Shifted neuronal balance during stimulus-response integration in schizophrenia: an fMRI study.

Schizophrenia is characterized by marked deficits in executive and psychomotor functions, as demonstrated for goal-directed actions in the antisaccade task. Recent studies, however, suggest that this deficit represents only one manifestation of a general deficit in stimulus-response integration and volitional initiation of motor responses. We here used functional magnetic resonance imaging to investigate brain activation patterns during a manual stimulus-response compatibility task in 18 schizophrenic patients and 18 controls. We found that across groups incongruent vs. congruent responses recruited a bilateral network consisting of dorsal fronto-parietal circuits as well as bilateral anterior insula, dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (preSMA). When testing for the main-effect across all conditions, patients showed significantly lower activation of the right DLPFC and, in turn, increased activation in a left hemispheric network including parietal and premotor areas as well as the preSMA. For incongruent responses patients showed significantly increased activation in a similar left hemispheric network, as well as additional activation in parietal and premotor regions in the right hemisphere. The present study reveals that hypoactivity in the right DLPFC in schizophrenic patients is accompanied by hyperactivity in several fronto-parietal regions associated with task execution. Impaired top-down control due to a dysfunctional DLPFC might thus be partly compensated by an up-regulation of task-relevant regions in schizophrenic patients.

Subtle cognitive deficits in severe alcohol addicts--do they show a specific profile?

Although alcohol dependency is a burden to society, data on cognitive performance in therapy-resistant patients after multiple withdrawals are poor. In this study, 22 patients without reported cognitive deficits and 20 control subjects performed extensive cognitive testing and a motor task assessing short-term memory. Patients displayed subtle deficits (mainly in executive function), while memory functions were relatively unimpaired. Our results suggest that subtle frontal-executive deficits may contribute to a poor prognosis, but could be missed by routine clinical tests.

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects.

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.

Executive control in chronic schizophrenia: A perspective from manual stimulus-response compatibility task performance.

BACKGROUND: Antisaccade deficits are a well-documented pathophysiological characteristic in schizophrenia. However, it is yet unclear whether these findings reflect a specific oculomotor deficit, general psychomotor impairment or disturbance in executive control mechanisms. METHODS: Performance in a manual stimulus-response compatibility (SRC) task and a neuropsychological test-battery covering different cognitive and motor domains were obtained in 28 patients with chronic schizophrenia. It was compared with a normative cohort of healthy subjects and validated by comparison with a sub-sample of that cohort consisting of 28 age, gender and education matched controls. RESULTS: Patients showed significantly worse performance than controls in tests requiring maintenance or manipulating of multiple components but were unimpaired in simple motor, memory or executive tasks. In the SRC task patients had a significantly worse performance in the congruent condition and also a significantly higher increase in error rate from the congruent to the incongruent condition. There were, however, neither a group difference nor a group-by-condition interaction with respect to reaction times. INTERPRETATION: : Our results provide evidence against an isolated oculomotor deficit but also against an undifferentiated psychomotor dysfunction in chronic schizophrenia. Rather, in synopsis with previous reports on antisaccade performance, it becomes evident that the degree of impairment follows closely the amount of executive control required in a task, which in turn may relate to dysfunctional top-down bias of the prefrontal cortex arising from unstable task instructions.

Muscarinic antagonist effects on executive control of attention.

Acetylcholine plays a major role in mediating attention processes. We investigated the muscarinic antagonist effect of scopolamine on functional neuro-anatomy of attention and cognition. We assessed 12 healthy volunteers while performing the Attention Network Task on 0.4 mg scopolamine and placebo in a single-blind randomized trial in a 1.5 T magnetic resonance scanner. Neurocognitive measures included verbal learning, verbal memory, verbal fluency, trail making, digit span, a continuous performance task and a planning task (Tower of London). When compared to placebo, scopolamine increased reaction times for conflicting stimulus processing, together with decreasing brain activation in the anterior cingulate cortex (a brain region involved in conflict processing) suggestive of a muscarinic antagonist effect on executive control of attention. Contrary to the notion of a predominantly right-hemispheric lateralization of cognitive processes associated with orienting attention, scopolamine reduced brain activity in left superior and left middle frontal brain areas. Our neuropsychological test data revealed a selective effect of scopolamine on verbal learning and memory while other cognitive domains, such as planning and working memory, were unaffected. These findings are consistent with muscarinic modulation of dopaminergic neurotransmission in frontal attention networks when processing conflicting information.

Nicotinic antagonist effects on functional attention networks.

Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three components of attention processes (i.e. alerting, orienting and executive control) in 12 healthy male subjects whilst performing the Attention Network Task (ANT) in a magnetic resonance imaging (MRI) scanner. Participants received 15 mg mecamylamine in a single blind and placebo- controlled randomized procedure 90 min prior to obtaining functional MRI data. Our results confirm previous reports of beneficial effects of cueing (alerting and orienting) and detrimental effects of conflict (executive control) on reaction times when performing the ANT. The functional MRI data confirmed distinct neural networks associated with each of the three attention components. Alerting was associated with increased left temporal lobe activation while orienting increased bilateral prefrontal, right precuneus and left caudate activation. Executive control activated anterior cingulate and precuneus. Mecamylamine slowed overall response time and down-regulated brain activation associated with orienting and to some extent brain activation associated with executive control when compared to placebo. These findings are consistent with nicotinic modulation of orienting attention by cueing and executive control when responding to conflicting information. The latter nicotine antagonist effect may be mediated via cholinergic modulation of dopamine neurotransmission in mesolimbic pathways.

Y-box protein-1 is actively secreted through a non-classical pathway and acts as an extracellular mitogen.

Y-box protein (YB)-1 of the cold-shock protein family functions in gene transcription and RNA processing. Extracellular functions have not been reported, but the YB-1 staining pattern in inflammatory glomerular diseases, without adherence to cell boundaries, suggests an extracellular occurrence. Here, we show the secretion of YB-1 by mesangial and monocytic cells after inflammatory challenges. It should be noted that YB-1 was secreted through a non-classical mode resembling that of the macrophage migration inhibitory factor. YB-1 release requires ATP-binding cassette transporters, and microvesicles protect YB-1 from protease degradation. Two lysine residues in the YB-1 carboxy-terminal domain are crucial for its release, probably because of post-translational modifications. The addition of purified recombinant YB-1 protein to different cell types results in increased DNA synthesis, cell proliferation and migration. Thus, the non-classically secreted YB-1 has extracellular functions and exerts mitogenic as well as promigratory effects in inflammation.