Abstract Adaptive behaviour requires the ability to process goal-relevant events at the expense of irrelevant ones. However, perception of a relevant visual event can transiently preclude access to consciousness of subsequent events — a phenomenon called attentional blink (AB). Here we investigated involvement of the left dorsolateral prefrontal cortex (DLPFC) in conscious access, by using transcranial direct current stimulation (tDCS) to potentiate or reduce neural excitability in the context of an AB task. In a sham-controlled experimental design, we applied between groups anodal or cathodal tDCS over the left DLPFC, and examined whether this stimulation modulated the proportion of stimuli that were consciously reported during the AB period. We found that tDCS over the left DLPFC affected the proportion of consciously perceived target stimuli. Moreover, anodal and cathodal tDCS had opposing effects, and exhibited different temporal patterns. Anodal stimulation attenuated the AB, enhancing conscious report earlier in the AB period. Cathodal stimulation accentuated the AB, reducing conscious report later in the AB period. These findings support the notion that the DLPFC plays a role in facilitating information transition from the unconscious to the conscious stage of processing.
Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAHenu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14–21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.
Phenylketonuria (PKU) is an inherited metabolic disease characterized by plasma hyperphenylalaninemia and several neurological symptoms that can be controlled by rigorous dietetic treatment. The cellular mechanisms underlying impaired brain functions are still unclear. It has been proposed, however, that phenylalanine interference in cognitive functions depends on impaired dopamine (DA) transmission in the prefrontal cortical area due to reduced availability of the precursor tyrosine. Here, using Pah(enu2) (ENU2) mice, the genetic murine model of PKU, we investigated all metabolic steps of catecholamine neurotransmission within the medial preFrontal Cortex (mpFC), availability of the precursor tyrosine, synthesis and release, to find an easy way to reinstate normal cortical DA neurotransmission.Analysis of blood and brain levels of tyrosine showed reduced plasma and cerebral levels of tyrosine in ENU2 mice. Western blot analysis demonstrated deficient tyrosine hydroxylase (TH) protein levels in mpFC of ENU2 mice. Cortical TH activity, determined in vivo by measuring the accumulation of l-3,4-dihydroxyphenylalanine (L-DOPA) in mpFC after inhibition of L-aromatic acid decarboxylase with NSD-1015, was reduced in ENU2 mice. Finally, a very low dose of L-DOPA, which bypasses the phenylalanine-inhibited metabolic steps, restored DA prefrontal transmission to levels found in healthy mice.The data suggests that a strategy of using tyrosine supplementation to treat PKU is unlikely to be effective, whereas small dose L-DOPA administration is likely to have a positive therapeutic effect.
Right Brain-Damaged patients (RBD) with left spatial neglect (N+), are characterised by deficits in orienting and re-orienting attention to stimuli in the contralesional left side of space. In a recent ERPs study with visual stimuli (Lasaponara et al., 2018) we have pointed out that the pathological attentional bias of N+ is matched with exaggerated novelty reaction and contextual updating of targets in the right ipsilesional space and reduced novelty reaction and contextual updating of targets in the left contralesional space. To characterise further the attentional performance of N+, here we measured Pupil Dilation (PDil), which is a reliable marker of noradrenergic-locus coeruleus activity and response to unexpected events/rewards. Compared to Neutral and Valid targets, N+ patients displayed a pathological reduction of PDil in response to infrequent Invalid targets in the left side of space, while in Healthy Controls (HC) and RBD without neglect (N-) the same targets enhanced PDil with respect to Neutral and frequent Valid targets. Invalid targets in the right side of space enhanced PDil in all experimental groups. Interestingly, both N- and N+ showed a consistent number of target omissions both in the left and right side of space. With respect to seen targets, N- showed reduced PDil in response to unseen targets both in the left and right side of space. In contrast, N+ had reduced PDil in response to unseen targets in the left side of space though not in the right side, where seen and unseen targets evoked comparable levels of PDil. These results disclose, for the first time, the PDil correlates of spatial attention in left spatial neglect and suggest that the pathological attentional bias suffered by N+ might enhance the autonomic responses reflected in PDil to unseen ipsilesional stimuli. This enhancement can contribute to biasing contextual updating and predictive coding of stimuli in the ipsilesional space, thus worsening the pathological attentional bias of N+.
It is currently unknown which genetic polymorphisms are involved in substance use disorder (SUD) comorbid with bipolar disorder (BD). The research on polymorphisms in BD comorbid with SUD (BD + SUD) is summarized in this systematic review. We looked for case-control studies that genetically compared adults and adolescents with BD and SUD, healthy controls, and BD without SUD. PRISMA was used to create our protocol, which is PROSPERO-registered (identification: CRD4221270818). The following bibliographic databases were searched indefinitely until December 2021 to identify potentially relevant articles: PubMed, PsycINFO, Scopus, and Web of Science. This systematic review, after the qualitative analysis of the study selection, included 17 eligible articles. In the selected studies, 66 polymorphisms in 29 genes were investigated. The present work delivers a group of potentially valuable genetic polymorphisms associated with BD + SUD: rs11600996 (ARNTL), rs228642/rs228682/rs2640909 (PER3), PONQ192R (PON1), rs945032 (BDKRB2), rs1131339 (NR4A3), and rs6971 (TSPO). It is important to note that none of those findings have been confirmed by two or more studies; thus, we believe that all the polymorphisms identified in this review require additional evidence to be confirmed.
