Alcohol dose effects on brain circuits during simulated driving: an fMRI study.

Driving while intoxicated remains a major public health hazard. Driving is a complex task involving simultaneous recruitment of multiple cognitive functions. The investigators studied the neural substrates of driving and their response to different blood alcohol concentrations (BACs), using functional magnetic resonance imaging (fMRI) and a virtual reality driving simulator. We used independent component analysis (ICA) to isolate spatially independent and temporally correlated driving-related brain circuits in 40 healthy, adult moderate social drinkers. Each subject received three individualized, separate single-blind doses of beverage alcohol to produce BACs of 0.05% (moderate), 0.10% (high), or 0% (placebo). 3 T fMRI scanning and continuous behavioral measurement occurred during simulated driving. Brain function was assessed and compared using both ICA and a conventional general linear model (GLM) analysis. ICA results replicated and significantly extended our previous 1.5T study (Calhoun et al. [2004a]: Neuropsychopharmacology 29:2097-2017). GLM analysis revealed significant dose-related functional differences, complementing ICA data. Driving behaviors including opposite white line crossings and mean speed independently demonstrated significant dose-dependent changes. Behavior-based factors also predicted a frontal-basal-temporal circuit to be functionally impaired with alcohol dosage across baseline scaled, good versus poorly performing drivers. We report neural correlates of driving behavior and found dose-related spatio-temporal disruptions in critical driving-associated regions including the superior, middle and orbito frontal gyri, anterior cingulate, primary/supplementary motor areas, basal ganglia, and cerebellum. Overall, results suggest that alcohol (especially at high doses) causes significant impairment of both driving behavior and brain functionality related to motor planning and control, goal directedness, error monitoring, and memory.

Neural bases of dysphoria in early Huntington's disease.

Psychiatric disorders, including disorders of emotion control, are common in Huntington's disease. The neurobiological mechanism of the increased rate of disorders of emotion control are not known. Emotion perception deficits have been reported in Huntington's disease, but studies of emotional experience have been limited. In the present study we aim to expand the research in emotion in Huntington's disease by examining the neural bases of induced dysphoria at an early stage of Huntington's disease. Ten Huntington's disease patients and 12 demographically matched healthy volunteers underwent [(15)O] water positron emission tomography while in a transient state of dysphoria induced by viewing negatively charged affect-laden stimuli. Both groups experienced dysphoric mood, but Huntington's disease patients responded to the stimuli with greater arousal, anger and fear than healthy controls. Induced dysphoric mood was associated with a widespread reduction of activity within the frontal and parietal lobes, thalamus, and cerebellum. These differences could not be explained based on the smaller gray matter volumes of the corresponding regions, although in Huntington's disease patients smaller caudate nucleus volumes predicted lower dorsal-lateral prefrontal activity. Areas of increased activity included the striate and extrastriate cortex, the left thalamus, the transverse temporal gyrus, and the posterior hippocampus. This study elucidates possible mechanisms contributing to psychiatric disturbances of emotion often found in patients with Huntington's disease.

The neural correlates of implicit sequence learning in schizophrenia.

Twenty-seven schizophrenia spectrum patients and 25 healthy controls performed a probabilistic version of the serial reaction time task (SRT) that included sequence trials embedded within random trials. Patients showed diminished, yet measurable, sequence learning. Postexperimental analyses revealed that a group of patients performed above chance when generating short spans of the sequence. This high-generation group showed SRT learning that was similar in magnitude to that of controls. Their learning was evident from the very 1st block; however, unlike controls, learning did not develop further with continued testing. A subset of 12 patients and 11 controls performed the SRT in conjunction with positron emission tomography. High-generation performance, which corresponded to SRT learning in patients, correlated to activity in the premotor cortex and parahippocampus. These areas have been associated with stimulus-driven visuospatial processing. Taken together, these results suggest that a subset of patients who showed moderate success on the SRT used an explicit stimulus-driven strategy to process the sequential stimuli. This adaptive strategy facilitated sequence learning but may have interfered with conventional implicit learning of the overall stimulus pattern.

The cerebellum and emotional experience.

While the role of the cerebellum in motor coordination is widely accepted, the notion that it is involved in emotion has only recently gained popularity. To date, functional neuroimaging has not been used in combination with lesion studies to elucidate the role of the cerebellum in the processing of emotional material. We examined six participants with cerebellar stroke and nine age and education matched healthy volunteers. In addition to a complete neuropsychological, neurologic, and psychiatric examination, participants underwent [15O]water positron emission tomography (PET) while responding to emotion-evoking visual stimuli. Cerebellar lesions were associated with reduced pleasant experience in response to happiness-evoking stimuli. Stroke patients reported an unpleasant experience to frightening stimuli similar to healthy controls, yet showed significantly lower activity in the right ventral lateral and left dorsolateral prefrontal cortex, amygdala, thalamus, and retrosplenial cingulate gyrus. Frightening stimuli led to increased activity in the ventral medial prefrontal, anterior cingulate, pulvinar, and insular cortex. This suggests that alternate neural circuitry became responsible for maintaining the evolutionarily critical fear response after cerebellar damage.

Prism adaptation in schizophrenia.

The prism adaptation test examines procedural learning (PL) in which performance facilitation occurs with practice on tasks without the need for conscious awareness. Dynamic interactions between frontostriatal cortices, basal ganglia, and the cerebellum have been shown to play key roles in PL. Disruptions within these neural networks have also been implicated in schizophrenia, and such disruptions may manifest as impairment in prism adaptation test performance in schizophrenia patients. This study examined prism adaptation in a sample of patients diagnosed with schizophrenia (N=91) and healthy normal controls (N=58). Quantitative indices of performance during prism adaptation conditions with and without visual feedback were studied. Schizophrenia patients were significantly more impaired in adapting to prism distortion and demonstrated poorer quality of PL. Patients did not differ from healthy controls on aftereffects when the prisms were removed, but they had significantly greater difficulties in reorientation. Deficits in prism adaptation among schizophrenia patients may be due to abnormalities in motor programming arising from the disruptions within the neural networks that subserve PL.

Polymorphism analysis of HOPA: a candidate gene for schizophrenia.

HOPA is a 25 kb Xq13 gene that codes for a member of the thyroid receptor co-activator protein (TRAP) family of nuclear receptor co-activators. In our prior research, polymorphisms in the opposite paired (Opa) domain of HOPA have been associated with a syndrome of aberrant behavior, most prominently psychosis, and hypothyroidism. These Opa domain polymorphisms are intriguing because subsequent research has demonstrated that changes in the Opa domain of the C. elegans orthologue of HOPA results in altered neurogenesis and release of transcriptional suppression. In an effort to determine whether other allelic polymorphisms in this gene exist and may potentially contribute to increased susceptibility to neuropsychiatric illness, we have performed single stranded conformational polymorphism (SSCP) analysis of all 45 exons and each of the two potential promoter regions of HOPA using DNA from a panel of patients with psychosis. We found a rare promoter polymorphism in an individual with schizoaffective disorder and extremely low thyroid stimulating hormone (TSH). The most common exonic polymorphism in HOPA is the previously demonstrated HOPA(12 bp) polymorphism. Transmission disequilibrium analysis of the HOPA(12 bp) polymorphism showed segregation with affected status in six of eight instances. We suggest that this evidence supports previous associations of HOPA(12 bp) with a broad range of neuropsychiatric illness and conclude that further studies of this uncommon polymorphism are merited.

Marijuana alters the human cerebellar clock.

The effects of marijuana on brain perfusion and internal timing were assessed using [15O] water PET in occasional and chronic users. Twelve volunteers who smoked marijuana recreationally about once weekly, and 12 volunteers who smoked daily for a number of years performed a self-paced counting task during PET imaging, before and after smoking marijuana and placebo cigarettes. Smoking marijuana increased rCBF in the ventral forebrain and cerebellar cortex in both groups, but resulted in significantly less frontal lobe activation in chronic users. Counting rate increased after smoking marijuana in both groups, as did a behavioral measure of self-paced tapping, and both increases correlated with rCBF in the cerebellum. Smoking marijuana appears to accelerate a cerebellar clock altering self-paced behaviors.