visual tests, but not by the severity of motor dysfunction. Drivers with PD made more navigation and safety errors than neurologically normal drivers on a RFT that placed demands on driver memory, attention, executive functions and visual perception. The PD group driver safety was degraded possibly due to an increase in the cognitive load in patients with limited reserves. Navigational errors and lower driver safety were associated more with impairments in cognitive and visual function than the motor severity of their disease in drivers with PD.

"Frontal lobe syndrome"? Subtypes of acquired personality disturbances in patients with focal brain damage.

Conceptualizations of the nature of acquired personality disturbances after brain damage, especially to prefrontal cortex, have progressed from clinical observations of a large, disparate set of disturbances to theories concerning neuroanatomically-based subgroups with prefrontal damage. However, hypothesized subtypes have not yet been studied systematically. Based on our previous investigations of acquired personality disturbances, we hypothesized five subtypes of acquired personality disturbances: Executive Disturbances, Disturbed Social Behavior, Emotional Dysregulation, Hypo-emotionality/De-Energization, and Distress, as well as an undisturbed group. Subtypes were investigated in 194 adults with chronic, stable, focal lesions located in various aspects of prefrontal lobes and elsewhere in the brain, using two different cluster analysis techniques applied to ratings on the Iowa Scales of Personality Change. One technique was a hypothesis-driven approach; the other was a set of strictly empirical analyses to assess the robustness of clusters found in the first analysis. The hypothesis-driven analysis largely supported the hypothesized set of subtypes. However, in contrast to the hypothesis, it suggested that disturbed social behavior and emotional dysregulation are not two distinct subtypes, but two aspects of one multifaceted type of disturbance. Additionally, the so-labeled "executive disturbances" group also showed disturbances in other domains. Results from the second (empirical) set of cluster analyses were consistent with findings from the hypothesis-driven cluster analysis. Overall, findings across the two cluster analyses indicated four subtypes of acquired personality disturbances: (1) executive disturbances in association with generalized disturbance, (2) dysregulation of emotions and behavior, (3) hypo-emotionality and de-energization, and (4) distress/anxiety. These findings show strong correspondence with subtypes suggested by prominent models of prefrontal systems based on neuroanatomically-defined circuits. Clarification of distinctive subtypes of acquired personality disturbances is a step toward enhancing our ability to tailor rehabilitative interventions for patients with prefrontal brain injuries.

Neural networks supporting audiovisual integration for speech: A large-scale lesion study.

Auditory and visual speech information are often strongly integrated resulting in perceptual enhancements for audiovisual (AV) speech over audio alone and sometimes yielding compelling illusory fusion percepts when AV cues are mismatched, the McGurk-MacDonald effect. Previous research has identified three candidate regions thought to be critical for AV speech integration: the posterior superior temporal sulcus (STS), early auditory cortex, and the posterior inferior frontal gyrus. We assess the causal involvement of these regions (and others) in the first large-scale (N = 100) lesion-based study of AV speech integration. Two primary findings emerged. First, behavioral performance and lesion maps for AV enhancement and illusory fusion measures indicate that classic metrics of AV speech integration are not necessarily measuring the same process. Second, lesions involving superior temporal auditory, lateral occipital visual, and multisensory zones in the STS are the most disruptive to AV speech integration. Further, when AV speech integration fails, the nature of the failure-auditory vs visual capture-can be predicted from the location of the lesions. These findings show that AV speech processing is supported by unimodal auditory and visual cortices as well as multimodal regions such as the STS at their boundary. Motor related frontal regions do not appear to play a role in AV speech integration.

The earliest behavioral expression of focal damage to human prefrontal cortex.

Damage to the prefrontal cortex in childhood can produce long-term impairments of emotion, behavior regulation, and executive functions, but little is known regarding the earliest expression of these impairments. We describe here detailed behavioral studies of a boy at 14 months of age ('PF1') who sustained focal damage in the right inferior dorsolateral prefrontal cortex due to resection of a vascular malformation on day 3 of life. The surgery was followed by a good medical recovery, and he reached developmental milestones at a normal rate. His neurological examination was normal, as were his mother's ratings of communication abilities, daily living skills, socialization, and motor skills. Multiple standardized laboratory paradigms were used to evaluate his behavior in structured and relatively unstructured situations designed to elicit positive and negative emotions and to place demands on attention. Relative to a comparison group of 50 age-matched boys with no neurological history, PF1 demonstrated significant impairments in the regulation of emotion and engagement of attention, particularly in unstructured conditions. These findings indicate that damage to prefrontal cortex in infancy begins to impact on emotional and cognitive development already during the first months of life.

Longitudinal decline of driving safety in Parkinson disease.

OBJECTIVE: To longitudinally assess and predict on-road driving safety in Parkinson disease (PD). METHODS: Drivers with PD (n = 67) and healthy controls (n = 110) drove a standardized route in an instrumented vehicle and were invited to return 2 years later. A professional driving expert reviewed drive data and videos to score safety errors. RESULTS: At baseline, drivers with PD performed worse on visual, cognitive, and motor tests, and committed more road safety errors compared to controls (median PD 38.0 vs controls 30.5; p < 0.001). A smaller proportion of drivers with PD returned for repeat testing (42.8% vs 62.7%; p < 0.01). At baseline, returnees with PD made fewer errors than nonreturnees with PD (median 34.5 vs 40.0; p < 0.05) and performed similar to control returnees (median 33). Baseline global cognitive performance of returnees with PD was better than that of nonreturnees with PD, but worse than for control returnees (p < 0.05). After 2 years, returnees with PD showed greater cognitive decline and larger increase in error counts than control returnees (median increase PD 13.5 vs controls 3.0; p < 0.001). Driving error count increase in the returnees with PD was predicted by greater error count and worse visual acuity at baseline, and by greater interval worsening of global cognition, Unified Parkinson's Disease Rating Scale activities of daily living score, executive functions, visual processing speed, and attention. CONCLUSIONS: Despite drop out of the more impaired drivers within the PD cohort, returning drivers with PD, who drove like controls without PD at baseline, showed many more driving safety errors than controls after 2 years. Driving decline in PD was predicted by baseline driving performance and deterioration of cognitive, visual, and functional abnormalities on follow-up.

Unsafe rear-end collision avoidance in Alzheimer's disease.

Drivers with cognitive impairment are at increased odds for vehicular crashes. Rear-end collisions (REC) are among the most common crash types. We tested REC avoidance in 61 drivers with mild Alzheimer's disease (AD) and 115 elderly controls using a high-fidelity interactive driving simulator. After a segment of uneventful driving, each driver suddenly encountered a lead vehicle stopped at an intersection, creating the potential for a collision with lead vehicle or with another vehicle following closely behind the driver. Eighty-nine percent of drivers with AD had unsafe outcomes, either an REC or an risky avoidance behavior (defined as slowing down abruptly or prematurely, or swerving out of the traffic lane) compared to 65% of controls (P=0.0007). Crash rates were similar in AD (5%) and controls (3%), yet a greater proportion of drivers with AD slowed down abruptly (70% vs. 37%, P<0.0001) or prematurely (66% vs. 45%, P=0.0115). Abrupt slowing increased the odds of being struck from behind by the following vehicle (P=0.0262). Unsafe outcomes were predicted by tests of visual perception, attention, memory, visuospatial/constructional abilities, and executive functions, as well as vehicular control measures during an uneventful driving segment. Drivers with AD had difficulty responding to driving conditions that pose a hazard for a REC. Some cognitive and visual tests were predictive of unsafe outcomes even after adjusting for disease status.

A neural basis for collecting behaviour in humans.

Collecting behaviour is commonplace in the normal population, but there has been little investigation of its neural basis in humans. The observation that collecting behaviour can assume pathological proportions in patients with certain patterns of brain damage led us to hypothesize that dysfunction in a system encompassing mesial prefrontal cortices accounts for abnormal collecting and may guide normal collecting. We tested the hypothesis in 86 subjects with focal lesions of the telencephalon, by relating the neuroanatomical placement of the lesions to the presence of repetitive and indiscriminate acquisition behaviour and impaired discard behaviour. The subjects had no history of psychiatric disease or abnormal collecting behaviour prior to lesion onset. Lesions were analysed with high-resolution three-dimensional MRI. Collecting behaviour was evaluated with a standardized questionnaire completed by a close relative of each subject. Thirteen subjects exhibited abnormal collecting, characterized by massive and disruptive accumulation of useless objects. In all cases, the abnormality of collecting behaviour was severe and persisted despite attempted interventions and obvious negative consequences. There were no differences between pathological collectors and non-collectors on tests of executive functions or anterograde memory. All subjects with pathological collecting behaviour had damage to the mesial frontal region (including the right polar sector and the anterior cingulate), but there was no damage to most of the subcortical structures that, in species such as rodents, are known to drive the acquisition and retention of objects. The evidence suggests that damage to the mesial frontal region disrupts a mechanism which normally modulates subcortically driven predispositions to acquire and collect, and adjusts these predispositions to environmental context.

Sleep remains disturbed in patients with obstructive sleep apnea treated with positive airway pressure: a three-month cohort study using continuous actigraphy.

OBJECTIVE: Some patients with obstructive sleep apnea (OSA) remain sleepy despite positive airway pressure (PAP) therapy. The mechanisms by which this occurs are unclear but could include persistently disturbed sleep. The goal of this study was to explore the relationships between subjective sleepiness and actigraphic measures of sleep during the first three months of PAP treatment. METHODS: We enrolled 80 patients with OSA and 50 comparison subjects prior to treatment and observed them through three months of PAP therapy. PAP adherence and presence of residual respiratory events were determined from PAP machine downloads. Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), and actigraphic data were collected before and at monthly intervals after starting PAP. RESULTS: Patients with OSA were sleepier and showed a greater degree of sleep disruption by actigraphy at the baseline. After three months of PAP, only ESS and number of awakenings (AWAKE#) normalized, while wake after sleep onset and sleep efficiency remained worse in patients with OSA. FOSQ was improved in patients with OSA but never reached the same level as that of comparison subjects. ESS and FOSQ improved slowly over the study period. CONCLUSIONS: As a group, patients with OSA show actigraphic evidence of persistently disturbed sleep and sleepiness-related impairments in day-to-day function after three months of PAP therapy. Improvements in sleepiness evolve over months with more severely affected patients responding quicker. Persistent sleep disruption may partially explain residual sleepiness in some PAP-adherent OSA patients.