Neural activation patterns during working memory tasks and OSA disease severity: preliminary findings.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with cognitive impairments in working memory (WM). Neuronal activation during WM tasks can be indirectly assessed by blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI). The purpose of this study was to describe BOLD-fMRI responses during 2 separate working memory tasks and a finger tapping task in men with OSA. A secondary aim was to explore the possible relation between OSA severity (apnea/hypopnea index) and BOLD-fMRI signal patterns. METHODS: Nine treatment-naïve men (mean age [+/- SD] of 45.7 [+/- 6.6] years) with OSA underwent BOLD fMRI testing on a research-dedicated university-based MRI scanner. During BOLD-fMRI subjects performed a Paced Auditory Serial Addition task (PASAT), an auditory N-Back task (2-BACK) task, and an alternating finger tapping. RESULTS: PASAT and 2-BACK tasks produced similar patterns of increased bilateral activation in posterior parietal, prefrontal and cerebellar regions. BOLD signal deactivations were observed within posterior cingulate, retrosplenial and inferior frontal regions during PASAT and 2-BACK, but not during tapping. With increased disease severity, BOLD activation patterns were increased in the right parietal lobe, but decreased in the cerebellar vermis. CONCLUSIONS: These preliminary findings suggest that the severity of OSA may correlate with neural activation during tasks of working memory, potentially reflecting compensatory neural responses in severe disease.

Reduced neural habituation in the amygdala and social impairments in autism spectrum disorders.

OBJECTIVE: Amygdala dysfunction has been proposed as a critical component in social impairment in autism spectrum disorders. This study was designed to investigate whether abnormal habituation characterizes amygdala dysfunction in autism spectrum disorders and whether the rate of amygdala habituation is related to social impairment. METHOD: Using functional MRI, the authors measured change over time in activation of the amygdala and fusiform gyrus to neutral facial stimuli in adults with autism spectrum disorders and healthy comparison adults. RESULTS: The comparison group evidenced significantly greater amygdala habituation bilaterally than the autism spectrum group. There were no group differences in overall fusiform habituation. For the autism spectrum group, lower levels of habituation of the amygdala to the face stimuli were associated with more severe social impairment. CONCLUSIONS: These results suggest amygdala hyperarousal in autism spectrum disorders in response to socially relevant stimuli. Further, sustained amygdala arousal may contribute to the social deficits observed in autism spectrum disorders.

Abnormal functional connectivity in autism spectrum disorders during face processing.

Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning adults with ASD and 21 age-and IQ-matched control adults. Activation during identification of previously viewed faces and houses using a one-back paradigm was compared. The fusiform face area (FFA) was individually localized in each participant and used as the seed point for functional connectivity analyses. The degree of correlation between FFA and the extended neural circuitry involved in face identification was tested. A whole brain analysis was also conducted in order to determine whether connectivity from the FFA to aberrant brain locations was present in the ASD group. Measures of clinical severity (ADOS social score and ADI-R social score) were included as independent variables into the functional connectivity analyses. Significant FFA-amygdala and FFA-superior temporal sulcus functional connectivity was found in both the ASD and control participants. However, the control group had significantly increased connectivity to the left amygdala and the posterior cingulate compared to ASD. Post hoc analyses additionally found increased connectivity to the thalamus in the controls. A significant relationship between abnormal functional connectivity and clinical severity in the ASD group was observed. Specifically, greater social impairment was associated with reduced FFA-amygdala connectivity and increased FFA-right inferior frontal connectivity. These results suggest that abnormal neural connections within the limbic system may contribute to the social impairments observed in ASD.

A twin study of cognitive function in chronic fatigue syndrome: the effects of sudden illness onset.

Variable reports of neuropsychological deficits in individuals with chronic fatigue syndrome (CFS) may, in part, be attributable to methodological limitations. In this study, these limitations were addressed by controlling for genetic and environmental influences and by assessing the effects of comorbid depression and mode of illness onset. Specifically, the researchers conducted a co-twin control study of 22 pairs of monozygotic twins, in which 1 twin met strict criteria for CFS and the co-twin was healthy. Twins underwent a structured psychiatric interview and comprehensive neuropsychological assessment evaluating 6 cognitive domains. Results indicated that twin groups had similar intellectual and visual memory functioning, but fatigued twins exhibited decreases in motor functions (p = .05), speed of information processing (p = .02), verbal memory (p = .02), and executive functioning (p = .01). Major depression did not affect neuropsychological functioning among fatigued twins, although twins with sudden illness onset demonstrated slowed information processing compared with those with gradual onset (p = .01). Sudden onset CFS was associated with reduced speed of information processing. If confirmed, these findings suggest the need to distinguish illness onset in future CFS studies and may have implications for treatment, cognitive rehabilitation, and disability determination.

Increased amygdala activation to neutral faces is associated with better face memory performance.

Recent evidence suggests that the role of the amygdala may extend beyond threat detection to include processing socially relevant stimuli in general. Thus, we investigated perception and memory for neutral faces; a stimulus-type that lacks emotional valence yet contains relevant social information. Participants viewed neutral faces or houses when undergoing functional MRI. Neutral face memory testing was conducted outside the scanner. In the functional MRI of faces vs. houses contrast, significant bilateral activation in the amygdala and lateral fusiform gyrus was observed. Increased bilateral amygdala activation was associated with better delayed-memory performance. These findings indicate that the role of the amygdala may include processing neutral yet socially relevant stimuli. Further, amygdala activation, independent of emotional valence, appears to be associated with memory enhancement.

Trail making test errors and executive function in schizophrenia and depression.

The Trail Making Test (TMT) frequently is used as a measure of executive cognitive function. However, traditional use of test completion time as the primary outcome score does not give the more detailed information on cognitive processes that analysis of test-taking errors may provide. The present study compared TMT performance of three groups: patients with schizophrenia, patients with major depression, and healthy control participants (n = 30 for each group). Three operationally defined error types were examined: (a) tracking, (b) perseverative, and (c) proximity. Although both patient groups were slower than the healthy control group, only the schizophrenia group made significantly more errors, particularly tracking errors, suggesting a greater degree of cognitive disorganization. Within-group analysis of a larger group of schizophrenia patients (n = 84) revealed that TMT time was most strongly associated with the Withdrawal-Retardation factor of the Brief Psychiatric Rating scale. In contrast, TMT errors were most strongly associated with the Conceptual Disorganization factor. Comparisons of TMT scores and other cognitive tests showed moderate to high associations with tests of working memory, psychomotor speed, and executive function. Stepwise regression analysis revealed an independent association between Digit Cancellation and Part B Time, indicating a unique contribution of visuomotor scanning to performance. In contrast, Part B errors were uniquely associated with the Verbal Series Attention Test and the Token Test, tests of mental tracking and executive-mediated working memory, respectively. These findings demonstrate the utility of TMT error analysis in revealing cognitive deficits not traditionally captured using completion time as the sole outcome variable.

Cerebral and cerebellar motor activation abnormalities in a subject with Joubert syndrome: functional magnetic resonance imaging (MRI) study.

Joubert syndrome is an autosomal recessive disorder characterized by hypotonia, ataxia, developmental delay, and a distinctive hindbrain malformation involving the cerebellum and brain stem, visualized radiographically on magnetic resonance imaging (MRI) as the "molar tooth sign." In postmortem brains from subjects with Joubert syndrome, there is an apparent absence of decussation of both corticospinal and superior cerebellar tracts, although the functional significance has not been elucidated. We sought to explore the cerebral and cerebellar activation pattern elicited by finger tapping in an adolescent with Joubert syndrome and in a normal control subject using functional MRI. In contrast to the typical highly lateralized activation seen in our control subject, the subject with Joubert syndrome demonstrated striking bilateral activation of the sensorimotor and cerebellar cortex. Although our functional MRI data do not indicate a clear absence of decussation, the abnormal activation pattern observed suggests altered brain functional organization in relation to anatomic differences. Malformation of the hindbrain could result in recruitment of alternative pathways, similar to what has been observed following ischemic injury to the developing or mature central nervous system.

Cognitive processing in monozygotic twins discordant for chronic fatigue syndrome.

Twenty-one pairs of monozygotic twins discordant for chronic fatigue syndrome (CFS) and 21 matched healthy control (HC) subjects were assessed with 5 untimed tests and 5 timed tests from the computer-based NeuroCognitive Assessment Battery (R. K. Mahurin, 1993). Random effects regression showed no difference between CFS and healthy twins on any of the cognitive tests. Further, the twin groups did not differ from the HC group on any content-dependent measure. In contrast, both sets of twins performed worse than the HC group on all speed-dependent tests except Finger Tapping. Self-rated fatigue and dysphoric mood were only weakly correlated with cognitive performance. These data point toward a shared genetic trait related to information processing that is manifest in the CFS context. The findings have implications for differentiating genetic and acquired vulnerability in the symptomatic expression of the disorder. ((c) 2004 APA, all rights reserved)

Age and features of movement influence motor overflow.

OBJECTIVES: To measure the magnitude and prevalence of motor overflow to the arm at rest during attempted unilateral arm movements. DESIGN: Cross-sectional assessment. SETTING: Motor physiology laboratory. PARTICIPANTS: Healthy young (n=20) and elderly (n=20) adult subjects. MEASUREMENTS: Surface electromyography (EMG) was obtained from bilateral forearm muscles during performance of 12 different unilateral finger-tapping tasks. RESULTS: For all subjects, faster movement rate (F=2.56-3.30, P<.05), cognitive distraction (F=4.09, P<.05), and fatigue (F=15.15, P<.001) were each associated with a significant increase in the magnitude of EMG in the arm intended to be at rest. In elderly subjects, tapping at maximum rate and fatigue were each associated with a further increase in motor overflow across the midline. In addition, better left hand dexterity correlated with greater motor overflow to the right hand during rapid left hand tapping (r=0.63, P<.005). Prevalence of motor overflow was also higher in older subjects for some tasks, for example during 1 Hz tapping by the right index finger (motor overflow present in 45%, vs 15% young subjects, P<.05). CONCLUSION: Several behavioral variables increase motor overflow across the midline in young and elderly adults. Motor overflow was even greater in elderly subjects with the most demanding tasks and was greater in those with better motor status, suggesting that this form of motor system change is a compensatory event of normal aging rather than age-related dysfunction. The results support the hypotheses that healthy aging is associated with an increase in the degree to which brain function is bilaterally organized.

Single-photon emission computerized tomography and neurocognitive function in patients with chronic fatigue syndrome.

OBJECTIVE: The purposes of this study were to compare functional imaging under control and experimental conditions among patients with chronic fatigue syndrome (CFS) and healthy persons and to examine perceived and objective performance on a test of attention and working memory previously found to be difficult for persons with CFS. METHODS: Single-photon emission computerized tomography scans were completed on 15 subjects with CFS and 15 healthy persons twice: at rest and when performing the Paced Auditory Serial Addition Test (PASAT). RESULTS: No group differences were found for performance on the PASAT despite CFS subjects' perceptions of exerting more mental effort to perform the task than healthy subjects. Inspection of the aggregate scans by group and task suggested a pattern of diffuse regional cerebral blood flow among subjects with CFS in comparison with the more focal pattern of regional cerebral blood flow seen among healthy subjects. Between-group region-of-interest analysis revealed that although CFS subjects showed less perfusion in the anterior cingulate region, the change in CFS subjects' activation of the left anterior cingulate region during the PASAT was greater than that observed for healthy subjects. The differences were not attributable to lesser effort by the subjects with CFS, confounding effects of mood perturbation, or to poorer performance on the experimental task. CONCLUSIONS: Further research regarding CFS subjects' diffuse cerebral perfusion and its relationship to inefficient neuropsychological performance is warranted.

The functional neuroanatomy of the placebo effect.

OBJECTIVE: Administration of placebo can result in a clinical response indistinguishable from that seen with active antidepressant treatment. Functional brain correlates of this phenomenon have not been fully characterized. METHOD: Changes in brain glucose metabolism were measured by using positron emission tomography in hospitalized men with unipolar depression who were administered placebo as part of an inpatient imaging study of fluoxetine. Common and unique response effects to administration of placebo or fluoxetine were assessed after a 6-week, double-blind trial. RESULTS: Placebo response was associated with regional metabolic increases involving the prefrontal, anterior cingulate, premotor, parietal, posterior insula, and posterior cingulate and metabolic decreases involving the subgenual cingulate, parahippocampus, and thalamus. Regions of change overlapped those seen in responders administered active fluoxetine. Fluoxetine response, however, was associated with additional subcortical and limbic changes in the brainstem, striatum, anterior insula, and hippocampus, sources of efferent input to the response-specific regions identified with both agents. CONCLUSIONS: The common pattern of cortical glucose metabolism increases and limbic-paralimbic metabolism decreases in placebo and fluoxetine responders suggests that facilitation of these changes may be necessary for depression remission, regardless of treatment modality. Clinical improvement in the group receiving placebo as part of an inpatient study is consistent with the well-recognized effect that altering the therapeutic environment may significantly contribute to reducing clinical symptoms. The additional subcortical and limbic metabolism decreases seen uniquely in fluoxetine responders may convey additional advantage in maintaining long-term clinical response and in relapse prevention.

Does cognitive function improve with quetiapine in comparison to haloperidol?

Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.