Richard Coppola

Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: A positron emission tomography study

To determine the neural circuitry engaged by performance of the Wisconsin Card Sorting Test (WCST), a neuropsychological test traditionally considered to be sensitive to prefrontal lesions, regional cerebral blood flow was measured with oxygen-15 water and positron emission tomography (PET) while young normal subjects performed the test as well as while they performed a specially designed sensorimotor control task. To consider which of the various cognitive operations and other experiential phenomena involved in the WCST PET scan are critical for the pattern of physiological activation and to focus on the working memory component of the test, repeat WCST scans were also performed on nine of the subjects after instruction on the test and practice to criteria. We confirmed that performance of the WCST engages the frontal cortex and also produces activation of a complex network of regions consistently including the inferior parietal lobule but also involving the visual association and inferior temporal cortices as well as portions of the cerebellum. The WCST activation in the dorsolateral prefrontal cortex (DLPFC) remained significant even after training and practice on the test, suggesting that working memory may be largely responsible for the physiological response in DLPFC during the WCST and, conversely, that the DLPFC plays a major role in modulating working memory.

Functional Magnetic Resonance Imaging Brain Mapping in Psychiatry: Methodological Issues Illustrated in a Study of Working Memory in Schizophrenia

Functional magnetic resonance imaging (fMRI) is a potential paradigm shift in psychiatric neuroimaging. The technique provides individual, rather than group-averaged, functional neuroimaging data, but subtle methodological confounds represent unique challenges for psychiatric research. As an exemplar of the unique potential and problems of fMRI, we present a study of 10 inpatients with schizophrenia and 10 controls performing a novel “n back” working memory (WM) task. We emphasize two key design steps: (1) the use of an internal activation standard (i.e., a physiological control region) to address activation validity, and (2) the assessment of signal stability to control for “activation” artifacts arising from unequal signal variance across groups. In the initial analysis, all but one of the patients failed to activate dorsolateral prefrontal cortex (DLPFC) during the working memory task. However, some patients (and one control) also tended to show sparse control region activation in spite of normal motor performance, a result that raises doubts about the validity of the initial analysis and concerns about unequal subject motion. Subjects were then matched for signal variance (voxel stability), producing a subset of six patients and six controls. In this comparison, the internal activation standard (i.e., motor activation) was similar in both groups, and five of six patients, including two whom were neuroleptic-naive, failed to activate DLPFC. In addition, a tendency for overactivation of parietal cortex was seen. These results illustrate some of the promise and pitfalls of fMRI. Although fMRI generates individual brain maps, a specialized survey of the data is necessary to avoid spurious or unreliable findings, related to artifacts such as motion, which are likely to be frequent in psychiatric patients.

Reduced Central Serotonin Transporters in Alcoholism

OBJECTIVE Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics. METHOD The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I] beta-CIT and single photon emission computed tomography, and psychopathological correlates were assessed. RESULTS A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal. CONCLUSIONS The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms.

Cognitive fitness of cost-efficient brain functional networks

The human brains capacity for cognitive function is thought to depend on coordinated activity in sparsely connected, complex networks organized over many scales of space and time. Recent work has demonstrated that human brain networks constructed from neuroimaging data have economical small-world properties that confer high efficiency of information processing at relatively low connection cost. However, it has been unclear how the architecture of complex brain networks functioning at different frequencies can be related to behavioral performance on cognitive tasks. Here, we show that impaired accuracy of working memory could be related to suboptimal cost efficiency of brain functional networks operating in the classical β frequency band, 15–30 Hz. We analyzed brain functional networks derived from magnetoencephalography data recorded during working-memory task performance in 29 healthy volunteers and 28 people with schizophrenia. Networks functioning at higher frequencies had greater global cost efficiency than low-frequency networks in both groups. Superior task performance was positively correlated with global cost efficiency of the β-band network and specifically with cost efficiency of nodes in left lateral parietal and frontal areas. These results are consistent with biophysical models highlighting the importance of β-band oscillations for long-distance functional connections in brain networks and with pathophysiological models of schizophrenia as a dysconnection syndrome. More generally, they echo the saying that “less is more”: The information processing performance of a network can be enhanced by a sparse or low-cost configuration with disproportionately high efficiency.

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.

Tourette Syndrome: Prediction of Phenotypic Variation in Monozygotic Twins by Caudate Nucleus D2 Receptor Binding

Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.

Specific versus Nonspecific Brain Activity in a Parametric N-Back Task

In this study functional magnetic resonance imaging (fMRI) was used to examine cerebral activity patterns in relation to increasing mental load of a working memory task. Aim of the experiment was to distinguish nonspecific task-related processes from specific workload processes analytically. Twelve healthy volunteers engaged in a spatial n-back task with four levels. FMRI data were acquired with the 3D-PRESTO pulse sequence. Analysis entailed a two-step multiple regression algorithm, which was specifically designed to measure and separate load-sensitive and load-insensitive activity simultaneously, while preserving the original high spatial resolution of the fMRI signal. Load-sensitive and load-insensitive activity was found in both dorsolateral-prefrontal and parietal cortex, predominantly bilaterally, and in the anterior cingulate. As expected, the left primary sensorimotor cortex showed predominantly load-insensitive activity. Load-sensitive activity reflects specific working memory functions, such as temporary retention and manipulation of information, while load-insensitive activity reflects supportive functions, such as visual orientation, perception, encoding, and response selection and execution. Good performance was correlated with a large area of load-sensitive activity in anterior cingulate, and with a small area of load-insensitive activity in the right parietal cortex. The findings indicate that nonspecific and specific working memory processes colocalize and are represented in multiple frontal and parietal regions. Implication of this analytical strategy for application in research on psychiatric disorders is discussed.

Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine.

BACKGROUND Most patients with major depressive disorder (MDD) experience a period of lengthy trial and error when trying to find optimal antidepressant treatment; identifying biomarkers that could predict response to antidepressant treatment would be of enormous benefit. We tested the hypothesis that pretreatment anterior cingulate cortex (ACC) activity could be a putative biomarker of rapid antidepressant response to ketamine, in line with previous findings that investigated the effects of conventional antidepressants. We also investigated patterns of ACC activity to rapid presentation of fearful faces compared with the normal habituation observed in healthy subjects. METHODS We elicited ACC activity in drug-free patients with MDD (n = 11) and healthy control subjects (n = 11) by rapidly presenting fearful faces, a paradigm known to activate rostral regions of the ACC. Spatial-filtering analyses were performed on magnetoencephalographic (MEG) recordings, which offer the temporal precision necessary to estimate ACC activity elicited by the rapid presentation of stimuli. Magnetoencephalographic recordings were obtained only once for both patients and control subjects. Patients were subsequently administered a single ketamine infusion followed by assessment of depressive symptoms 4 hours later. RESULTS Although healthy subjects had decreased neuromagnetic activity in the rostral ACC across repeated exposures, patients with MDD showed robust increases in pretreatment ACC activity. Notably, this increase was positively correlated with subsequent rapid antidepressant response to ketamine. Exploratory analyses showed that pretreatment amygdala activity was negatively correlated with change in depressive symptoms. CONCLUSIONS Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamines antidepressant effects.

Cerebral morphometric abnormalities in Tourette's syndrome: A quantitative MRI study of monozygotic twins

Article abstract—Although the pathologic substrate of Tourettes syndrome (TS) is unknown, studies have implicated subtle changes in the basal ganglia. To further investigate structural basal ganglia pathology in TS, we performed morphometric analyses of MRIs of 10 monozygotic twin pairs discordant for severity of TS but concordant for the presence of tic disorders (mean age, 16.3 years; range, 9 to 31 years). Right caudate volume was slightly but significantly reduced in the relatively more severely affected twins as a group compared with the less affected twins (mean difference = 6%, p < 0.01). Most of this difference was attributable to volume reduction in the anterior right caudate (p < 0.02), which was smaller in the more severely affected twin in nine of 10 twin sets. The mean volume of the left lateral ventricle was 16% smaller in the more severely affected twins than in the less severely affected twins (p < 0.01). The normal asymmetry of the lateral ventricles (left greater than right) was not present in the more severely affected twins, who had a trend toward a larger right lateral ventricle. Moreover, the difference within a pair in the degree of loss of the normal ventricular asymmetry correlated with the difference within a pair in the severity of the tic disorder (r = 0.75, p < 0.02). There were no other basal ganglia, ventricular volumetric, or asymmetry abnormalities. These findings partially replicate other MRI studies and suggest that subtle structural abnormalities in the CNS, particularly in the caudate, may play a role in the pathophysiology of TS. Because monozygotic twins are genetically identical, these structural abnormalities must reflect adverse environmental events.

The G72/G30 Gene Complex and Cognitive Abnormalities in Schizophrenia

A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p=0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p=0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.