Prefrontal activation during Stroop and Wisconsin card sort tasks in children with developmental coordination disorder: a NIRS study.

We used near-infrared spectroscopy to examine dorsolateral prefrontal cortex (DLPFC) activation over time in 10 children with or at-risk-for developmental coordination disorder (DCD) and 11 typically developing children (ages 8-12) during tasks involving executive processing. The groups performed with similar accuracy on the Stroop and Wisconsin card sort (WCST), but their underlying neural activation differed. Typically developing children modulated DLPFC activity over time and showed rightward lateralization during Stroop but no lateralization during WCST. The DCD group exhibited high and sustained activation across hemispheres and tasks, which we suggest is a compensatory effort to maintain response accuracy.

An fMRI study of working memory in persons with bipolar disorder or at genetic risk for bipolar disorder.

First-degree relatives of persons with bipolar disorders (BDs) carry elevated risk for the illness, and manifest deficits in attention and memory (possible "endophenotypes"). However, there is only one published functional magnetic resonance imaging (fMRI) study of candidate endophenotypes in BD. We used fMRI to examine brain function in BD and in first-degree relatives performing a 2-back working memory (WM) task, and correlated brain activity with mood measures taken at the scanning session. Subjects (age 32-46) were 19 persons with BD, 18 unmedicated, non-psychotic first-degree relatives (RELs) of persons with BD, and 19 matched controls, ascertained from a long-term follow-up of a prenatal cohort study in New England. fMRI signal during 2-back and 0-back WM tasks was measured on a Siemens 1.5T MR scanner. fMRI data were analyzed using SPM-2. Persons with BD and RELs failed to suppress activation in the left anterior insula (BA 13) during WM, whereas controls suppressed activation. Compared to controls, RELs also failed to suppress activation in the orbitofrontal cortex (OFC) and superior parietal cortex. Controls and RELs exhibited greater activation than BD individuals in the left frontopolar cortex (BA 10) during WM. Results remained significant after controlling for confounders except for mild attenuation of OFC findings. Significant correlations between brain activity, mood, and WM suggest that activity in WM circuits is affected by activity in emotion-regulatory circuits. Persons with BD and RELs exhibit altered activity in the frontopolar cortex and insula, which may represent biomarkers of genetic risk for BD.

Elaborative verbal encoding and altered anterior parahippocampal activation in adolescents and young adults at genetic risk for schizophrenia using FMRI.

BACKGROUND: First-degree relatives of persons with schizophrenia are at elevated risk for the illness, demonstrate deficits in verbal memory, and exhibit structural abnormalities in the medial temporal lobe (MTL). We used functional magnetic resonance imaging (fMRI) to assess brain activity in the MTL during novel and repeated word-pair encoding. METHODS: Participants were 21 non-psychotic, first-degree relatives of persons with schizophrenia and 26 matched healthy controls (ages 13-28). fMRI signal change was measured using a Siemens 1.5T MR scanner, and data were analyzed using SPM-2. Verbal memory was assessed using the Miller Selfridge (MS) Context Memory test prior to scanning. RESULTS: The groups were comparable on demographics, intelligence and post-scan word recognition. Relatives at genetic risk (GR) had significantly more psychopathology than controls and worse performance on the MS test (p < .05). GR participants exhibited greater repetition suppression of activation in the left and right anterior parahippocampus (PHA, in the region of the entorhinal cortex region), after controlling for possible confounders. Controls and GR participants with above-median MS performance showed significantly greater repetition suppression of activation in left inferior frontal gyrus than those scoring below the median. CONCLUSIONS: This is the first study to demonstrate an alteration of brain activity in the PHA in persons at GR for schizophrenia.

Auditory verbal working memory load and thalamic activation in nonpsychotic relatives of persons with schizophrenia: an fMRI replication.

First-degree relatives of persons with schizophrenia are at genetic risk for the illness and show deficits on high-load information-processing tasks. In a prior study of auditory working memory (WM) using functional MRI (fMRI), the authors demonstrated that adult relatives had significantly increased activation in the dorsomedial (DM) thalamus, anterior cingulate, and prefrontal cortex (H. W. Thermenos et al., 2004). In this study, the authors extended this work using a parametric WM task designed for fMRI in an independent, unmedicated sample. Twelve nonpsychotic relatives of persons with schizophrenia and 13 healthy controls were administered multiple versions of an auditory continuous performance test during fMRI. Data were analyzed using Statistical Parametric Mapping software. Compared with controls, relatives showed significantly greater task-elicited activation in the DM thalamus. When fMRI signal change was modeled as a function of increasing WM load, there was a significant Group x Load interaction, with relatives showing significantly greater task-elicited activation in the right DM thalamus compared with controls. Greater DM thalamic activation in the relatives remained significant when WM performance, vocabulary score, and education were controlled. This replication suggests that altered thalamic activation is a feature of neurobiological risk for schizophrenia.

Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory.

OBJECTIVE: Adult first-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness, demonstrate working memory (WM) impairments, and manifest alterations in dorsolateral prefrontal cortical (DLPFC) function during WM. Because substantially less is known about these phenotypes in adolescent subjects we sought to demonstrate that young relatives of persons with schizophrenia manifest impaired WM and altered prefrontal activation. METHODS: Participants were 21 non-psychotic, unmedicated first-degree relatives of persons with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type and 24 unmedicated controls, recruited from the community and hospitals in metropolitan Boston (ages 13-28). We compared groups on an auditory WM task with interference prior to scanning and used functional magnetic resonance imaging (fMRI) to compare groups while performing visual 2-back WM and control vigilance tasks. Blood oxygen level dependent signal change was measured using two whole-brain gradient echo EPI pulse acquisitions (21 contiguous, 5mm axial slices), acquired on a Siemens 1.5T MR scanner. Data were analyzed using Statistical Parametric Mapping-99. RESULTS: The high risk subjects were significantly impaired on the auditory WM task, had significantly greater Phobic Anxiety, and marginally greater Psychoticism than controls on the Symptom Checklist-90-Revised, and showed significantly greater task-elicited activation in the right DLPFC (BA 46). Psychopathology, IQ, and in-scanner WM performance did not account for group differences in brain activation. CONCLUSIONS: Data support a physiological difference (an exaggerated fMRI response) in DLPFC in adolescents at genetic risk for schizophrenia, independent of psychosis. Future work can study the relationship of these measures to possible onset of schizophrenia.

A double dissociation within striatum between serial reaction time and radial maze delayed nonmatching performance in rats.

Lesions involving the intralaminar thalamic nuclei have been associated with impairments in working memory and intentional motor function in human clinical cases and animal models of amnesia. The intralaminar nuclei have afferent and efferent connections related to striatum. To test whether disruption of striatal function can account for impairments produced by intralaminar lesions, we investigated the effects of striatal lesions on two tasks known to be impaired by intralaminar damage in the rat: radial maze delayed nonmatching (DNM), a measure of spatial working memory, and self-paced serial reaction time (SRT), a measure of intentional response speed. We compared the effects of lesions in four sites: the medial and lateral caudate putamen, nucleus accumbens, and olfactory tubercle. We found that lesions of the medial, accumbens, or tubercle sites impaired DNM performance, and that lesions of the lateral caudate putamen increased choice response time for the SRT task. There was a double dissociation between the effects of the ventral and the lateral lesions on these two tasks. For both tasks, the effects of striatal lesions were qualitatively similar and at least as large as intralaminar lesions in previous studies. These results provide evidence that striatal dysfunction can account for the DNM and SRT impairments produced by intralaminar lesions. The dissociation of functional impairments suggests that lateral sensorimotor areas of caudate putamen are important for responding based on external sensory stimuli and limbic-related areas in ventral striatum are important for responding based on information held in working memory.

The effect of working memory performance on functional MRI in schizophrenia.

INTRODUCTION: Studies of prefrontal cortical (PFC) function in schizophrenia have been inconsistent, with studies showing both increased and decreased PFC activation compared to healthy controls. Discrepant findings may be due to task performance effects or demographic differences between samples. We report functional magnetic resonance imaging (fMRI) data comparing subjects with schizophrenia and healthy controls performing a 2-back working memory (WM) task, addressing the effects of task performance. METHODS: Twenty-two controls and 14 patients with DSM-IV schizophrenia, scanned on a Siemens 1.5 T scanner, performed a visual letter 2-back task and control task (CPT-X) during fMRI. Data were analyzed using Statistical Parametric Mapping (SPM)-99. RESULTS: After statistical adjustment for performance differences, persons with schizophrenia showed significantly greater activation than controls in the right medial frontal gyrus and left inferior parietal lobule/medial temporal gyrus region (BA 39/40), and a trend toward greater activation in the left ventrolateral PFC. This pattern was also observed in demographically matched subgroups of participants. CONCLUSIONS: Data are consistent with findings reported in recent studies showing increased PFC and parietal activation in schizophrenia when the effects of reduced WM task performance in patients with schizophrenia are addressed. Further studies are needed to clarify the pathophysiological basis of WM load sensitivity in schizophrenia and its relationship to genes.

Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine.

BACKGROUND: Postmenopausal women with depression frequently have co-occurring symptoms of hot flashes (vasomotor symptoms), sleep disturbance, anxiety, and pain. Treatment strategies that target all of these symptoms together have not been investigated to date. METHOD: Study participants were postmenopausal women, 40 to 60 years old, with major depressive disorder (DSM-IV criteria) and vasomotor symptoms. The study design included a 2-week, single-blind placebo run-in phase followed by an 8-week open-label flexible-dosing (60-120 mg per day) study of duloxetine for women who did not respond to placebo. The primary outcome measure was change in Montgomery-Asberg Depression Rating Scale (MADRS) score during 8 weeks of duloxetine therapy. Secondary outcome measures included changes in vasomotor symptoms, sleep quality, anxiety, and pain. Analyses were conducted using non-parametric methods. Patients were enrolled in the study from May 31, 2005, through May 22, 2006. RESULTS: Of 30 women eligible to participate in this study, 20 initiated treatment with open-label duloxetine. Fourteen (70.0%) of these women completed the study. There was a statistically significant decrease in MADRS scores after 8 weeks of treatment (p < .001), with scores declining from 19.0 (interquartile range [IQR] = 15.0-21.0) to 5.5 (IQR = 3.0-9.0). There was also a statistically significant improvement in vasomotor symptoms (p = .003), anxiety (p = .002), sleep quality (p < .001), and pain (p < .05). CONCLUSIONS: Postmenopausal women with depression and vasomotor symptoms had significant improvement in depression, vasomotor symptoms, sleep, anxiety, and pain after 8 weeks of open-label duloxetine therapy. Given the common co-occurrence of these symptoms in postmenopausal women, duloxetine may offer important therapeutic benefits for postmenopausal women who have depression and menopause-related symptoms.

RETRACTED: Elaborative Verbal Encoding and Altered Anterior Parahippocampal Activation in Adolescents and Young Adults at Genetic Risk for Schizophrenia Using fMRI.

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