Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression

Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either “man-made” or “not man-made.” For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.     

Deficits in verbal declarative memory function in women with childhood sexual abuse-related posttraumatic stress disorder

Several studies have shown deficits in verbal declarative memory function in posttraumatic stress disorder (PTSD). Most of these studies have been performed in men with combat-related PTSD compared with healthy subjects; relatively little is known about memory function in women with abuse-related PTSD, or whether these effects are specific to PTSD or are a nonspecific outcome of exposure to early abuse. The purpose of this study was to assess declarative memory function in women with and without a history of early childhood sexual abuse and PTSD. Forty-three women with and without a history of early childhood sexual abuse and PTSD underwent neuropsychological testing with subtests of the Wechsler Memory Scale--Revised for measurement of verbal and visual memory and subtests of the Wechsler Adult Intelligence Scale for measurement of IQ, and behavioral ratings of PTSD and other psychiatric symptoms. Abused women with PTSD had deficits in verbal declarative memory as measured with the subtests of the Wechsler Memory Scale--Revised compared with women with early abuse without PTSD and nonabused women without PTSD. There were no significant differences in IQ. These findings suggest that early abuse with PTSD is associated with deficits in verbal declarative memory, and that these effects are not related to the nonspecific effects of childhood abuse.     

Effects of glucocorticoids on declarative memory function in major depression.

BACKGROUND: Major depression has been associated with hypercortisolemia in a subset of patients with depression. Administration of exogenous cortisol and other glucocorticoids to healthy human subjects has been observed to result in a transient impairment in verbal declarative memory function. The purpose of this study was to assess the effects of the glucocorticoid, dexamethasone, on verbal declarative memory function in patients with untreated unipolar major depressive disorder (MDD). METHODS: Fifty two men and women with (n = 28) and without (n = 24) MDD received placebo or dexamethasone (1 mg and 2 mg on 2 successive days) in a double-blind, randomized fashion. Declarative memory was assessed with paragraph recall at baseline (day 1) and day 3. RESULTS: There was a significant interaction between diagnosis and drug (dexamethasone vs. placebo) on paragraph recall. In the healthy subjects, memory improved from baseline to day 3 with placebo and was unchanged with dexamethasone, whereas in MDD patients memory function showed a pattern of decreasing with placebo and improving with dexamethasone from baseline to day 3. CONCLUSIONS: These findings are consistent with an altered sensitivity of declarative memory function in MDD to regulation by glucocorticoids. Possible explanations of the findings include alterations in glucocorticoid receptors in the hippocampus or other brain regions mediating declarative memory, or differential sensitivity to dexamethasone-induced reductions in cortisol, in patients with MDD.     

Reduced somatostatin in subgenual anterior cingulate cortex in major depression

β-Amyloid hyperproduction has been observed in response to alterations in neuronal intracellular cholesterol storage, efflux, and synthesis, induced in rats by a high-fat diet. It has been suggested that cholesterol homeostasis is altered in Alzheimer's disease resulting in higher β- and γ-secretase activity. In the current study the neuronal activation status of sterol regulatory element binding protein 2 (SREBP2) as well as its involvement in β-secretase BACE1 activity was investigated in high-fat fed rats (26% fat and 4% cholesterol for 20 weeks), and in SK-N-BE neuroblastoma cells exposed to 20 μM cholesterol. This work demonstrates that in the brain a hyperlipidic diet is able to induce a hyper-expression of BACE1 and determine an unbalance in cerebral cholesterol homeostasis so that SREBP2 is activated. In addition, we show for the first time the involvement of SREBP2 on expression of BACE1 in SK-N-BE cells exposed to high cholesterol. Although the enhanced risk of Alzheimer's disease in metabolic syndrome is related to several factors, our results suggest that SREBP2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer's disease progression.     

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. Hum Brain Mapp 35:4293–4302, 2014. © 2014 Wiley Periodicals, Inc .     

Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression

OBJECTIVE: To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of children with major depressive disorder (MDD). METHOD: Single-voxel proton magnetic resonance spectroscopic (H-MRS) examinations of the anterior cingulate cortex were conducted in 13 psychotropic-na?ve children and adolescents with MDD and 13 age- and sex-matched healthy children and adolescents. Ten of the 13 MDD patient-control pairs also had a H-MRS examination of occipital cortex. RESULTS: Anterior cingulate glutamatergic (Glx) concentrations were significantly lower (19% decrease) in MDD patients versus controls (9.27 +/- 0.43 versus 11.47 +/- 0.26, respectively, p = 0.000). Reduced anterior cingulate Glx in MDD patients was associated with increased severity of functional impairment. These results remained comparably significant after controlling for age and anterior cingulate volume. Occipital cortex Glx did not differ between MDD patients and controls. CONCLUSIONS: These preliminary findings provide new evidence of localized functional neurochemical marker alterations in Glx in anterior cingulate cortex in pediatric MDD. Altered anterior cingulate Glx neurotransmission may be involved in the pathogenesis of MDD.     

Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder.

BACKGROUND: Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. METHODS: Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. RESULTS: Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. CONCLUSIONS: These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.     

History of depression and women's current health and functioning during midlife

OBJECTIVE: To examine the association of past depression with current physical and mood symptoms and functioning in a community cohort of middle-aged African-American, White, and Hispanic women without current depression and whether the associations varied by severity of prior depression. METHODS: The study was conducted as part of a longitudinal multisite investigation of middle-aged women's health, the Study of Women's Health Across the Nation (SWAN). Nine hundred twenty-two women, aged 42-52 years, participated in The Structured Clinical Interview for the Diagnosis of DSM-IV Axis I Disorders (SCID) at study entry at three SWAN sites; 780 did not have current depression and formed the analytic sample. chi(2), ANOVAs and Cochran-Armitage Trend tests were conducted as appropriate to evaluate bivariate relationships between history of major depression and covariates and outcomes. Multivariable logistic regression analyses included significant covariates in final analyses. RESULTS: Women (24.3%) had a history of major depression: 14.9% single episode, 9.4% recurrent and 12.6% had minor depression. In multivariable logistic regression analyses, compared to no history of depression, any past depression predicted high body pain [odds ratios (ORs), 1.8-2.3; 95% CIs, 1.05-4.02]. Recurrent depression predicted poor social functioning (OR, 2.1; 95% CI, 1.20-3.80) and current treatment for back pain (OR, 4.2; 95% CI, 1.78-9.82). Minor depression predicted mood symptoms (OR, 1.9; 95% CI, 1.16-3.20). CONCLUSIONS: Midlife women with past major or minor depression are at risk for physical symptoms, body pain, and poor social functioning even in the absence of current depression. Primary care providers may underestimate the health impact of prior depression without current depression.     

Subgenual anterior cingulate activation to valenced emotional stimuli in major depression

Major depression has been associated with anomalous activation in the subgenual anterior cingulate cortex, but its response to emotional stimuli is poorly understood. The primary goal of this study was to compare levels of activation in the subgenual anterior cingulate cortex of diagnosed depressed and nondepressed participants in response to happy and sad facial expressions of affect. Whereas cognitive theories of depression predict increased activation to negative stimuli, depressed participants were found to exhibit increased activation to both types of stimuli in the subgenual anterior cingulate cortex. Importantly, the loci were in different regions of the subgenual anterior cingulate cortex, suggesting that there is functional specialization in the processing of negatively and positively valenced stimuli.     

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel Ca_V1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the ‘missing heritability'' of complex phenotypes.     

Executive functioning and verbal memory in young patients with unipolar depression and schizophrenia

Although neuropsychological studies have consistently reported executive deficits in schizophrenia, studies of executive functions in depression have produced equivocal results. The aim of this study was to examine the profile and the specificity of the executive impairment and its association with memory performance in young patients with unipolar depression. We compared patients with depression to normal control subjects and schizophrenics. Twenty young inpatients with unipolar depression, 14 schizophrenics and 20 age-, education- and IQ-matched control subjects were assessed with a neuropsychological battery including: (1) verbal memory task; (2) frontal tasks (WCST, Cognitive Estimate, Verbal fluency, verbal and visuo-spatial span) and a new complex sorting test (Delis test). Depressed patients and schizophrenics exhibited executive deficits. Unlike schizophrenics, depressed patients did not show memory impairment. Deficits in several 'higher-level' functions combined to produce executive impairments in patients with depression including complex integration for concept formation, spontaneous cognitive flexibility and initiation ability. Impaired functions in schizophrenia and in depressed patients were similar but were differently related to clinical variables. The pattern of memory failure in our schizophrenics is believed to reflect retrieval and encoding deficits. Our findings highlight the heterogeneity of skills grouped under the term 'executive functions' that are vulnerable in depression or schizophrenia.     

Working‐memory fMRI reveals cingulate hyperactivation in euthymic major depression

While cognitive impairments are well documented for the acute episode of major depressive disorder (MDD), less is known about cognitive functioning in the euthymic state. For working memory, dysfunctional activation of lateral prefrontal and cingulate cortex has been reported in the acute episode. This study investigates working‐memory function and its neurobiological correlate in euthymic MDD patients, particularly whether dysfunctional activation persists when depressive symptoms improve. We investigated 56 subjects with functional magnetic resonance imaging (fMRI) at 3 Tesla. To challenge working‐memory function, a classical verbal n‐back task (0‐, 1‐, and 2‐back) was used in 28 well‐characterized, euthymic, unipolar MDD patients and 28 healthy control subjects matched according to age, sex, and educational level. Data were analyzed using SPM5. In the absence of significant behavioral differences, we observed comparable overall patterns of brain activation in both groups. As expected, both groups showed stronger activation of the typical working‐memory network with increasing memory load. However, significant hyperactivation of the cingulate cortex was observed in euthymic patients, while lateral prefrontal activation was comparable between patients and controls. Working‐memory challenge in the euthymic state of MDD revealed a dissociation of lateral prefrontal and cingulate brain function. Cingulate function, which is important for both emotional and cognitive processing and their integration, is still abnormal when mood is restored. This could reflect a different speed of normalization in prefrontal and limbic cortices, persistent systematic changes in neuronal networks after an episode of MDD, or a compensatory mechanism to maintain working‐memory performance. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Attenuated anterior cingulate activation during a verbal fluency task in elderly patients with a history of multiple-episode depression.

OBJECTIVE: Previous studies have suggested that, in elderly patients, prior depression plays a role in the recurrence of depression. The aim of this study was to investigate cerebral brain function in recovered depressed elderly and investigate the relationship between this brain function and the number of depressive episodes. METHODS: Twenty elderly depressive patients in recovery and 10 healthy volunteers were included in this study. The depressive patients were divided into those who had experienced a single depressive episode and those who had experienced multiple episodes. Functional magnetic resonance imaging was performed in each participant during a verbal fluency task. The data were analyzed using statistical parametric mapping. RESULTS: Activation in the anterior cingulate cortex was significantly attenuated in patients who had experienced multiple depressive episodes, compared with the other two groups. There were no significant differences in areas of activation between patients with a single depressive episode and healthy volunteers. CONCLUSIONS: These findings suggest that attenuated activation in the anterior cingulate cortex may be associated with multiple episodes of depression in the elderly and with the vulnerability to cycling or recurrence.     

The relationships of positive and negative symptoms with neuropsychological functioning and their ability to predict verbal memory in psychotic major depression

Neuropsychological functioning, in relation to positive and negative symptoms in psychotic major depression (PMD), has not been as thoroughly studied as it has been in schizophrenia. Thus, the current study investigated the associations between positive and negative symptoms with cognitive functioning, with an emphasis on verbal memory in PMD. Attention, working memory, and the executive functioning domains were analyzed among 49 PMD participants. Positive symptoms did not correlate significantly with any measures of verbal memory but did correlate with one measure of attention, working memory, and executive functioning. Negative symptoms correlated significantly with two California Verbal Learning Test-II (CVLT-II) measures of verbal memory and three measures of executive function. Hierarchical regressions were conducted to determine if negative symptoms could predict verbal memory performance after controlling for depression. Of the two verbal memory measures, negative symptoms significantly explained additional variance for CVLT Recognition, but not for CVLT Trials 1-5 total score. Our results provide some evidence that, consistent with the schizophrenia literature, negative symptoms contributed more to verbal memory deficits in PMD than positive symptoms, regardless of depression severity.     

Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls

OBJECTIVE: To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of pediatric patients with obsessive-compulsive disorder (OCD) without major depressive disorder (MDD) versus pediatric patients with MDD without OCD and healthy controls. METHOD: Single-voxel proton magnetic resonance spectroscopic examinations of the anterior cingulate cortex were conducted in 14 psychotropic-na?ve children and adolescents with MDD without OCD, 10 to 19 years of age, 14 case-matched healthy controls, and 20 nondepressed, psychotropic-na?ve pediatric patients with OCD 7 to 19 years of age. RESULTS: Anterior cingulate glutamatergic concentrations were significantly reduced in both patients with OCD (15.1% decrease) and patients with MDD (18.7% decrease) compared with controls. Anterior cingulate glutamatergic concentrations did not differ significantly between patients with OCD and those with MDD. CONCLUSIONS: Altered anterior cingulate glutamatergic neurotransmission may be involved in the pathogenesis of OCD and MDD. These preliminary findings further suggest that reduced anterior cingulate glutamate does not differentiate pediatric patients with OCD from pediatric patients with MDD.     

Post-traumatic stress disorder and declarative memory functioning: a review

Declarative memory dysfunction is associated with post-traumatic stress disorder (PTSD). This paper reviews this literature and presents two frameworks to explain the nature of this dysfunction: that memory deficits are a product of neurobiological abnormalities caused by PTSD and/or that pre-existing memory deficits serve as a risk factor for the development of PTSD following trauma exposure. Brain regions implicated in declarative memory deficits include the hippocampus and prefrontal cortex, and imaging and biochemistry studies as they relate to memory dysfunction are described. Prospective and twin studies provide support for a risk factor model.     

Intracranially recorded memory-related potentials reveal higher posterior than anterior hippocampal involvement in verbal encoding and retrieval

The human hippocampus is essential for both encoding and recollection, but it remains controversial whether there is a functionally different involvement of anterior versus posterior parts of the hippocampus in these memory processes. In the present study, we examined encoding and retrieval processes via intrahippocampal recordings in 27 patients with unilateral temporal lobe epilepsy. Multicontact depth electrodes were implanted along the longitudinal axis of the hippocampus as part of the presurgical evaluation. In a continuous word recognition test, subjects had to indicate whether words were new or already presented. Recognized old words, as compared to new words, resulted in a larger P600 component, as well as in a larger late negative component (LNC, 600-900 msec). In addition, subsequently remembered words elicited a larger positivity (400 to 900 msec) than later forgotten words. We found differences concerning the distribution along the hippocampus for the LNC old-new effect, reflecting successful retrieval, as well as for the subsequent memory effect, reflecting successful encoding. Both effects were larger the further posterior an electrode was located in the hippocampus. Findings are suggestive for a predominant posterior hippocampal involvement in both verbal encoding and retrieval.