Alcohol-dependent individuals usually favor instant gratification of alcohol use and ignore its long-term negative consequences, reflecting impaired decision-making. According to the somatic marker hypothesis, decision-making abilities are subtended by an extended brain network. As chronic alcohol consumption is known to be associated with brain shrinkage in this network, the present study investigated relationships between brain shrinkage and decision-making impairments in alcohol-dependent individuals early in abstinence using voxel-based morphometry. Thirty patients performed the Iowa Gambling Task and underwent a magnetic resonance imaging investigation (1.5T). Decision-making performances and brain data were compared with those of age-matched healthy controls. In the alcoholic group, a multiple regression analysis was conducted with two predictors (gray matter [GM] volume and decision-making measure) and two covariates (number of withdrawals and duration of alcoholism). Compared with controls, alcoholics had impaired decision-making and widespread reduced gray matter volume, especially in regions involved in decision-making. The regression analysis revealed links between high GM volume in the ventromedial prefrontal cortex, dorsal anterior cingulate cortex and right hippocampal formation, and high decision-making scores (P < 0.001, uncorrected). Decision-making deficits in alcoholism may result from impairment of both emotional and cognitive networks.

α-Tocopherol is the principal source of vitamin E, an essential nutrient that plays a crucial role in maintaining healthy brain function. Infant formula is routinely supplemented with synthetic α-tocopherol, a racaemic mixture of eight stereoisomers with less bioactivity than the natural stereoisomer RRR-α-tocopherol. α-Tocopherol stereoisomer profiles have not been previously reported in the human brain. In the present study, we analysed total α-tocopherol and α-tocopherol stereoisomers in the frontal cortex (FC), hippocampus (HPC) and visual cortex (VC) of infants (n 36) who died of sudden infant death syndrome or other conditions. RRR-α-tocopherol was the predominant stereoisomer in all brain regions (P<0·0001) and samples, despite a large intra-decedent range in total α-tocopherol (5–17 μg/g). Mean RRR-α-tocopherol concentrations in FC, HPC and VC were 10·5, 6·8 and 5·5 μg/g, respectively. In contrast, mean levels of the synthetic stereoisomers were RRS, 1–1·5; RSR, 0·8–1·0; RSS, 0·7–0·9; and Σ2S 0·2–0·3 μg/g. Samples from all but two decedents contained measurable levels of the synthetic stereoisomers, but the intra-decedent variation was large. The ratio of RRR:the sum of the synthetic 2R stereoisomers (RRS+RSR+RSS) averaged 2·5, 2·3 and 2·4 in FC, HPC and VC, respectively, and ranged from 1 to at least 4·7, indicating that infant brain discriminates against synthetic 2R stereoisomers in favour of RRR. These findings reveal that RRR-α-tocopherol is the predominant stereoisomer in infant brain. These data also indicate that the infant brain discriminates against the synthetic 2R stereoisomers, but is unable to do so completely. On the basis of these findings, investigation into the impact of α-tocopherol stereoisomers on neurodevelopment is warranted.

Emotional processes are enhanced in aging, such that aging is characterized by superior emotional regulation. This article provides a brief review of the neural bases supporting this effect with a focus on functional neuroimaging studies of perception and episodic memory. The most consistent finding across these studies is that older adults show an alteration in the recruitment of the amygdala, but greater recruitment of the frontal cortex. These Fronto-amygdalar Age-related Differences in Emotion (FADE) may reflect emotional regulation strategies mediated by frontal brain regions that dampen emotion-related activations in the amygdala. (JINS, 2009, 15, 819–825.)

Two discrete areas in frontal cortex are involved in generating saccadic eye movements—the frontal eye field (FEF) and the supplementary eye field (SEF). Whereas FEF represents saccades in a topographic retinotopic map, recent evidence indicates that saccades may be represented craniotopically in SEF. To further investigate the relationship between these areas, the topographic organization of afferents to FEF from SEF in Macaco mulatto was examined by placing injections of distinct retrograde tracers into different parts of FEF that represented saccades of different amplitudes. Central FEF (lateral area 8A), which represents saccades of intermediate amplitudes, received afferents from a larger portion of SEF than did lateral FEF (area 45), which represents shorter saccades, or medial FEF (medial area 8A), which represents the longest saccades in addition to pinna movements. Moreover, in every case the zone in SEF that innervated lateral FEF (area 45) also projected to medial FEF (area 8A). In one case, a zone in rostral SEF projected to both lateral area 8A from which eye movements were evoked by microstimulation as well as medial area 8A from which pinna movements were elicited by microstimulation. This pattern of afferent convergence and divergence from SEF onto the retinotopic saccade map in FEF is indicative of some sort of map transformation between SEF and FEF. Such a transformation would be necessary to interconnect a topographic craniotopic saccade representation in SEF with a topographic retinotopic saccade representation in FEF.

Inferior temporal (IT) cortex is a “high-order” region of extrastriate visual cortex important for visual form perception and recognition in adult primates. The pattern of cortical afferents from both ipsilateral and contralateral hemispheres to anterior IT cortex was determined in infant macaque monkeys 7–18 weeks of age following injections of wheat-germ agglutinin-HRP. Within the ipsilateral hemisphere, the locations and laminar distribution of labeled cells were similar to those observed after comparable injections in adult monkeys. Specifically, ipsilateral afferents derived from visual areas V4, TEO, anterior and posterior IT, and STP, from parahippocampal, perirhinal, and parietal zones, and from several anterior zones including lateral and ventral frontal cortex, the insula, and cingulate cortex. Within the contralateral hemisphere, we observed labeled cells in homotopic regions of IT and in parahippocampal and perirhinal areas, as has been reported for adult monkeys. However, we also identified additional contralateral regions not previously known to provide input to anterior IT, including lateral and ventral frontal cortex, cingulate cortex, and STP. Overall, the strongest and most widespread projections from outside the temporal lobe were found in the youngest monkey, suggesting that some of these projections may represent transient circuitry necessary for the development of complex visual response properties in anterior IT.

The understanding of decision-making systems has come together in recent years to form a unified theory of decision-making in the mammalian brain as arising from multiple, interacting systems (a planning system, a habit system, and a situation-recognition system). This unified decision-making system has multiple potential access points through which it can be driven to make maladaptive choices, particularly choices that entail seeking of certain drugs or behaviors. We identify 10 key vulnerabilities in the system: (1) moving away from homeostasis, (2) changing allostatic set points, (3) euphorigenic “reward-like” signals, (4) overvaluation in the planning system, (5) incorrect search of situation-action-outcome relationships, (6) misclassification of situations, (7) overvaluation in the habit system, (8) a mismatch in the balance of the two decision systems, (9) over-fast discounting processes, and (10) changed learning rates. These vulnerabilities provide a taxonomy of potential problems with decision-making systems. Although each vulnerability can drive an agent to return to the addictive choice, each vulnerability also implies a characteristic symptomology. Different drugs, different behaviors, and different individuals are likely to access different vulnerabilities. This has implications for an individual's susceptibility to addiction and the transition to addiction, for the potential for relapse, and for the potential for treatment.

Many neuroactive steroids (NS) demonstrate neurotrophic and neuroprotective actions, including protection against apoptosis via Bcl-2 protein. NS are altered in post-mortem brain tissue from subjects with bipolar disorder, and several agents with efficacy in mania elevate NS in rodents. We therefore hypothesized that lithium and valproate may elevate NS, and compensatory NS increases may occur in Bcl-2 knockout mice. NS levels (allopregnanolone, pregnenolone) were determined in frontal cortex by negative ion chemical ionization gas chromatography/mass spectrometry in male Wistar Kyoto rats treated chronically with lithium, valproate, or vehicle. NS were also investigated in heterozygous Bcl-2 knockout mice. Allopregnanolone levels are significantly elevated in lithium-treated (p<0.05), but not in valproate-treated, rats. Pregnenolone levels also tend to be higher following lithium treatment (p=0.09). Knockout of Bcl-2 significantly increases pregnenolone levels in mice (p<0.01), while allopregnanolone levels are unaltered. NS induction may be relevant to mechanisms contributing to lithium therapeutic efficacy and neuroprotection.

Category and letter fluency tasks have been used to demonstrate psychological and neurological dissociations between semantic and phonological aspects of word retrieval. Some previous neuroimaging and lesion studies have suggested that category fluency (semantic-based word retrieval) is mediated primarily by temporal cortex, while letter fluency (letter-based word retrieval) is mediated primarily by frontal cortex. Other studies have suggested that both letter and category fluency are mediated by frontal cortex. We tested these hypotheses using voxel-based lesion symptom mapping (VLSM) in a group of 48 left-hemisphere stroke patients. VLSM maps revealed that category and letter fluency deficits correlate with lesions in temporal and frontal cortices, respectively. Other regions, including parietal cortex, were significantly implicated in both tasks. Our findings are therefore consistent with the hypothesis that temporal cortex subserves word retrieval constrained by semantics, whereas frontal regions are more critical for strategic word retrieval constrained by phonology. (JINS, 2006, 12, 896–900.)

The therapeutic efficacy of mood stabilizers may involve the regulation of gene expression mediated by transcription factor activation. In this study, we investigated AP-1 and cAMP response element-binding protein (CREB) DNA-binding activity in the rat frontal cortex and hippocampus of rats fed a control diet, a lithium diet for 7 wk, or 6 wk of lithium, followed by withdrawal for 7 d. Subsequently, animals were exposed to restraint stress or no stress and the DNA-binding activities assessed at 2, 8 and 24 h post-stress. AP-1 activity was increased in both brain regions by lithium, an effect that persisted with lithium discontinuation. Restraint stress induced AP-1 activity in the frontal cortex of the control group. This stress-induced effect on AP-1 activity was attenuated in lithium-treated and lithium-withdrawn animals. AP-1 DNA binding was also induced by stress in the hippocampus of control animals and the activity diminished over time in the lithium and lithium-withdrawn groups. CREB activity also increased in the frontal cortex and hippocampus of the lithium-treated group. Stress increased CREB activity in the frontal cortex of the controls, and was slightly attenuated with lithium treatment. CREB activity in the hippocampus was insensitive to stress. The proteins involved in the AP-1 and CREB transcription complexes were also characterized. Our findings of increased AP-1 and CREB binding after lithium are consistent with lithium's inhibitory effect on glycogen synthase kinase-3β, which has been show to negatively regulate AP-1 and CREB transcriptional activity.

Phonemic and semantic fluency involve the capacity to generate words beginning with particular letters or belonging to particular categories, respectively. The former has been associated with frontal lobe function and the latter with temporoparietal function, but neuroimaging studies indicate overlap of underlying neural networks. Schizophrenia patients may experience disproportionate semantic fluency impairment owing to abnormal semantic organization; however, executive dysfunction in schizophrenia suggests possible disproportionate phonemic fluency impairment. Moreover, little is known about the diagnostic specificity of either verbal fluency deficit to schizophrenia or their stability over time. We examined 83 schizophrenia patients, 15 bipolar disorder patients, and 83 normal controls. Both fluency types were impaired in schizophrenia patients. Schizophrenia patients as a whole manifested disproportionate semantic fluency impairment relative to bipolar disorder patients, but only a subset of schizophrenia patients manifested disproportionate semantic fluency impairment relative to controls. Few characteristics, except to some extent paranoid-nonparanoid subtype, meaningfully differentiated schizophrenia patients with and without this disproportionate impairment. Verbal fluency measures were moderately stable over a 4-year period in schizophrenia patients and controls (.48 < rs < .79). These results mirror a literature that overall suggests a small degree of disproportionate semantic fluency impairment in schizophrenia, but also some heterogeneity in fluency deficits. (JINS, 2003, 9, 79–88.)

Numerous studies have suggested that frontal cortex plays a strategic, rather than an absolute, role in memory performance. Typically, frontal patients are reported to have impaired recall but normal recognition memory. A recent meta-analysis, however, has questioned this conclusion. To further investigate the role of frontal cortex in long-term memory, patients with focal frontal lesions and age- and education-matched controls were tested on a new version of the California Verbal Learning Test (CVLT–II). Frontal patients exhibited a number of deficits on this test, including overall poorer recall, an increased tendency to make intrusions, reduced semantic clustering, and impaired yes/no recognition performance. Further analysis of the error rates in the yes/no recognition task revealed that frontal patients were most likely to mistakenly endorse 2 types of distractors: semantically related words and words from an interference list. These findings are discussed with respect to the role of frontal dysfunction in false recollections and poor source memory, as well as the distinction between the roles of frontal and temporal cortex in long-term memory. (JINS, 2002, 8, 539–546.)