Biomedical subjects

K F Berman

Publications and source records attributed to K F Berman.

At least 19 recordsLinked to original sources

PubMed2001

Prefrontal neurons and the genetics of schizophrenia.

This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness.

Alleles↗

PubMed2001

Evidence for abnormal cortical functional connectivity during working memory in schizophrenia.

OBJECTIVE: Disturbed neuronal interactions may be involved in schizophrenia because it is without clear regional pathology. Aberrant connectivity is further suggested by theoretical formulations and neurochemical and neuroanatomical data. The authors applied to schizophrenia a recently available functional neuroimaging analytic method that permits characterization of cooperative action on the systems level. METHOD: Thirteen medication-free patients and 13 matched healthy comparison subjects performed a working memory (n-back) task and sensorimotor baseline task during positron emission tomography. "Functional connectivity" patterns, reflecting distributed correlated activity that differed most between groups, were extracted by a canonical variates analysis. RESULTS: More than half the variance was explained by a single pattern showing inferotemporal, (para-)hippocampal, and cerebellar loadings for patients versus dorsolateral prefrontal and anterior cingulate activity for comparison subjects. Expression of this pattern perfectly separated all patient scans from comparison scans, thus showing promise as a trait marker. This result was validated prospectively by successfully classifying unrelated scans from the same patients and data from a new cohort. An additional 19% of variance corresponded to the pattern activated by the working memory task. Expression of this pattern was more variable in patients during working memory but not the control condition, suggesting inability to sustain a task-adequate neural network, consistent with the disconnection hypothesis. CONCLUSIONS: Pronounced disruptions of distributed cooperative activity in schizophrenia were found. A pattern showing disturbed frontotemporal interactions showed promise as a trait marker and may be useful for future investigations.

Adult↗

PubMed2000

H(2)(15)O PET validation of steady-state arterial spin tagging cerebral blood flow measurements in humans.

Steady-state arterial spin tagging approaches can provide quantitative images of CBF, but have not been validated in humans. The work presented here compared CBF values measured using steady-state arterial spin tagging with CBF values measured in the same group of human subjects using the H(2)(15)O IV bolus PET method. Blood flow values determined by H(2)(15)O PET were corrected for the known effects of incomplete extraction of water across the blood brain barrier. For a cortical strip ROI, blood flow values determined using arterial spin tagging (64+/-12 cc/100 g/min) were not statistically different from corrected blood flow values determined using H(2)(15)O PET (67+/-13 cc/100 g/min). However, for a central white matter ROI, blood flow values determined using arterial spin tagging were significantly underestimated compared to corrected blood flow values determined using H(2)(15)O PET. This underestimation could be caused by an underestimation of the arterial transit time for white matter regions.

Adult↗

PubMed2000

Effects of dextroamphetamine on cognitive performance and cortical activation.

Monoaminergic neurotransmitters are known to have modulatory effects on cognition and on neurophysiological function in the cortex. The current study was performed with BOLD fMRI to examine physiological correlates of the effects of dextroamphetamine on working-memory performance in healthy controls. In a group analysis dextroamphetamine increased BOLD signal in the right prefrontal cortex during a task with increasing working-memory load that approached working-memory capacity. However, the effect of dextroamphetamine on performance and on signal change varied across individuals. Dextroamphetamine improved performance only in those subjects who had relatively low working-memory capacity at baseline, whereas in the subjects who had high working-memory capacity at baseline, it worsened performance. In subjects whose performance deteriorated, signal change was greater than that in subjects who had an improvement in performance, and these variations were correlated (Spearman rho = 0.89, P<0.02). These data shed light on the manner in which monoaminergic tone, working memory, and prefrontal function interact and, moreover, demonstrate that even in normal subjects the behavioral and neurophysiologic effects of dextroamphetamine are not homogeneous. These heterogeneic effects of dextroamphetamine may be explained by genetic variations that interact with the effects of dextroamphetamine.

Adult↗

PubMed2000

A comparison of rCBF patterns during letter and semantic fluency.

To evaluate the functional neuroanatomies underlying letter and category fluency, 18 normal controls were studied with oxygen-15 water regional cerebral blood flow positron emission tomography. Three counterbalanced conditions each consisted of 6 trials (45 s each): letter fluency (generating words when cued with a particular letter), semantic fluency (generating words when cued with a particular category), and a control condition (generating days of the week and months of the year). Relative to the control, participants activated similar brain regions during both fluency tasks, including the anterior cingulate, left prefrontal regions, thalamus, and cerebellum; reductions were found in parietal and temporal regions. In a direct comparison of the 2 fluency tasks, inferior frontal cortex and temporoparietal cortex (hypothesized to participate in a phonologic loop for accessing word pronunciation) were activated more during letter than semantic fluency, whereas left temporal cortex (associated with access to semantic storage) was activated more during semantic than letter fluency. This study identifies subtle differences in the neural networks underlying letter and semantic fluency that may underlie the dissociation of these abilities in patients.

Adult↗

PubMed2000

Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia.

OBJECTIVE: Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal pathology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia. METHOD: The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic ((1)H-MRS) imaging (to measure N-acetylaspartate as a marker of neuronal pathology) and with [(15)O]water positron emission tomography (PET) during performance of the Wisconsin Card Sorting Test (to measure activation of the working memory cortical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with (1)H-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task). RESULTS: Measures of N-acetylaspartate in the dorsolateral prefrontal cortex strongly correlated with activation of the distributed working memory network, including the dorsolateral prefrontal, temporal, and inferior parietal cortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortical regions and in comparison subjects did not show these relationships. CONCLUSIONS: These findings directly implicate a population of dorsolateral prefrontal cortex neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamental to the pathophysiology of the disorder.

Adult↗

PubMed1999

Individual differences in PET activation of object perception and attention systems predict face matching accuracy.

We sought to investigate how individual differences in the regional patterns of cerebral blood flow (rCBF) relate to task performance during the perceptual matching of faces. We analyzed rCBF data obtained by PET and H2150 from nine young healthy, right-handed, adult males (mean age 29i3 years) using a statistical model of regional covariance, the Scaled Subprofile Model (SSM). SSM analysis performed on a voxel-basis for scan subtractions comparing face-matching and control tasks extracted two patterns whose subject expression in a multiple regression analysis was highly predictive of task accuracy (R2 = 0.87, p < 0.002). The pattern reflecting this linear combination was principally characterized by higher rCBF in regions of bilateral occipital and occipitotemporal cortex, right orbitofrontal cortex, left thalamus, basal ganglia, midbrain, and cerebellum with relatively lower rCBF in anterior cingulate, regions in bilateral prefrontal and temporal cortex, right thalamus, and right inferior parietal cortex. The results indicate that individual subject differences in face matching performance are specifically associated with the functional interaction of cortical and subcortical brain regions previously implicated in aspects of object perception and visual attentional processing.

Adult↗

PubMed1999

Regional cerebral blood flow in Down syndrome adults during the Wisconsin Card Sorting Test: exploring cognitive activation in the context of poor performance.

BACKGROUND: Prior studies have indicated abnormal frontal lobes in Down syndrome (DS). The Wisconsin Card Sorting Test (WCST) has been used during functional brain imaging studies to activate the prefrontal cortex. Whether this activation is dependent on successful performance remains unclear. To determine frontal lobe regional cerebral blood flow (rCBF) response in DS and to further understand the effect of performance on rCBF during the WCST, we studied DS adults who perform poorly on this task. METHODS: Initial slope (IS), an rCBF index, was measured with the 133Xe inhalation technique during a Numbers Matching Control Task and the WCST. Ten healthy DS subjects (mean age 28.3 years) and 20 sex-matched healthy volunteers (mean age 28.7 years) were examined. RESULTS: Performance of DS subjects was markedly impaired compared to controls. Both DS and control subjects significantly increased prefrontal IS indices compared to the control task during the WCST. CONCLUSIONS: Prefrontal activation in DS during the WCST was not related to performance of that task, but may reflect engagement of some components involved in the task, such as effort. Further, these results show that failure to activate prefrontal cortex during WCST in schizophrenia is unlikely to be due to poor performance alone.

Adult↗

PubMed1999

Context-dependent, neural system-specific neurophysiological concomitants of ageing: mapping PET correlates during cognitive activation.

We used PET to explore the neurophysiological changes that accompany cognitive disability in ageing, with a focus on the frontal lobe. Absolute regional cerebral blood flow (rCBF) was measured in 41 healthy volunteers, evenly distributed across an age range of 18-80 years, during two task paradigms: (i) the Wisconsin Card Sorting Test (WCST), which depends heavily on working memory and is particularly sensitive to dysfunction of the dorsolateral prefrontal cortex (DLPFC); and (ii) Raven's Progressive Matrices (RPM), which may also have a working memory component, but depends more on visuo-spatial processing and is most sensitive to dysfunction of postrolandic regions. We used voxel-wise correlational mapping to determine age-related changes in WCST and RPM activation and developed a method to quantitate and localize statistical differences between the correlation maps for the two task paradigms. Because both WCST and RPM performance declined with age, as expected, correlational analyses were performed with and without partialling out the effect of task performance. Task-specific reductions of rCBF activation with age were found in the DLPFC during the WCST and in portions of the inferolateral temporal cortex involved in visuo-spatial processing during the RPM. We also found reduced ability to suppress rCBF in the right hippocampal region during the WCST and in mesial and polar portions of the prefrontal cortex during both task conditions. Task-dependent alterations with age in the relationship between the DLPFC and the hippocampus were also documented; because the collective pattern of changes in the hippocampal-DLPFC relationship with ageing was opposite to that seen in a previous study using dextroamphetamine, we postulated a dopaminergic mechanism. These results indicate that, despite some cognitive overlap between the two tasks and the age-related cognitive decline in both, many of the changes in rCBF activation with age were task-specific, reflecting functional alteration of the different neural circuits normally engaged by young subjects during the WCST and RPM. Reduced activation of areas critical for task performance (i.e. the DLPFC during the WCST and posterior visual association areas of the inferolateral temporal cortex during the RPM), in conjunction with the inability to suppress areas normally not involved in task performance (i.e. the left hippocampal region during the WCST and mesial polar prefrontal cortex during both the WCST and RPM), suggest that, overall, reduced ability to focus neural activity may be impaired in older subjects. The context dependency of the age-related changes is most consistent with systems failure and disordered connectivity.

Adolescent↗

PubMed1998

Changing patterns of brain activation during maze learning.

Recent research has found that patterns of brain activation involving the frontal cortex during novel task performance change dramatically following practice and repeat performance. Evidence for differential left vs. right frontal lobe activation, respectively, during episodic memory encoding and retrieval has also been reported. To examine these potentially related issues regional cerebral blood flow (rCBF) was measured in 15 normal volunteers using positron emission tomography (PET) during the naive and practiced performance of a maze task paradigm. SPM analysis indicated a largely right-sided, frontal lobe activation during naive performance. Following training and practice, performance of the same maze task elicited a more posterior pattern of rCBF activation involving posterior cingulate and precuneus. The change in the pattern of rCBF activation between novel and practiced task conditions agrees with results found in previous studies using repeat task methodology, and indicates that the neural circuitry required for encoding novel task information differs from that required when the same task has become familiar and information is being recalled. The right-sided preponderance of activation during naive performance may relate to task novelty and the spatially-based nature of the stimuli, whereas posterior areas activated during repeat performance are those previously found to be associated with visuospatial memory recall. Activation of these areas, however, does not agree with previously reported findings of left-sided activation during verbal episodic memory encoding and right-sided activation during retrieval, suggesting different neural substrates for verbal and visuospatial processing within memory.

Adult↗

PubMed1998

Mapping voxel-based statistical power on parametric images.

Using a classic technique based on the noncentral F-distribution method for computing statistical power, we developed a general approach to the estimation of voxel-based power in functional brain image data analysis. We applied this method to PET data from a large sample (N = 40) of subjects performing the Wisconsin Card Sorting (WCST) paradigm analyzed with SPM95, produced statistical power maps for a range of samples sizes and smoothing filter widths, and examined the effects of sample size and image smoothing on the expected reliability of activation findings. At an uncorrected alpha of 0.01, a fixed filter size of 10 mm3, and a range of power thresholds, maps revealed that the power to reject the null hypothesis in brain regions implicated in the task at Ns of 5 and 10 may not be sufficient to ensure reliable replication of significant findings and so should be interpreted with caution. At sample sizes approaching 20 subjects, sufficient power was found in the right dorsolateral prefrontal cortex (BA 46/9), right and left inferior parietal lobule (BA 40), and left inferior temporal lobe (BA 37), comprising the cortical network typically observed during the WCST. Filter size needed to maximize power varied widely, but systematically, across the brain, tending to follow known neuroanatomical landmarks. Statistical power considerations in brain imaging studies are critical for controlling the rate of false negatives and assuring reliable detection of cognitive activation. The variation of filter size for maximizing power across the brain suggests that the underlying neuroanatomy of functional units is an important consideration in the a priori selection of filter size.

Algorithms↗

PubMed1998

Uncoupling cognitive workload and prefrontal cortical physiology: a PET rCBF study.

Working memory is a fundamental cognitive building block involved in the short-term maintenance and transformation of information. In neuropsychological studies, working memory has been shown to be of limited capacity; however, the neurophysiological concomitants of this capacity limitation have not been explored. In this study we used the [15O] water PET rCBF technique and statistical parametric mapping to examine normal subjects while they performed two cognitive tasks, both individually and simultaneously. One task was the Wisconsin Card Sorting Test, a complex reasoning task involving working memory, and the other was a rapidly paced auditory verbal shadowing task. When both tasks were performed simultaneously, there were significant decrements in performance compared with the individual task performance scores, indicating that cognitive workload had been increased. Analysis of the rCBF maps showed that when the two tasks were performed together, in contrast to when they were performed separately, there was less prefrontal activation. These results suggest that increases in cognitive workload do not necessarily recruit and then sustain cortical neurophysiological resources to a maximum, but rather may actually be accompanied by a diminution in cortical activity.

Adult↗

PubMed1998

Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET.

The PET H2 15O-bolus method was used to image regional brain activity in normal human subjects during intense pain induced by intradermal injection of capsaicin and during post-capsaicin mechanical allodynia (the perception of pain from a normally non-painful stimulus). Images of regional cerebral blood flow were acquired during six conditions: (i) rest; (ii) light brushing of the forearm; (iii) forearm intradermal injection of capsaicin, (iv) and (v) the waning phases of capsaicin pain; and (vi) allodynia. Allodynia was produced by light brushing adjacent to the capsaicin injection site after ongoing pain from the capsaicin injection had completely subsided. Capsaicin treatment produced activation in many discrete brain regions which we classified as subserving four main functions: sensation-perception (primary somatosensory cortex, thalamus and insula); attention (anterior cingulate cortex); descending pain control (periaqueductal grey); and an extensive network related to sensory-motor integration (supplementary motor cortex, bilateral putamen and insula, anterior lobe and vermis of the cerebellum and superior colliculus). Comparison of the noxious and non-noxious stimuli yielded several new insights into neural organization of pain and tactile sensations. Capsaicin pain, which had no concomitant tactile component, produced little or no activation in secondary somatosensory cortex (SII), whereas light brushing produced a prominent activation of SII, suggesting a differential sensitivity of SII to tactile versus painful stimuli. The cerebellar vermis was strongly activated by capsaicin, whereas light brush and experimental allodynia produced little or no activation, suggesting a selective association with C-fibre stimulation and nociceptive second-order spinal neurons. The experimental allodynia activated a network that partially overlapped those activated by both pain and light brush alone. Unlike capsaicin-induced pain, allodynia was characterized by bilateral activation of inferior prefrontal cortex, suggesting that prefrontal responses to pain are context dependent.

Acute Disease↗

PubMed1998

Global cerebral blood flow decreases during pain.

Positron emission tomography studies have identified a common set of brain regions activated by pain. No studies, however, have quantitatively examined pain-induced CBF changes. To better characterize CBF during pain, 14 subjects received positron emission tomography scans during rest, during capsaicin-evoked pain (250 micrograms, intradermal injection), and during innocuous vibration. Using the H215O intravenous bolus method with arterial blood sampling, global CBF changes were assessed quantitatively. Painful stimulation produced a 22.8% decrease in global CBF from resting levels (P < 0.0005). This decrease was not accounted for by arterial PCO2 or heart rate changes. Although the exact mechanism remains to be determined, this pain-induced global decrease represents a previously unidentified response of CBF.

Adult↗

PubMed1997

Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women.

There is considerable evidence from animal studies that gonadal steroid hormones modulate neuronal activity and affect behavior. To study this in humans directly, we used H215O positron-emission tomography to measure regional cerebral blood flow (rCBF) in young women during three pharmacologically controlled hormonal conditions spanning 4-5 months: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate (Lupron), Lupron plus estradiol replacement, and Lupron plus progesterone replacement. Estradiol and progesterone were administered in a double-blind cross-over design. On each occasion positron-emission tomography scans were performed during (i) the Wisconsin Card Sorting Test, a neuropsychological test that physiologically activates prefrontal cortex (PFC) and an associated cortical network including inferior parietal lobule and posterior inferolateral temporal gyrus, and (ii) a no-delay matching-to-sample sensorimotor control task. During treatment with Lupron alone (i.e., with virtual absence of gonadal steroid hormones), there was marked attenuation of the typical Wisconsin Card Sorting Test activation pattern even though task performance did not change. Most strikingly, there was no rCBF increase in PFC. When either progesterone or estrogen was added to the Lupron regimen, there was normalization of the rCBF activation pattern with augmentation of the parietal and temporal foci and return of the dorsolateral PFC activation. These data directly demonstrate that the hormonal milieu modulates cognition-related neural activity in humans.

Adult↗

PubMed1996

Prefrontal function in schizophrenia: confounds and controversies.

A wealth of clinical data indirectly implicate dysfunction of frontal cortex in schizophrenia, including negative symptoms, the pattern of neuropsychological deficits, and abnormal eye movements. Neuroimaging studies have provided direct evidence of frontal, particularly prefrontal, malfunction, but the results have been inconsistent and controversial. The burning question is whether prefrontal hypofunction is a pathophysiological characteristic of schizophrenia per se or an artifact of the imaging protocol. In studies of patients at rest, 'hypofrontality' has been an inconsistent finding, probably because resting is physiologically and psychologically variable. Cognitive activation paradigms, especially during working memory tasks, have been reliable in showing prefrontal hypofunction in patients, but these results have been challenged as artifacts of poor performance. Performance differences have been addressed by studying patients and controls matched either for poor performance or for normal performance. The former approach, which has the potential of elucidating the specificity of physiological mechanisms associated with poor performance, has shown that prefrontal activity in patients with schizophrenia differs quantitatively and qualitatively from that of normals and of other patient populations who perform at a comparable level. The latter approach, which tends not to find prefrontal differences between patients and controls, may be selecting out important aspects of the disease by focusing on unaffected neural functions. While there are pitfalls to each approach and no single study can address all the potential phenomenological confounds, overall, the functional neuroimaging database in patients with schizophrenia suggests that prefrontal cognitive deficits are because of prefrontal pathophysiology and not the inverse.

Cognition↗

PubMed1996

Dextroamphetamine enhances "neural network-specific" physiological signals: a positron-emission tomography rCBF study.

Previous studies in animals and humans suggest that monoamines enhance behavior-evoked neural activity relative to nonspecific background activity (i.e., increase signal-to-noise ratio). We studied the effects of dextroamphetamine, an indirect monoaminergic agonist, on cognitively evoked neural activity in eight healthy subjects using positron-emission tomography and the O15 water intravenous bolus method to measure regional cerebral blood flow (rCBF). Dextroamphetamine (0.25 mg/kg) or placebo was administered in a double-blind, counterbalanced design 2 hr before the rCBF study in sessions separated by 1-2 weeks. rCBF was measured while subjects performed four different tasks: two abstract reasoning tasks--the Wisconsin Card Sorting Task (WCST), a neuropsychological test linked to a cortical network involving dorsolateral prefrontal cortex and other association cortices, and Ravens Progressive Matrices (RPM), a nonverbal intelligence test linked to posterior cortical systems--and two corresponding sensorimotor control tasks. There were no significant drug or task effects on pCO2 or on global blood flow. However, the effect of dextroamphetamine (i.e., dextroamphetamine vs placebo) on task-dependent rCBF activation (i.e., task - control task) showed double dissociations with respect to task and region in the very brain areas that most distinctly differentiate the tasks. In the superior portion of the left inferior frontal gyrus, dextroamphetamine increased rCBF during WCST but decreased it during RPM (ANOVA F (1,7) = 16.72, p < 0.0046). In right hippocampus, blood flow decreased during WCST but increased during RPM (ANOVA F(1,7) = 18.7, p < 0.0035). These findings illustrate that dextroamphetamine tends to "focus" neural activity, to highlight the neural network that is specific for a particular cognitive task. This capacity of dextroamphetamine to induce cognitively specific signal augmentation may provide a neurobiological explanation for improved cognitive efficiency with dextroamphetamine.

Adult↗

PubMed1996

Functional lateralization of the prefrontal cortex during traditional frontal lobe tasks.

We attempted to identify brain regions functionally lateralized during cognitive tasks traditionally linked to the prefrontal cortex (PFC) by measuring regional cerebral blood flow with H2(15)O positron emission tomography (PET). Fourteen normal subjects were scanned six times while performing six different cognitive conditions comprising three task paradigms putatively sensitive to PFC integrity: the Wisconsin Card Sort (WCS), Delayed Response Alternation (DA), and the Spatial Delayed Response (SDR) Tasks, and three matched sensorimotor control tasks. Multivariate and repeated measures analyses indicated that for all three cognitive paradigms there were no significant hemisphere, hemisphere-by-condition, or hemisphere-by-region effects. However, with more liberal statistical comparison (paired t tests), the superior frontal gyrus showed lateralization during both the WCS and SDR tasks (both R > L). These results suggest that, although some asymmetries may be found using liberal analyses, there is less evidence of lateralized brain function during performance of these tasks of PFC function, than in language and motor systems. Implications for testing PFC function in neuropsychiatric groups are discussed.

Adult↗