The impact of a CACNA1C gene polymorphism on learning and hippocampal formation in healthy individuals: a diffusion tensor imaging study.

BACKGROUND: Genome-wide association studies have identified the CACNA1C single nucleotide polymorphism (SNP) rs1006737 as one of the most consistent genetic findings as susceptibility locus for major psychiatric disorders. Furthermore, animal and genetic imaging studies have reported strong functional evidence for the association of CACNA1C with learning, memory, neural plasticity, and its association with the hippocampal formation. In the present study we investigated the impact of the CACNA1C SNP rs1006737 on the fractional anisotropy (FA) in the hippocampal formation as well as on verbal learning and memory in healthy individuals. METHODS: 118 healthy individuals (72 males, 46 females, age 18-56years) initially underwent diffusion tensor imaging (DTI), 100 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) to examine the impact of the CACNA1C SNP rs1006737 on the hippocampal formation as predefined region of interest (ROI). Furthermore, all participants completed the Verbal Learning and Memory Test (VLMT). RESULTS: In the VLMT genotype was significantly associated with learning performance. Bonferroni corrected post-hoc tests indicated a diminished performance at the beginning of the learning curve in risk allele carriers compared to non-risk allele carriers. The TBSS ROI analysis revealed one cluster of reduced FA in risk allele carriers compared to non-risk allele carriers located in the right hippocampal formation. Moreover, an association between the initial learning performance and FA values was found. DISCUSSION: These findings demonstrate that genetic variation in the CACNA1C SNP rs1006737 is associated with FA reduction in the hippocampal formation as well as with differences in learning performance in healthy individuals.

Altered neural function during episodic memory encoding and retrieval in major depression.

Memory impairments are common in major depression. Neural processing during non-emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty-six participants (23 depressed patients) performed a non-emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval.

Increased neural activity during overt and continuous semantic verbal fluency in major depression: mainly a failure to deactivate.

Major depression is associated with impairments in semantic verbal fluency (VF). However, the neural correlates underlying dysfunctional cognitive processing in depressed subjects during the production of semantic category members still remain unclear. In the current study, an overt and continuous semantic VF paradigm was used to examine these mechanisms in a representative sample of 33 patients diagnosed with a current episode of unipolar depression and 33 statistically matched healthy controls. Subjects articulated words in response to semantic category cues while brain activity was measured with functional magnetic resonance imaging (fMRI). Compared to controls, patients showed poorer task performance. On the neural level, a group by condition interaction analysis, corrected for task performance, revealed a reduced task-related deactivation in patients in the right parahippocampal gyrus, the right fusiform gyrus, and the right supplementary motor area. An additional and an increased task-related activation in patients were observed in the right precentral gyrus and the left cerebellum, respectively. These results indicate that a failure to suppress potentially interfering activity from inferior temporal regions involved in default-mode network functions and visual imagery, accompanied by an enhanced recruitment of areas implicated in speech initiation and higher-order language processes, may underlie dysfunctional cognitive processing during semantic VF in depression. The finding that patients with depression demonstrated both decreased performance and aberrant brain activation during the current semantic VF task demonstrates that this paradigm is a sensitive tool for assessing brain dysfunctions in clinical populations.

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.

Enhanced resting-state oscillations in schizophrenia are associated with decreased synchronization during inattentional blindness.

Patients suffering from schizophrenia have been characterized by an apparent lack of theta (around 6 Hz) and gamma (>40 Hz) brain oscillatory activity during task execution. The neurocognitive reasons for these abnormal synchronization patterns, however, remain elusive. Recording the electroencephalogramm (EEG) during a selective visual attention task, the current study investigates whether abnormal brain oscillatory resting-state activity in the theta band might account for a lack of task-related brain oscillatory activity in schizophrenia. EEGs were recorded from 26 patients with schizophrenia and 26 healthy matched controls during rest and during the execution of a selective visual attention task, in which an unexpected object (monkey) appeared on the screen. On a behavioral level, patients were less likely to report perceiving the unexpected event than controls. Controls showed a stronger increase in task-related theta power than patients in prefrontal, parietal, and occipital brain regions. Task-related theta power change differed between patients who perceived, and patients who did not perceive the unexpected event. Moreover, patients showed higher levels of theta power during rest than controls, whereas the absolute theta power values during the selective attention task did not differ between groups. These results suggest that the failure to increase oscillatory activity during a cognitive task can be accounted for by abnormally high oscillatory activity in a resting state. This finding has important implications for future studies examining abnormal brain oscillatory activity in schizophrenia, which usually treat resting-state activity as a baseline for task-related activity.

Neural processing of overt word generation in healthy individuals: the effect of age and word knowledge.

Verbal fluency is a classical and widely used neuropsychological instrument to assess cognitive abilities. Results of previous studies indicate an influence on verbal fluency performance of both, age and word knowledge. So far, no imaging study has investigated the neural mechanisms underlying an age and word knowledge related decline on the quantitative verbal output in a highly demanding overt and continuous semantic fluency task. Fifty healthy volunteers (age 22-56 years, verbal IQ 95-143) overtly and continuously articulated words in response to ten visually presented semantic categories while BOLD signal was measured with fMRI. Verbal responses were recorded with an MRI compatible microphone and transcribed after the scanning session. The number of produced words as well as age, word knowledge and level of education was implemented in the design matrix enabling a separate analysis of these factors on both, neural responses and behavioral differences. There was a significant correlation of level of education and number of generated words, but no significant correlations of generated words and age or word knowledge were observed. On the neural level, a widespread network was found for the word production task as contrasted with the resting condition, encompassing the bilateral superior temporal gyri, the cerebellum and the SMA. An age related positive correlation was found in the bilateral inferior and middle frontal gyri, the anterior cingulate gyrus, the left precentral gyrus and the right insula. A lower word knowledge resulted in enhanced BOLD responses in the right superior temporal gyrus and the left superior frontal gyrus. Results are interpreted in terms of compensation mechanisms countervailing potential age and word knowledge related effects.

Genetic variation in CACNA1C affects neural processing in major depression.

Genetic studies found the A allele of the single nucleotide polymorphism rs1006737 in the CACNA1C gene, which encodes for the alpha 1C subunit of the voltage-dependent, L-type calcium ion channel Cav1.2, to be overrepresented in patients with major depressive disorder (MDD). Altered prefrontal brain functioning and impaired semantic verbal fluency (SVF) are robust findings in these patients. A recent functional magnetic resonance imaging (fMRI) study found the A allele to be associated with poorer performance and increased left inferior frontal gyrus (IFG) activation during SVF tasks in healthy subjects. In the present study, we investigated the effects of rs1006737 on neural processing during SVF in MDD. In response to semantic category cues, 40 patients with MDD and 40 matched controls overtly generated words while brain activity was measured with fMRI. As revealed by whole brain analyses, genotype significantly affected brain activity in patients. Compared to patients with GG genotype, patients with A allele demonstrated increased task-related activation in the left middle/inferior frontal gyrus and the bilateral cerebellum. Patients with A allele also showed enhanced functional coupling between left middle/inferior and right superior/middle frontal gyri. No differential effects of genotype on SVF performance or brain activation were found between diagnostic groups. The current data provide further evidence for an impact of rs1006737 on the left IFG and demonstrate that genetic variation in CACNA1C modulates neural responses in patients with MDD. The observed functional alterations in prefrontal and cerebellar areas might represent a mechanism by which rs1006737 influences susceptibility to MDD.