A genome-wide supported variant in CACNA1C influences hippocampal activation during episodic memory encoding and retrieval

The alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene is one of the best replicated susceptibility loci for bipolar disorder, schizophrenia and major depression. It is involved in learning, memory and brain plasticity. Genetic studies using functional magnetic resonance imaging (fMRI) reported evidence of association with the CACNA1C single nucleotide polymorphism rs1006737 with functional correlates of episodic memory encoding and retrieval, especially activations in the hippocampus. These results, however, are inconsistent with regard to the magnitude and directionality of effect. In the present study, brain activation was measured with fMRI during an episodic memory encoding and retrieval task using neutral faces in two independent samples of 94 and 111 healthy subjects, respectively. Within whole brain analyses, a main effect of genotype emerged mainly in the right hippocampus during encoding as well as retrieval within the first sample: Carriers of the minor allele (A) exhibited lower activations compared to G/G allele carriers. This effect could be replicated within the second sample, however, only for the retrieval condition. The results strengthen findings that rs1006737 is associated with neural systems related to memory processes in hippocampal regions which are detectable in healthy subjects.     

Prism adaptation differently affects motor-intentional and perceptual-attentional biases in healthy individuals

Prism adaptation (PA) has been shown to affect performance on a variety of spatial tasks in healthy individuals and neglect patients. However, little is still known about the mechanisms through which PA affects spatial cognition. In the present study we tested the effect of PA on the perceptual-attentional “where” and motor-intentional “aiming” spatial systems in healthy individuals. Eighty-four participants performed a line bisection task presented on a computer screen under normal or right-left reversed viewing conditions, which allows for the fractionation of “where” and “aiming” bias components (Schwartz et al., 1997). The task was performed before and after a short period of visuomotor adaptation either to left- or right-shifting prisms, or control goggles fitted with plain glass lenses. Participants demonstrated initial leftward “where” and “aiming” biases, consistent with previous research. Adaptation to left-shifting prisms reduced the leftward motor-intentional “aiming” bias. By contrast, the “aiming” bias was unaffected by adaptation to the right-shifting prisms or control goggles. The leftward “where” bias was also reduced, but this reduction was independent of the direction of the prismatic shift. These results mirror recent findings in neglect patients, who showed a selective amelioration of right motor-intentional “aiming” bias after right prism exposure ( [Fortis et al., 2009] and [Striemer and Danckert, 2010a]). Thus, these findings indicate that prism adaptation primarily affects the motor-intentional “aiming” system in both healthy individuals and neglect patients, and further suggest that improvement in neglect patients after PA may be related to changes in the aiming spatial system.     

Blunted reward responsiveness in remitted depression

Major depressive disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted major depressive disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re-occurrence of the disorder.     

Blunted reward responsiveness in remitted depression

Major depressive disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted major depressive disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re-occurrence of the disorder.     

L型钙离子通道α1C亚基基因多态性与精神分裂症的相关性

目的探讨L型钙离子通道α1C亚基(calcium channel,voltage-dependent,L type,alpha 1C subunit,CACNA1C)基因多态性与精神分裂症的关系。方法纳入118例精神分裂症患者及122名对照,采用变性高效液相色谱法对其CACNA1C基因rs10848683、rs2238032、rs2299661位点进行基因分型,通过病历资料收集患者感知觉障碍、思维障碍、情感障碍和行为障碍等临床表现,采用阳性与阴性症状量表(positive and negative syndrome scale,PANSS)评估患者症状。结果 rs2238032和rs2299661位点基因型和等位基因在患者组与对照组间分布有统计学差异(均P0.05),而rs10848683位点基因型和等位基因分布在组间无统计学差异(P0.05)。rs2238032位点TT基因型(OR=0.394)和rs2299661位点CG(OR=0.326)与精神分裂症的患病风险有关联(均P0.05)。rs10848683位点各基因型患者行为障碍分布有统计学差异(P0.05);rs2238032各基因型患者思维障碍、情感障碍和PANSS得分有统计学差异(均P0.05);rs2299661各基因型患者感知觉障碍、PANSS得分有统计学差异(均P0.05)。单体型分析示,CTC(OR=1.811)、CTG(OR=0.432)和TGC(OR=1.771)与精神分裂症关联有统计学意义(P0.05)。结论 CACNA1C基因多态性与精神分裂症及其临床表现有关联。     

Neuronal correlates and serotonergic modulation of behavioural inhibition and reward in healthy and antisocial individuals

Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT_2C-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic.     

CACNA1C polymorphism and brain cortical structure in bipolar disorder

BackgroundThe CACNA1C gene encodes the 1C subunit of L-type voltage-gated calcium channels and has been associated with several psychiatric syndromes — including bipolar disorder — in many genome-wide association studies. Experimental and clinical studies have reported changes with respect to behaviour and biomarkers in risk allele carriers, corroborating the essential role of the CACNA1C gene in neurons, during development and in the mature brain. However, the association of this gene with regional cortical thickness has not been evaluated in patients with bipolar disorder.MethodsUsing magnetic resonance imaging, we measured the average cortical thickness of 68 brain regions in 87 patients genotyped for the single-nucleotide polymorphism rs1006737 in CACNA1C.ResultsWe found associations with the mean thickness of several cortical areas: the left lateral orbitofrontal and rostral anterior cingulate cortices, as well as other parts of the frontal and parietal cortices.Limitations: This cross-sectional cohort study could not fully differentiate correlation from causation.ConclusionThe CACNA1C polymorphism rs1006737 is associated with the mean thickness of cortical brain areas that have been shown to be altered in bipolar disorder.     

Listening to numbers affects visual and haptic bisection in healthy individuals and neglect patients

There is evidence that humans represent numbers in the form of a mental number line (MNL). Here we show that the MNL modulates the representation of visual and haptic space both in healthy individuals and right-brain-damaged patients, both with and without left unilateral spatial neglect (USN). Participants were asked to estimate the midpoint of visually or haptically explored rods while listening to task-irrelevant stimuli: a small digit ("2"), a large digit ("8"), or a non-numerical auditory stimulus ("blah"). In a control silent condition, the bisection error of USN patients was biased rightwards (namely, the marker of USN) only in the visual modality. Regardless of the direction of the bisection error committed in silent trials, listening to the small digit shifted the perceived midline leftwards, and listening to the large digit shifted the perceived midline rightwards, compared to a control condition in which a neutral syllable ("blah") was presented. The shift induced by listening to numbers occurred independently of the modality of response (i.e., both in vision and haptics), and in every group of participants. Interestingly, the effect of auditory numbers processing on space estimation was overall larger for haptically than for visually explored space in all participants. In conclusion, the present data show that listening to irrelevant numbers affects space perception also in patients with left USN, indicating that the spatial representation and attention processes disrupted by USN are not involved in these numerical magnitude-spatial effects.     

The effects of CACNA1C gene polymorphism on spatial working memory in both healthy controls and patients with schizophrenia or bipolar disorder

CACNA1C gene polymorphism (rs1006737) is a susceptibility factor for both schizophrenia (SCZ) and bipolar disorder (BP). However, its role in working memory, a cognitive function that is impaired in both diseases, is not clear. Using three samples, including healthy controls, patients with SCZ, and patients currently in manic episodes of BP, this study tested the association between the SNP rs1006737 and spatial working memory as measured by an N-back task and a dot pattern expectancy (DPX) task. Among SCZ patients and healthy controls, the clinical risk allele was associated with impaired working memory, but the association was either in opposite direction or non-significant in patients with BP. These results indicated that rs1006737 may have differential effects on working memory in different disease populations and pointed to the necessity for more studies in different patient populations.     

Hippocampal function in healthy carriers of the CLU Alzheimer's disease risk variant

Alzheimer's disease is a devastating, common, progressive dementia with considerable heritability. Recently, a genetic variant associated with the disease was discovered at CLU (rs11136000) with genome-wide support. Here we show, using an imaging genetics approach in a large genotyped sample, that healthy carriers of the variant exhibit altered coupling between hippocampus and prefrontal cortex during memory processing, mirroring clinical evidence of disturbed connectivity in patients and providing a neurogenetic mechanism for CLU-associated risk and protection.     

Hemiplegic migraine type 2 caused by a novel variant within the P-type ATPase motif in ATP1A2 concomitant with a CACNA1A variant

BackgroundFamilial hemiplegic migraine (FHM) is an inherited autosomal dominant disorder characterized by migraine with reversible hemiplegia. FHM1 is caused by variants in CACNA1A, encoding a P/Q type neuronal voltage-gated calcium channel α subunit, which is also associated with episodic ataxia type 2 (EA2). FHM2 is associated with ATP1A2, which codes for an Na⁺/K⁺-ATPase isoform 2 subunit.Case presentationWe identified an FHM2 family, the mother and her daughter, with a novel variant in ATP1A2, p.Gly377Asp, located in a well-conserved P-type ATPase motif. Additionally, the mother harbored deletion in the CACNA1A, associated with EA2, but her daughter did not. The mother presented migraine with typical aura without motor deficit, whereas her daughter had migraine accompanied by recurrent motor deficit and altered consciousness. The additional CACNA1A deletion in the mother might serve as a modifier.ConclusionOur report emphasizes the importance of genetic analysis to diagnose neurological ion channel/transporter diseases.     

CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia

Affective deficits are one common denominator of schizophrenia (SZ), bipolar disorder (BD) and obsessive compulsive disorder (OCD) with the amygdala indicated as one of the major structures involved in emotion regulation. Previous findings of differences in amygdala volume between healthy controls and patients with SZ, BD or OCD diverge with respect to the affected hemisphere, size and direction of the effect. Variability in the CACNA1C gene has been linked to BD, SZ as well as structural and functional variation in the amygdala in healthy people and patients with BD. We were interested to investigate whether amygdala volumes differ between hemispheres, diagnostic or genotype groups, and whether any interactive effects exist. We combined genotyping of SNP rs1006737 in CACNA1C with structural MRI measurements of relative gray matter (GM) amygdala volume in patients with SZ, BD or OCD as well as healthy controls (N _Total = 72). The CACNA1C genotype showed a significant effect on relative GM amygdala volume in patients with SZ. There was a significant left versus right relative GM amygdala volume decrease in patients with SZ or BD. The effects of hemisphere and diagnosis (controls vs. patients with SZ) on relative GM amygdala volume were genotype specific. Our data suggest that the CACNA1C genotype may account for some heterogeneity in the effects of hemisphere and diagnosis on amygdala volume when comparing patients with SZ and controls and point to disturbed Ca²⁺-signaling as a plausible mechanism contributing to the pathology in patients with SZ.