Long-term cognitive impairment after critical illness.

BACKGROUND: Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized. METHODS: We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders. RESULTS: Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months. CONCLUSIONS: Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.).

Probabilistic categorization: how do normal participants and amnesic patients do it?

In probabilistic categorization tasks, various cues are probabilistically (but not perfectly) predictive of class membership. This means that a given combination of cues sometimes belongs to one class and sometimes to another. It is not yet clear how categorizers approach such tasks. Here, we review evidence in favor of two alternative conceptualizations of learning in probabilistic categorization: as rule-based learning, or as incremental learning. Each conceptualization forms the basis of a way of analyzing performance: strategy analysis assumes rule-based learning, while rolling regression analysis assumes incremental learning. Here, we contrasted the ability of each to predict performance of normal categorizers. Both turned out to predict responses about equally well. We then reviewed performance of patients with damage to regions deemed important for either rule-based or incremental learning. Evidence was again about equally compatible with either alternative conceptualization of learning, although neither predicted an involvement of the medial temporal lobe. We suggest that a new way of conceptualizing probabilistic categorization might be fruitful, in which the medial temporal lobe help set up representations that are then used by other regions to assign patterns to categories.

Yes/no recognition, forced-choice recognition, and the human hippocampus.

Two recent studies reported that yes/no recognition can be more impaired by hippocampal lesions than forced-choice recognition when the targets and foils are highly similar. This finding has been taken in support of two fundamental proposals: (1) yes/no recognition tests depend more on recollection than do forced-choice tests; and (2) the hippocampus selectively supports the recollection process. Using the same stimulus materials as in the earlier studies, we tested five memory-impaired patients with circumscribed hippocampal lesions and 15 controls. As in the earlier studies, participants studied 12 pictures of objects and then took either a 12-item forced-choice test with four alternatives or a 60-item yes/no test. Patients were impaired on both tests but did more poorly on the yes/no test. However, a yes/no test based on 12 study items would conventionally involve only 24 test items (i.e., 12 study items and 12 foil items). When we scored only the first 24 test items, the patients performed identically on the yes/no and forced-choice tests. Examination of the data in blocks of 12 trials indicated that the scores of the patients declined as testing continued. We suggest that a yes/no test of 60 items is difficult relative to a 12-item forced-choice test due to the increased study-test delay and due to increased interference, not because of any fundamental difference between the yes/no and forced-choice formats. We conclude that hippocampal lesions impair yes/no and forced-choice recognition to the same extent.

Basal ganglia volumes following CO poisoning: A prospective longitudinal study.

Carbon monoxide (CO) poisoning may result in focal and diffuse neuropathological changes, including basal ganglia lesions. The effect of CO poisoning on basal ganglia volumes over time is unclear. We assessed basal ganglia volumes longitudinally following CO poisoning. We prospectively enrolled 73 CO poisoned patients who underwent brain MR imaging on day 1 (baseline), 2 weeks, and 6 months post-CO poisoning. Basal ganglia volumes were obtained. One patient had bilateral globus pallidus lesions at two weeks and 6 months. Of the CO-poisoned patients 28% had volume reduction in at least one basal ganglia structure by 6 months, of which 21% had putamen, 15% had caudate, 15% had globus pallidus, and 16% had total basal ganglia volume reduction. Putamen volumes were significantly smaller from baseline to six months (p = 0.02). Verbal memory and mental processing speed correlated with smaller putamen and globus pallidus volumes. Carbon monoxide poisoning results in basal ganglia volume reduction 6 months post CO poisoning. Slow mental processing speed and impaired memory correlated with smaller putamen and globus pallidus volumes. Clinicians need to be aware of basal ganglia neuropathologic changes in the absence of observable lesions following CO poisoning.

Conditional discrimination and reversal in amnesia subsequent to hypoxic brain injury or anterior communicating artery aneurysm rupture.

Human anterograde amnesia can develop following bilateral damage to the hippocampus and medial temporal lobes, as in hypoxic brain injury, or following damage to the basal forebrain, as following anterior communicating artery (ACoA) aneurysm rupture. In both cases, the mnestic deficit may be similar when assessed by standard neuropsychological measures. However, animal and computational models suggest that there are qualitative differences in the pattern of impaired and spared memory abilities following damage to hippocampus versus basal forebrain. Here, we show such a dissociation in human amnesia using a single two-stage task, involving conditional discrimination and reversal. Consistent with a prior study, 10 individuals with anterograde amnesia subsequent to hypoxic brain injury were spared on acquisition but impaired at reversal. However, 10 individuals with amnesia subsequent to ACoA aneurysm showed the opposite pattern of impaired acquisition but spared reversal. The differences between groups cannot be easily ascribed to severity of mnestic or cognitive deficit, since the two amnesic groups performed similarly on neuropsychological tests of memory, intelligence and attention. The results illustrate qualitative differences in memory impairments in hypoxic and ACoA amnesics and highlight the importance of considering etiology in evaluating mnemonic deficits in amnesic populations.

On the contribution of perceptual fluency and priming to recognition memory.

Repetition priming has been shown to be independent of recognition memory. Thus, the severely amnesic patient E.P. has demonstrated intact stem completion priming and perceptual identification priming, despite at-chance performance on recognition memory tasks. It has also been shown that perceptual fluency can influence feelings of familiarity, in the sense that items perceived more quickly tend to be identified as familiar. If studied items are identified more fluently, due to perceptual priming, and fluency leads to familiarity, why do severely amnesic patients perform no better than chance on recognition memory tasks? One possibility is that severely amnesic patients do not exhibit normal fluency. Another possibility is that fluency is not a sufficiently strong cue for familiarity. In two experiments, 2 severely amnesic patients, 3 moderately amnesic patients, and 8 controls saw words slowly clearing from a mask. The participants identified each word as quickly as possible and then made a recognition (old/new) judgment. All the participants exhibited fluency, in that old responses were associated with shorter identification times than new responses were. In addition, for the severely amnesic patients, priming was intact, and recognition memory performance was at chance. We next calculated how much priming and fluency should elevate the probability of accurate recognition. The tendency to identify studied words rapidly (.6) and the tendency to label these rapidly identified words old (.6) would result in 36% of the studied words being labeled old. Other studied words were identified slowly (.4) but were still labeled old (.4), resulting in an additional 16% of studied words labeled old. Thus, the presence of fluency increases the probability of accurate recognition judgments to only 52% (chance = 50%). This finding explains why amnesic patients can exhibit both priming and fluency yet still perform at chance on recognition tests.

White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning.

BACKGROUND: Carbon monoxide (CO) poisoning may result in white matter hyperintensities (WMH) and neurocognitive impairments. OBJECTIVE: To assess in a prospective study WMH in CO-poisoned patients and their relationship to cognitive functioning. METHODS: Seventy-three consecutive CO-poisoned patients were studied. MR scans and neurocognitive tests were administered on day 1 (within 36 hours after CO poisoning), 2 weeks, and 6 months. Age- and sex-matched control subjects for white matter analyses only were obtained from the authors' normative imaging database. MR scans were rated for WMH in the periventricular and centrum semiovale regions, using a 4-point rating scale. Two independent raters rated the scans, and a consensus was reached. RESULTS: Thirty percent of CO-poisoned patients had cognitive sequelae. Twelve percent of the CO-poisoned patients had WMH, with significantly more periventricular, but not centrum semiovale, WMH than control subjects. The WMH in CO-poisoned patients did not change from day 1 to 6 months. Centrum semiovale hyperintensities were related to worse cognitive performance. Duration of loss of consciousness correlated with cognitive impairment at all three times. Initial carboxyhemoglobin levels correlated with loss of consciousness but not with WMH or cognitive sequelae. CONCLUSIONS: CO poisoning can result in brain injury manifested by WMH and cognitive sequelae. The WMH were not related to CO poisoning severity. The WMH occurred in both the periventricular and the centrum semiovale regions; however, only those in the centrum semiovale were significantly associated with cognitive impairments.

Verbal memory deficits associated with fornix atrophy in carbon monoxide poisoning.

Magnetic resonance (MR) images and neuropsychological testing data of 69 carbon monoxide (CO) poisoned patients were prospectively obtained within 1 day of CO poisoning, two weeks and six months. CO patients' Day 1 cross-sectional fornix surface area measurements, corrected for head size by using a fornix-to-brain ratio (FBR), were compared to normal age and gender-matched controls. Additionally, a within-subjects analysis was performed comparing the mean areas between CO patients' Day 1, 2 weeks and 6-month FBR. The FBR was correlated with patients' neuropsychological data. There were no significant differences between CO patients' Day 1 fornix measurements compared to normal control subjects. However, significant atrophic changes in the fornix of CO poisoned patients occurred at two weeks with no progressive atrophy at 6 months. By 6 months, CO patients showed significant decline on tests of verbal memory (when practice effects were taken into account), whereas visual memory, processing speed and attention/concentration did not decline. This study indicates that CO results in brain damage and cognitive impairments in the absence of lesions and other neuroanatomic markers.

Short-term memory for duration and distance in humans: role of the hippocampus.

Control participants and hypoxic participants with bilateral hippocampal damage were tested for short-term memory (STM) for presentation duration of a single object, STM for a single object, STM for spatial distance information, and time estimation. Delays of 1, 4, 8, 12, or 16 s were used for all the STM and time estimation tests. Results indicated that relative to controls, hypoxic participants were significantly impaired for STM for duration and distance information at the long but not short delays. Similarly, time estimation was accurate only to 8 s for hypoxic participants, but STM for a single object was only mildly affected. Results suggest that the hippocampus may be required for the processing of spatial and temporal STM information.

Acute psychosis associated with diving.

There are only a few reported cases of psychiatric disorders presenting a s decompression sickness (DCS). Previous reports indicate that DCS can result in personality change, depression, Munchausen's syndrome, and pseudo stroke. We report two cases of acute psychoses that occurred following diving as suspected DCS and were treated with hyperbaric oxygen, which did not improve the psychotic features. One patient had symptoms of DCS including myalgias, weakness, and fatigue; however the symptoms were inconsistent. The symptom onset and nitrogen loading from his dive profiles made the diagnosis of DCS unlikely. The second patient exhibited mild joint pain, fatigue, and psychosis that was temporally associated with diving but no other symptoms of DCS. Following a detailed medical evaluation we determined that these two patients did not have DCS or arterial gas embolism (AGE). Although it is highly unlikely that a pure psychotic episode will arise as a result of DCS, physicians caring for divers with symptoms of DCS or AGE and acute psychosis may consider a trial of recompression therapy while completing the medical evaluation. Divers with acute psychosis without signs and symptoms and benign dive profiles are unlikely to have DCS or AGE.

Spared discrimination and impaired reversal eyeblink conditioning in patients with temporal lobe amnesia.

The effect of medial temporal lobe damage on a 2-tone delay discrimination and reversal paradigm was examined in human classical eyeblink conditioning. Eight medial temporal lobe amnesic patients and their demographically matched controls were compared. Amnesic patients were able to distinguish between 2 tones during the initial discrimination phase of the experiment almost as well as control participants. Amnesic patients were not able to reverse the previously acquired 2-tone discrimination. In contrast, the control participants showed improved discrimination performance after the reversal of the tones. These findings support the hypothesis that the hippocampus and associated temporal lobe regions play a role in eyeblink conditioning that becomes essential in more complex versions of the task, such as the reversal of an acquired 2-tone discrimination.

Unexpected ratio of allozyme expression in diploid and triploid individuals of the clonal hybrid fish Phoxinus eos-neogaeus.

Phoxinus eos-neogaeus, a North American freshwater fish, was formed by hybridization between P. neogaeus and P. eos. Individuals of P. eos-neogaeus express one allozyme of P. eos and one allozyme of P. neogaeus for enzymes for which the parental allozymes are distinctive. We performed densitometry on phosphoglucomutase (PGM) and one glucose-6-phosphate isomerase locus (GPI-A) separated by cellulose acetate electrophoresis to determine if the parental species' allozymes are expressed in proportion to the number of genomes present in diploid and triploid individuals, and if these enzymes are regulated separately in different tissues. In diploids, activity of the P. eos allozyme was greater than the P. neogaeus allozyme in eye, liver, and muscle but not in heart (one sample t-test, P = 0.05) for PGM. The activity of the P. eos GPI-A allozyme was significantly greater than the P. neogaeus allozyme in heart, eye and muscle but not in liver (one sample t-test, P = 0.05). The expected ratio of eos:neogaeus expression in triploid P. eos-neogaeus x eos individuals is 2:1. For PGM, the observed ratio of eos:neogaeus expression was not significantly different from 2:1 in all four tissues. The P. eos allozyme for GPI was expressed less than expected in all four tissues (one-sample t-test, P = 0.05). Thus, greater than expected expression of the P. eos allozyme was not observed in triploid individuals as it was in the diploids. These data show that PGM and GPI are regulated separately, and that regulation differs by tissue, and in fish of distinct ploidy levels. J. Exp. Zool. 284:663-674, 1999.

Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a disease of acute respiratory failure manifested by severe hypoxemia with a high mortality rate. Previous outcome studies of ARDS have assessed survival and/or pulmonary function as the primary outcome variables. Cognitive or psychological outcomes following ARDS have not been described, despite the possibility that ARDS patients are at risk for brain injury through hypoxemia or other mechanisms. In the current study 55 consecutive ARDS survivors completed a battery of neuropsychological tests and questionnaires regarding health status, cognitive and psychological outcomes at the time of hospital discharge and 1 yr after onset of ARDS. At hospital discharge, 100% (55 of 55) of survivors exhibited cognitive and affective impairments, as well as problems with health status which affected their quality of life. At 1 yr after ARDS, 17 of 55 (30%) patients still exhibited generalized cognitive decline. Forty-three of 55 (78%) patients had all or at least one of the following: impaired memory, attention, concentration and/or decreased mental processing speed. One year after ARDS a substantial portion of ARDS survivors exhibit impaired health status and cognitive sequelae which may be due to hypoxemia, emboli, inflammation, drug toxicity, and/or other etiologies.

MRI, quantitative MRI, SPECT, and neuropsychological findings following carbon monoxide poisoning.

Carbon monoxide (CO) poisoning has been shown to result in neuropathologic changes and cognitive impairments due to anoxia and other related biochemical mechanisms. The present study investigated brain-behaviour relationships between neuropsychological outcome and SPECT, MRI, and Quantitative magnetic resonance imaging (QMRI) in 21 patients with CO poisoning. Ninety-three per cent of the patients exhibited a variety of cognitive impairments, including impaired attention, memory, executive function, and mental processing speed. Ninety-five per cent of the patients experienced affective changes including depression and anxiety. The results from the imaging studies revealed that 38% of the patients had abnormal clinical MRI scans, 67% had abnormal SPECT scans, and 67% had QMRI findings including hippocampal atrophy and/or diffuse cortical atrophy evidenced by an enlarged ventricle-to-brain ratio (VBR). Hippocampal atrophy was also found on QMRI. SPECT and QMRI appear to be sensitive tools which can be used to identify the neuropathological changes and cerebral perfusion defects which occur following CO poisoning. Cerebral perfusion defects include frontal and temporal lobe hypoperfusion. Significant relationships existed between the various imaging techniques and neuropsychological impairments. The data from this study indicate that a multi-faceted approach to clinical evaluation of the neuropathological and neurobehavioural changes following CO poisoning may provide comprehensive information regarding the neuroanatomical and neurobehavioural effects of CO poisoning.

Continuing decline of memory skills with significant recovery of intellectual function following severe carbon monoxide exposure: clinical, psychometric, and neuroimaging findings.

Extensive clinical, psychometric, and neuroimaging data are presented and interpreted with regard to a 35-year-old, White male college graduate who was exposed to severe carbon monoxide (CO) poisoning. The patient was comatose for 21 days following the exposure. Several other people, who were in the same room as the patient, died due to the toxic effects of the CO. The patient was employed premorbidly as a systems level lead computer programmer. The patient received medical and neuropsychological follow-up for 3 years post-CO exposure. Neuropsychological evaluations revealed a gradual, but incomplete recovery of general intellectual function. The patient continued to exhibit severe memory deficits with some evidence for small additional memory decline over time. Characteristic and permanent vestibular and gait disturbances were also noted, along with a variety of neuropsychological deficits that improved over time with the exception of memory function. The patient also experienced significant affective and personality changes. Neuroimaging studies reveal a generalized cortical atrophy as shown by significantly enlarged ventricles and a ventricle-to-brain ratio that exceeded 4 standard deviations above the norm. The observed atrophic changes are consistent with CO-induced anoxic type injury, which was also accompanied by bilateral lesions of the globus pallidus, caudate, and hippocampus. Despite obtaining average levels of general intellectual functioning over time, significant memory impairments, depression, and personality disturbances severely impaired the patients' vocational recovery and ability to return to work.

Neuropsychological impairments following hantavirus pulmonary syndrome.

Recently an outbreak of acute respiratory infection associated with the hantavirus occurred in the southwestern United States. Hantavirus pulmonary syndrome (HPS) is a life threatening illness that carries with it a high mortality rate. Patients with HPS experience prolonged periods of hypoxemia requiring mechanical ventilation and treatment in intensive care units. We have recently seen 2 survivors of HPS. A neuropsychological test battery was administered immediately following their acute hospitalization and at 1 year postrecovery from HPS. Both patients exhibited cognitive impairments immediately following HPS as well as persistent cognitive impairments at 1 year. The cognitive impairments seen in these two HPS survivors are similar to those seen in other patients who have experienced brain anoxia, including memory impairments. It is also possible that hantavirus may directly cause brain injury with concomitant cognitive impairments. Additional research needs to be carried out in order to determine the extent and severity of the cognitive impairments in survivors of HPS.

Three dimensional image reconstruction of neuroanatomical structures: methods for isolation of the cortex, ventricular system, hippocampus, and fornix.

Magnetic Resonance (MR) imaging allows volumetric quantification of a variety of neuroanatomical structures using two dimensional (2D) images as well as three-dimensional (3D) reconstruction of the brain and any of its constituent parts. Three-dimensional analysis permits integration of the neuroanatomical changes which occur in pathologic states, with the cognitive and behavioral changes elucidated through neuropsychological assessment. This paper describes uniform methods for 3D neuroanatomical isolation of the neocortex, ventricular system, and hippocampus in both normal and pathologic states. The 3D methods are described in detail using two different software programs, ANALYZE and IMAGE. Three-dimensional neuroanatomical reconstructions were carried out on a patient who sustained a very severe traumatic brain injury. The 3D image analysis in the patient with traumatic brain injury, revealed structural changes in frontal and temporal cortex, ventricular dilation, and hippocampal atropy. The neuropsychological impairments in this patient, were consistent with the observed neuroanatomical changes revealed on 3D image reconstruction. This technology permits precise determinations of the extent and severity of the neuroanatomical changes which follow neurological injury disease.

Hippocampal volume in normal aging and traumatic brain injury.

PURPOSE: To present a normative database of hippocampal and temporal horn volume and to clarify the relationship between these measures and cognitive outcome in patients with traumatic brain injury. METHODS: Ninety-six healthy volunteers and 94 patients with traumatic brain injury were examined with coronal intermediate and T2-weighted MR imaging. Multispectral segmentation and volume analyses were performed. The volumetry of the hippocampus and temporal horn was characterized in the control subjects. Volumetric measures in a group of patients with traumatic brain injury who had received MR imaging 3 months or less after injury were compared with measurements in other patients in the chronic phase of recovery. The relationship between neuropsychological testing and volumetric measures was analyzed with particular emphasis on the correlation between cognitive outcome and hippocampal and temporal horn volumes. RESULTS: No significant age group differences were found in the normative group from age 16 to 65. Left and right hippocampal volumes were interrelated and did not differ from each other. This was also true for the temporal horns. Hippocampal and temporal horn volumes were not significantly related. Women had larger hippocampi relative to cranial volume. Comparisons between patients with traumatic brain injury and control subjects showed significant yet modest bilateral atrophic changes in hippocampal and temporal horn enlargement in the patients with brain injury. Hippocampal and temporal horn volumes correlated significantly with each other in the group with traumatic brain injury. Cognitive outcome was modestly related to hippocampal and temporal horn volumes. However, in a specific subgroup whose images were acquired between 71 and 210 days after injury, strong correlations were noted in which temporal horn volume correlated highly with IQ and hippocampal volume correlated with verbal memory function. CONCLUSION: Hippocampal and temporal horn volumes appear to be independent variables in healthy control subjects. Traumatic brain injury results in significant hippocampal atrophy and temporal horn enlargement. The hippocampus and temporal horn volumes were inversely correlated in the group with traumatic brain injury, suggesting a differential relationship of these structures in patients with brain injury as compared with control subjects. In the subacute phase, the volume of the temporal horn may be indicative of intellectual outcome and that of the hippocampus appears to be indicative of verbal memory function.