A functional lesion in developmental dyslexia: left angular gyral blood flow predicts severity.

Functional imaging studies have shown reduced regional cerebral blood flow (rCBF) in temporal and inferior parietal regions in dyslexia. To relate such abnormalities to the severity of dyslexia, correlations between reading skill and rCBF during a series of reading tasks and visual fixation were mapped for 17 right-handed dyslexic men, ages 18-40, and 14 matched controls. These correlations uniquely identified the left angular gyrus as the most probable site of a functional lesion in dyslexia: Here, higher rCBF was associated with better reading skill in controls (p <.01), but with worse reading skill in dyslexia (p <.01). This suggests that greater reliance on this region normally facilitates reading, but impairs reading in dyslexia. Thus, developmental dyslexia may share a common localization with alexia.

Wisconsin Card Sorting Test performance following head injury: dorsolateral fronto-striatal circuit activity predicts perseveration.

The Wisconsin Card Sorting Test (WCST) has been argued to be a sensitive indicator of frontal lobe function. However, several recent studies have failed to find a consistent relationship between structural damage to this cortical area and perseveration on the test. In the present study, positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose was used to examine the relationship of regional brain metabolism to perseverative responding on the WCST in patients with a history of closed-head injury. An inverse relationship was found between perseverative responses and metabolism in the right, but not the left, dorsolateral prefrontal cortex and caudate nucleus. Perseverative responding was not related to metabolism in several other regions of the frontal lobes and basal ganglia, including the putamen and the frontal poles bilaterally. These data suggest that the functional integrity of the right dorsolateral frontal-subcortical circuit is critical for WCST performance.

Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorders.

BACKGROUND: Abnormal left/right (L/R) hemispheric ratios of regional cerebral glucose metabolic rates (rCMRglc) (hippocampus and inferior prefrontal cortex) have been noted in unmedicated panic disorder patients. METHODS: An independent group of panic disorder patients placed on imipramine was studied with positron-emission tomography, testing for evidence of normalization versus persistence of the abnormal rCMRglc ratios. Differences in orbital frontal rCMRglc values between the imipramine-treated and the previously reported unmedicated panic disorder patients were tested examining for evidence that the differences would resemble those noted in obsessive-compulsive disorder (OCD) patients treated with clomipramine. RESULTS: We found the same abnormally low L/R hippocampal and posterior inferior prefrontal rCMRglc ratios in the imipramine-treated panic disorder patients. In addition, we found posterior orbital frontal rCMRglc decreases in the imipramine-treated panic disorder patients compared with the unmedicated panic disorder patients. CONCLUSIONS: These abnormal asymmetries found in unmedicated panic disorder patients and now in imipramine-treated panic disorder patients may reflect a trait abnormality. The orbital frontal rCMRglc differences between the imipramine-treated and unmedicated patients are similar to changes noted in OCD patients treated with clomipramine and may reflect direct or indirect effects of imipramine treatment in panic disorder patients.

Abnormalities in the distributed network of sustained attention predict neuroleptic treatment response in schizophrenia.

The regional cerebral metabolic rates of 19 male medication-withdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless of the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics.

A magnetic resonance imaging study of planum temporale asymmetry in men with developmental dyslexia.

BACKGROUND: Imaging studies have suggested anomalous anatomical asymmetries in language-related regions of the temporal and parietal lobes in individuals with developmental dyslexia. Autopsy studies have reported unusual symmetry of the planum temporale (PT) in patients with dyslexia. Methodological limitations characterize much of this literature, however. OBJECTIVE: To examine the size and asymmetry of the PT and its extension into the parietal lobe (planum parietale [PP]) in men with well-characterized, persistent dyslexia by using magnetic resonance imaging and 3-dimensional surface rendering techniques. METHODS: The brains of 16 right-handed dyslexic men aged 18 to 40 years and 14 matched control subjects were studied with magnetic resonance imaging. Most of these subjects were previously studied with positron emission tomography, which demonstrated functional abnormalities in temporal and parietal brain regions in the dyslexic group. The area of the PT was determined with the aid of 3-dimensional surface-rendering techniques. The size of the PP was estimated by measuring the length of the posterior ascending ramus on 3 parasagittal slices. RESULTS: Approximately 70% to 80% of both groups showed equivalent leftward (left > right) asymmetries of the PT; approximately 50% to 60% showed equivalent rightward (right > left) asymmetries of the PP. These asymmetries showed equivalent moderate inverse correlations with each other in both groups. CONCLUSIONS: These results challenge the notion that anomalous asymmetry of the PT is strongly associated with developmental dyslexia. Given the heterogeneity of the dyslexic population, some subgroup of dyslexic individuals (i.e., those with developmental language disorders) may show unusual symmetry or reversed asymmetry in this region. However, anomalous asymmetry of the planum did not contribute to functional abnormalities demonstrated in these patients by positron emission tomography.

Effects of triazolam and ethanol on proactive interference: evidence for an impairment in retrieval inhibition.

The effects of two memory-impairing drugs, ethanol and triazolam, on proactive interference (PI) in memory were studied. Following ingestion of either one of these drugs or a placebo, subjects studied an A-B list (e.g., BEE-WASP) of paired associates, followed by an A-C list (e.g., BEE-HONEY) on the interference trial, and a D-E list (e.g., KING-QUEEN) followed by an A-C list on the control trial. A PI effect was found in the data, such that subjects produced fewer correct second list targets on the interference trial than on the control trial. Neither ethanol nor triazolam was found to influence the size of the PI effect. However, both drugs were found to increase B intrusions on the test of the A-C list, to impair subjects' ability to produce more than one studied response for each cue word, and to impair the subjective experience of retrieved memory information. These data suggest that ethanol and triazolam impair an inhibitory process that normally operates as one component of intentional retrieval, playing an important role in the suppression of unwanted information during a memory task.

Phonological and orthographic components of word recognition. A PET-rCBF study.

Pronunciation (of irregular/inconsistent words and of pseudowords) and lexical decision-making tasks were used with 15O PET to examine the neural correlates of phonological and orthographic processing in 14 healthy right-handed men (aged 18-40 years). Relative to a visual-fixation control task, all four experimental tasks elicited a left-lateralized stream of activation involving the lingual and fusiform gyri, perirolandic cortex, thalamus and anterior cingulate. Both pronunciation tasks activated the left superior temporal gyrus, with significantly greater activation seen there during phonological (pseudoword) than during orthographic (real word) pronunciation. The left inferior frontal cortex was activated by both decision-making tasks; more intense and widespread activation was seen there during phonological, than during orthographic, decision making, with the activation during phonological decision-making extending into the left insula. Correlations of reference voxels in the left superior temporal gyrus and left inferior frontal region with the rest of the brain were highly similar for the phonological and orthographic versions of each task type. These results are consistent with connectionist models of reading, which hypothesize that both real words and pseudowords are processed within a common neural network.

Opiate receptor avidity and cerebral blood flow in Alzheimer's disease.

Positron emission tomography was performed on 12 Alzheimer's patients and 12 age-matched normal controls following the administration of the opiate receptor antagonist 6-deoxy-6-beta-[18F]fluoronaltrexone (cyclofoxy, CF). Tracer kinetic analysis was used to determine the volume of distribution of CF, a measure of unoccupied mu and kappa receptor density, i.e. opiate receptor avidity in 34 brain regions. Regional cerebral blood flow rates (CBF) were determined on the same day with H2[15O]. Global gray CF avidity and global gray CBF were found to be lower in the Alzheimer's patients and correlated (r=0.73, P<0.03). Regional CBF differences were superimposed on global CBF changes in the Alzheimer's patients, with the subcortex relatively spared. Multivariate statistical analyses, however, failed to demonstrate regional specificity for the CF avidity changes. Furthermore, percent changes in regional CF avidity were not correlated with percent changes in regional CBF (r=0.12, P=NS). These findings demonstrate involvement of the opiate system in Alzheimer's disease. Although, neurodegeneration is the likely underlying process responsible for both the changes in CF avidity and CBF in Alzheimer's disease, the differences with respect to the patterns of these losses suggest that the intermediate mechanisms leading from neurodegeneration to loss are distinct.

The brain metabolic patterns of clozapine- and fluphenazine-treated patients with schizophrenia during a continuous performance task.

BACKGROUND: The comparison of the effects of 2 classes of neuroleptic drugs on regional brain functional activities may reveal common mechanisms of antipsychotic drug efficacy. METHODS: The regional cerebral glucose metabolic rates of patients with schizophrenia who were and were not receiving neuroleptic drugs and normal control subjects were obtained by positron emission tomography using fludeoxyglucose F 18 as the tracer. RESULTS: Compared with normal controls and patients not receiving medication, fluphenazine hydrochloride- and clozapine-treated patients had lower global gray matter absolute metabolic rates throughout the cortex. When normalized regional glucose metabolic rates were examined, both medications lowered rates in the superior prefrontal cortex and increased rates in the limbic cortex. Fluphenazine, but not clozapine, increased metabolic rates in the subcortical and lateral temporal lobes, whereas clozapine, but not fluphenazine, decreased inferior prefrontal cortex activity. CONCLUSIONS: These changes are consistent with the idea that neuroleptic drugs lead to "compensation" and "adaptation" rather than "normalization" of the functional activities of brain structures in schizophrenia. The overall similarity of their global and regional metabolic effects suggests that both classes of antipsychotic drugs share some common mechanisms of action. One possibility is that of inducing a shift in the balance of cortical to limbic cortex activity. Differential effects in the inferior prefrontal cortex and the basal ganglia might underlie differences in the therapeutic efficacy and side effect profile of clozapine and fluphenazine.

A positron emission tomographic study of impaired word recognition and phonological processing in dyslexic men.

BACKGROUND: Developmental dyslexia is characterized by impaired word recognition, which is thought to result from deficits in phonological processing. Improvements during the course of development are thought to disproportionately involve orthographic components of reading; phonological deficits persist into adulthood. OBJECTIVE: To localize the neural correlates of impaired word recognition and phonological processing in men with developmental dyslexia. METHODS: Regional cerebral blood flow was measured with oxygen 15 positron emission tomography in 17 men with dyslexia and in 14 matched controls during the performance of phonological and orthographic tasks--pronunciation (reading aloud) and lexical decision making--designed to activate posterior and anterior perisylvian cortices, respectively. RESULTS: Altered patterns of activation (reduced activation, unusual deactivation) were seen in dyslexic men in mid- to posterior temporal cortex bilaterally and in inferior parietal cortex, predominantly on the left, during both pronunciation and decision making. In contrast, dyslexic men demonstrated essentially normal activation of left inferior frontal cortex during both phonological and orthographic decision making. CONCLUSION: These, along with prior findings, are compatible with a hypothesis of bilateral involvement of posterior temporal and parietal cortices in dyslexia.

The ratio of mesial to neocortical temporal lobe blood flow as a predictor of dementia.

OBJECTIVE: The hypothesis tested was that an increased ratio of cerebral blood flow (rCBF) in the mesocortical temporal lobe to that of the neocortical temporal lobe (MES/ NEO ratio) would be related to clinical measures of dementia severity and would help distinguish Alzheimer's patients from normal controls. DESIGN: The rCBF of nine Alzheimer's patients (5 males and 4 females; age = 65.9 +/- 6.0 years, range 55-71; Folstein Mini-Mental Status Examination = 18.6 +/- 7.4, range 9-28) and 10 age-matched normal controls (7 males, 3 females; age = 66.0 +/- 5.7 years, range 58-75) was determined by positron emission tomography (PET) using H2(15)0 and the method of Alpert et al. RESULTS: Alzheimer's disease patients had a significantly higher MES/NEO ratio (1.19 +/- .17) than the age-matched normal controls (.854 +/- .14; t = .-4.74, df = 17, P = .0002). Using a MES/NEO ratio of 1 as the cutoff point for discrimination between Alzheimer's patients and normal controls, the ratio demonstrated 100% sensitivity (no. of correctly identified Alzheimer's patients/no. of Alzheimer's patients) and 90% specificity (no. of correctly identified unaffected subjects/no. of unaffected subjects). Further, those patients with the highest MES/NEO ratios had the lowest overall measures of cognitive function (Folstein Mini-Mental Status Examination: r = -.75, P < .02, 1-tail; Mattis Dementia Rating Scale: r = -0.655, P = .028, 1-tail) scores. CONCLUSIONS: The findings are consistent with other in vivo and postmortem studies, suggesting that functional and structural changes of the lateral temporal lobe in Alzheimer's disease occur relatively early in the disease process and appear to be distinguishable from those changes accompanying normal aging. In contrast, the memory loss and pathology of the mesial temporal lobe that is characteristic of the early stages of Alzheimer's patients do not appear to be associated with a reduction in cerebral blood flow in the resting Alzheimer's patient. Nevertheless, the clinical significance of the results must await findings of longitudinal studies of larger numbers of Alzheimer's patients and controls.

Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders.

OBJECTIVE: The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients. METHOD: Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism. RESULTS: Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism. CONCLUSIONS: These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

Monitoring the source of memory in detoxified alcoholics.

The ability to monitor the source of remembered information and related reflective cognitive processes was examined in normal volunteers and detoxified alcoholics. Normal volunteers were very accurate judges of whether remembered events were presented as stimuli or were self-generated, even when memory was tested 2 days later. In contrast, a subgroup of otherwise cognitively unimpaired alcoholics demonstrated impairments in the ability to track the source of remembered knowledge and were also less able to inhibit intrusion errors in recalling information from memory. These findings provide preliminary evidence of an impairment in cognitive control functions in certain alcoholics. This conclusion is supported by associated findings indicating that, among alcoholics, performance on explicit memory tasks that required reflective cognitive operations were positively correlated with glucose utilization rates in left prefrontal, temporal, and posterior orbital frontal cortical regions.

Anterior paralimbic mediation of procaine-induced emotional and psychosensory experiences.

BACKGROUND: Procaine activates limbic structures in animals. In humans, acute intravenous administration of procaine yields emotional and psychosensory experiences and temporal lobe fast activity. We studied procaine's acute effects on cerebral blood flow (CBF) in relationship to clinical responses. METHODS: Cerebral blood flow was assessed by positron emission tomography with oxygen-15-labeled water in 32 healthy volunteers. Data were analyzed with statistical parametric mapping and magnetic resonance imaging-directed regions of interest. RESULTS: Procaine increased global CBF and, to a greater extent, anterior paralimbic CBF. Subjects with intense procaine-induced fear compared with those with euphoria had greater increases in left amygdalar CBF. Absolute and normalized left amygdalar CBF changes tended to correlate positively with fear and negatively with euphoria intensity. Procaine-induced visual hallucinations appeared associated with greater global and occipital CBF increases. Absolute occipital CBF increases appeared to correlate positively with visual hallucination intensity. CONCLUSIONS: Procaine increased anterior paralimbic CBF, and different clinical responses appeared to be associated with different patterns of CBF changes.

Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys.

OBJECTIVE: Considerable evidence suggests that low concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in CSF are associated with a history of aggressive behavior in both human and nonhuman primates. The purpose of this investigation was to examine the relationships among CSF 5-HIAA concentration, history of aggressive behavior, and cerebral glucose metabolism in a group of nonhuman primates whose CSF 5-HIAA had been sampled several times over the preceding 2 years and whose social behavior had been observed since birth. METHOD: The subjects were nine adult male rhesus monkeys studied under isoflurane anesthesia. Cerebral glucose utilization was measured by [18F]fluorodeoxyglucose positron emission tomography. Aggressiveness ratings were made by a primatologist who had had frequent contact with the animals over several years. RESULTS: There was a significant negative correlation between ratings of aggressive behavior and CSF 5-HIAA concentrations. There was also a negative correlation between the dose of pentobarbital required to induce anesthesia and level of CSF 5-HIAA. Moreover, there were significant negative correlations between CSF 5-HIAA levels and both whole brain glucose utilization and regional glucose utilization in the orbital-frontal cortex. CONCLUSIONS: These results suggest that both increased aggressiveness and low concentrations of CSF 5-HIAA are associated with higher brain glucose metabolism in rhesus monkeys under standardized anesthesia. Aggressive nonhuman primates with low CSF 5-HIAA concentrations may have "innate" tolerance toward functional gamma-aminobutyric acid A receptor agonists such as pentobarbital, isoflurane, and possibly alcohol.

Relationship of genetically transmitted alpha EEG traits to anxiety disorders and alcoholism.

We tested the hypothesis that a heritable EEG trait, the low voltage alpha (LV), is associated with psychiatric disorders. Modest to moderate evidence for genetic linkage of both panic disorder and the low voltage alpha trait to the same region of chromosome 20q has recently been reported, raising the issue of whether there is a phenotypic correlation between these traits. A total of 124 subjects including 50 unrelated index subjects and 74 relatives were studied. Alpha EEG power was measured and EEG phenotypes were impressionistically classified. Subjects were psychiatrically interviewed using the SADS-L and blind-rated by RDC criteria. Alcoholics were four times more likely to be LV (including so-called borderline low voltage alpha) than were nonalcoholic, nonanxious subjects. Alcoholics with anxiety disorder are 10 times more likely to be LV. However, alcoholics without anxiety disorder were similar to nonalcoholics in alpha power. An anxiety disorder (panic disorder, phobia, or generalized anxiety) was found in 14/17 LV subjects as compared to 34/101 of the rest of the sample (P < 0.01). Support for these observations was found in the unrelated index subjects in whom no traits would be shared by familial clustering. Lower alpha power in anxiety disorders was not state-dependent, as indicated by the Spielberger Anxiety Scale. Familial covariance of alpha power was 0.25 (P < 0.01). These findings indicate there may be a shared factor underlying the transmissible low voltage alpha EEG variant and vulnerability to anxiety disorders with associated alcoholism. This factor is apparently not rare, because LV was found in approximately 10% of unrelated index subjects and 5% of subjects free of alcoholism and anxiety disorders.

An effect of triazolam on visual attention and information processing.

This study explored whether benzodiazepines selectively affect aspects of attention and/or visual information processing, as they do memory. A cued visual-search paradigm was employed, using normal volunteers and a single dose of triazolam. This paradigm provided for a detailed examination of two aspects of visual attention and information processing: 1) controlled versus automatic attention allocation (via central and peripheral cues), and 2) the extent to which processing an item in a non-cued location affects performance (via cue-validity). Triazolam, compared to placebo, significantly increased response time, and Drug Condition interacted with Cue-Validity but not Cue-Type. Based on these data, we argue that triazolam does not affect attention allocation but does affect attentional disengagement and/or attention switching mechanisms.

Head motion during positron emission tomography: is it significant?

High sensitivity for detecting local brain function differences from subsequent PET images acquired at different cerebral stimulation states requires interscan head motion to be minimized. This motion was measured by an optical lever system during scanning (130 min) of 15 subjects in a dual-dose injection study. Despite motion restriction by a face-mask restraint system, rotations in the sagittal and coronal planes (up to 4.1 degrees and 2.4 degrees, respectively) significantly influenced the measured means and variances of local metabolic differences between states. Hence, adjustments for head movement by retrospective, digital slice realignment or, better, real-time corrections are important.

Benzodiazepine receptors mediate regional blood flow changes in the living human brain.

We studied the effects of a high-affinity gamma-aminobutyric acid (GABA)-benzodiazepine-receptor agonist (lorazepam) and an antagonist (flumazenil) in humans, using H2(15)O positron-emission tomography. Administration of lorazepam to healthy volunteers caused time- and dose-dependent reductions in regional cerebral blood flow and self-reported alterations in behavioral/mood parameters. Flumazenil administration reversed these changes. These observations indicated that benzodiazepine-induced effects on regional cerebral blood flow and mood/behavior are mediated at some level through GABA-benzodiazepine receptors, although the specific mechanism remains unclear. The approach described here provides a method for quantifying GABA-benzodiazepine-receptor-mediated neurotransmission in the living human brain and may be useful for studying the role of these receptors in a variety of neuropsychiatric disorders.

Procaine-induced increases in limbic rCBF correlate positively with increases in occipital and temporal EEG fast activity.

Previous independent EEG and PET studies suggest that administration of intravenous procaine hydrochloride selectively activates limbic brain structures. To further elucidate procaine's effects and explore the relationship between quantitative EEG (qEEG) and regional cerebral blood flow (rCBF), we simultaneously recorded qEEG and sampled rCBF using O-15 water PET in 20 healthy volunteers during single-blind injections of saline (baseline condition) followed by intravenous procaine (1.84 mg/kg). After thorough screening of EEG records, a subgroup of 7 subjects with EEG data relatively free of both muscle and movement artifacts was selected for analysis. Quantitative spectral EEG data from right occipital and temporal leads were then correlated with each subject's PET rCBF values on a pixel by pixel basis, both at baseline and after procaine. The most striking finding was that the increases in occipital and temporal omega activity from baseline to procaine positively correlated with rCBF increases in the amygdala and its efferents (p < .05), in a pattern very similar to the rCBF increases seen after procaine administration. This suggests that omega activity may reflect activation of deeper brain limbic structures. Also, the convergence of EEG and PET data further supports procaine's selective limbic activation.