Thierry Gallarda

Influence of prefrontal target region on the efficacy of repetitive transcranial magnetic stimulation in patients with medication-resistant depression: a [18F]-fluorodeoxyglucose PET and MRI study

It is currently unknown whether the antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) depends on specific characteristics of the stimulated frontal area, such as metabolic changes. We investigated the effect of high-frequency rTMS, administered over the most hypometabolic prefrontal area in depressed patients in a two-site, double-blind, randomized placebo-controlled add-on study. Forty-eight patients with medication-resistant major depression underwent magnetic resonance imaging and [(18)F]-fluorodeoxyglucose positron emission tomography (PET) in order to determine a target area for rTMS. After randomization to PET-guided (n = 16), standard (n = 18), or sham rTMS (n = 14) conditions, the patients received 10 sessions of 10-Hz rTMS (1600 pulses/session) at 90% motor threshold. Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores did not differ between PET-guided, standard and sham groups at 2-wk end-point. Exploratory comparison of left PET-guided (n = 9), right PET-guided, standard, and sham rTMS revealed significant effects. The highest improvement in MADRS scores was observed with left PET-guided (60 + or - 31%), significantly superior to sham (30 + or - 37%, p = 0.01) and right-guided (31 + or - 33%, p = 0.02) stimulation. Comparison between left PET-guided and standard rTMS (49 + or - 28%) was not significant (p = 0.12). Comparison between stimulation over dorsolateral prefrontal cortex (BA 9-46), stimulation of other areas, and sham rTMS was statistically significant. Stimulation over BA 9-46 region (n = 15) was superior to sham rTMS (p = 0.02). The results do not support the general hypothesis of increased antidepressant effects of high-frequency rTMS with prefrontal hypometabolism-related PET guidance. Nonetheless, whether metabolism and anatomy characteristics of left frontal area underneath the coil might account for an increase or speeding up of rTMS effects needs further investigation.

Apathy and Depression in Mild Alzheimer's Disease: A Cross-Sectional Study Using Diagnostic Criteria

Apathy and depression are the most frequent neuropsychiatric symptoms in Alzheimers disease (AD). In a cross-sectional observational study of 734 subjects with probable mild AD, we evaluated the prevalence of apathy and depression. After the use of specific diagnostic criteria, we tested the interaction between the two syndromes and their relation with specific comorbidities, and different functional outcomes. Depression was diagnosed using the diagnostic criteria for depression in AD, and apathy with the diagnostic criteria for apathy in neuropsychiatric disorders. According to the specific diagnostic criteria, depression had a 47.9% prevalence, while apathy prevalence was 41.6%. Apathy and depression were associated in 32.4% of patients (n = 225). 9.4% (n = 65) had only apathy, 15.4% (n = 107) had only depression, and 42.9% had no apathy and no depression (n = 298). The three most frequent depressive symptoms were fatigue or loss of energy (59.4%), decreased positive affect or pleasure in response to social contacts and activities (46.2%), and psychomotor agitation or retardation (36.9%). Concerning apathy, loss of goal-directed cognition was the most frequently altered (63.6%), followed by loss of goal-directed action (60.6%) and loss of goal-directed emotion (43.8%). Patients with both apathy and depression more frequently required a resource allowance for dependency. Neurological comorbidities were more frequent in the apathy and depression and depression alone groups (p < 0.001). Apathy and depression overlap considerably, and this might be explained by the presence of some non-specific symptoms in both diagnostic criteria. The need for social support is higher when a patient fulfills the two diagnostic criteria.

Baseline Brain Metabolism in Resistant Depression and Response to Transcranial Magnetic Stimulation

Neuroimaging studies of patients with treatment-resistant depression (TRD) have reported abnormalities in the frontal and temporal regions. We sought to determine whether metabolism in these regions might be related to response to repetitive transcranial magnetic stimulation (TMS) in patients with TRD. Magnetic resonance images and baseline resting-state cerebral glucose uptake index (gluMI) obtained using 18F-fluorodeoxyglucose positron emission tomography were analyzed in TRD patients who had participated in a double-blind, randomized, sham-controlled trial of prefrontal 10u2009Hz TMS. Among the patients randomized to active TMS, 17 responders, defined as having 50% depression score decrease, and 14 nonresponders were investigated for prestimulation glucose metabolism and compared with 39 healthy subjects using a voxel-based analysis. In nonresponders relative to responders, gluMI was lower in left lateral orbitofrontal cortex (OFC), and higher in left amygdala and uncinate fasciculus. OFC and amygdala gluMI negatively correlated in nonresponders, positively correlated in responders, and did not correlate in healthy subjects. Relative to healthy subjects, both responders and nonresponders displayed lower gluMI in right dorsolateral prefrontal (DLPFC), right anterior cingulate (ACC), and left ventrolateral prefrontal cortices. Additionally, nonresponders had lower gluMI in left DLPFC, ACC, left and right insula, and higher gluMI in left amygdala and uncus. Hypometabolisms were partly explained by gray matter reductions, whereas hypermetabolisms were unrelated to structural changes. The findings suggest that different patterns of frontal–temporal–limbic abnormalities may distinguish responders and nonresponders to prefrontal magnetic stimulation. Both preserved OFC volume and amygdala metabolism might precondition response to TMS.

Age-related changes in the functional network underlying specific and general autobiographical memory retrieval: a pivotal role for the anterior cingulate cortex.

Age-related changes in autobiographical memory (AM) recall are characterized by a decline in episodic details, while semantic aspects are spared. This deleterious effect is supposed to be mediated by an inefficient recruitment of executive processes during AM retrieval. To date, contrasting evidence has been reported on the neural underpinning of this decline, and none of the previous studies has directly compared the episodic and semantic aspects of AM in elderly. We asked 20 young and 17 older participants to recall specific and general autobiographical events (i.e., episodic and semantic AM) elicited by personalized cues while recording their brain activity by means of fMRI. At the behavioral level, we confirmed that the richness of episodic AM retrieval is specifically impoverished in aging and that this decline is related to the reduction of executive functions. At the neural level, in both age groups, we showed the recruitment of a large network during episodic AM retrieval encompassing prefrontal, cortical midline and posterior regions, and medial temporal structures, including the hippocampus. This network was very similar, but less extended, during semantic AM retrieval. Nevertheless, a greater activity was evidenced in the dorsal anterior cingulate cortex (dACC) during episodic, compared to semantic AM retrieval in young participants, and a reversed pattern in the elderly. Moreover, activity in dACC during episodic AM retrieval was correlated with inhibition and richness of memories in both groups. Our findings shed light on the direct link between episodic AM retrieval, executive control, and their decline in aging, proposing a possible neuronal signature. They also suggest that increased activity in dACC during semantic AM retrieval in the elderly could be seen as a compensatory mechanism underpinning successful AM performance observed in aging. These results are discussed in the framework of recently proposed models of neural reorganization in aging.

Don’t be Too Strict with Yourself! Rigid Negative Self-Representation in Healthy Subjects Mimics the Neurocognitive Profile of Depression for Autobiographical Memory

Autobiographical memory (AM) comprises representation of both specific (episodic) and generic (semantic) personal information. Depression is characterized by a shift from episodic to semantic AM retrieval. According to theoretical models, this process (“overgeneralization”), would be linked to reduced executive resources. Moreover, “overgeneral” memories, accompanied by a negativity bias in depression, lead to a pervasive negative self-representation. As executive functions and AM specificity are also closely intricate among “non-clinical” populations, “overgeneral” memories could result in depressive emotional responses. Consequently, our hypothesis was that the neurocognitive profile of healthy subjects showing a rigid negative self-image would mimic that of patients. Executive functions and self-image were measured and brain activity was recorded, by means of fMRI, during episodic AMs retrieval in young healthy subjects. The results show an inverse correlation, that is, a more rigid and negative self-image produces lower performances in both executive and specific memories. Moreover, higher negative self-image is associated with decreased activity in the left ventro-lateral prefrontal and in the anterior cingulate cortex, repeatedly shown to exhibit altered functioning in depression. Activity in these regions, on the contrary, positively correlates with executive and memory performances, in line with their role in executive functions and AM retrieval. These findings suggest that rigid negative self-image could represent a marker or a vulnerability trait of depression by being linked to reduced executive function efficiency and episodic AM decline. These results are encouraging for psychotherapeutic approaches aimed at cognitive flexibility in depression and other psychiatric disorders.

The Castle of Remembrance: New insights from a cognitive training programme for autobiographical memory in Alzheimer's disease

Autobiographical memory deficits are prominent from the early stages of Alzheimers disease (AD) and result in a loss of personal identity. Nevertheless, standardised methods of autobiographical memory stimulation for the neuropsychological rehabilitation of patients with AD remain underdeveloped. Our aim was to evaluate the impact of a new cognitive training programme for autobiographical memory (REMau) on both the episodic and semantic components of autobiographical memory performance across lifetime periods, as well as on mood. Pre/post evaluations were conducted on two groups of patients with early to moderate AD, assigned to one of two different training activities: either the REMau or a cognitive training programme focused on collective semantic memory. Statistical comparisons showed significant improvement of episodic and semantic autobiographical memory performance in the REMau group, which was more pronounced for the semantic component, as well as improved mood. By contrast, deleterious pre/post differences were observed in the other group. Most interestingly, this study showed that the REMau programme boosted autobiographical memory from the reminiscence bump period, which is considered crucial for the construction and maintenance of personal identity. We discuss the theoretical and practical implications of these results for the reduction of autobiographical memory deficits in AD.

Depression predictors within six months of ischemic stroke: The DEPRESS Study

Background Depression negatively affects rehabilitation and quality of life after stroke. Identifying in the acute phase patients at high risk for post-stroke depression would facilitate early detection of depressive symptoms. Methods The DEPRESS (Depression Predictors after Ischemic Stroke) study was a prospective cohort study designed to identify baseline predictors of depression occurring within six months after ischemic stroke and high-risk patients for post-stroke depression. All patients without aphasia were screened for depression by a neurologist using the Patient Health Questionnaire, and the diagnosis was confirmed by a psychiatrist with the Mini International Neuropsychiatric Interview. In severely aphasic patients, depression was diagnosed using the Aphasic Depression Rating Scale and the Visual Analog Mood Scale. Results Depression was present in 61 of 251 (24%) patients enrolled in the DEPRESS study. Female gender, prior history of depression, major physical disability, prior history of stroke, stressful life event exposure in the month preceding stroke onset, and pathologic crying were significant predictors of depression within six months after ischemic stroke. Depression was more frequent in patients with left caudate and/or lenticular nucleus lesion (OR = 2.4, 95% confidence interval, 0.97–5.91), but the difference was not significant. The presence of ≥2 predictors identified the largest proportion of depressed patients (62%) in the smallest proportion of the cohort (36%). Conclusion Female gender, prior history of depression, major physical disability, prior history of stroke, recent stressful life event exposure before stroke, and pathologic crying were significant predictors of post-stroke depression occurring within six months after stroke onset.

Cognitive Decline and Reorganization of Functional Connectivity in Healthy Aging: The Pivotal Role of the Salience Network in the Prediction of Age and Cognitive Performances

Normal aging is related to a decline in specific cognitive processes, in particular in executive functions and memory. In recent years a growing number of studies have focused on changes in brain functional connectivity related to cognitive aging. A common finding is the decreased connectivity within multiple resting state networks, including the default mode network (DMN) and the salience network. In this study, we measured resting state activity using fMRI and explored whether cognitive decline is related to altered functional connectivity. To this end we used a machine learning approach to classify young and old participants from functional connectivity data. The originality of the approach consists in the prediction of the performance and age of the subjects based on functional connectivity by using a machine learning approach. Our findings showed that the connectivity profile between specific networks predicts both the age of the subjects and their cognitive abilities. In particular, we report that the connectivity profiles between the salience and visual networks, and the salience and the anterior part of the DMN, were the features that best predicted the age. Moreover, independently of the age of the subject, connectivity between the salience network and various specific networks (i.e., visual, frontal) predicted episodic memory skills either based on a standard assessment or on an autobiographical memory task, and short-term memory binding. Finally, the connectivity between the salience and the frontal networks predicted inhibition and updating performance, but this link was no longer significant after removing the effect of age. Our findings confirm the crucial role of episodic memory and executive functions in cognitive aging and suggest a pivotal role of the salience network in neural reorganization in aging.

Episodic memory and self-reference via semantic autobiographical memory: insights from an fMRI study in younger and older adults

Self-referential processing relies mainly on the medial prefrontal cortex (MPFC) and enhances memory encoding (i.e., Self-Reference Effect, SRE) as it improves the accuracy and richness of remembering in both young and older adults. However, studies on age-related changes in the neural correlates of the SRE on the subjective (i.e., autonoetic consciousness) and the objective (i.e., source memory) qualitative features of episodic memory are lacking. In the present fMRI study, we compared the effects of a self-related (semantic autobiographical memory task) and a non self-related (general semantic memory task) encoding condition on subsequent episodic memory retrieval. We investigated encoding-related activity during each condition in two groups of 19 younger and 16 older adults. Behaviorally, the SRE improved subjective memory performance in both groups but objective memory only in young adults. At the neural level, a direct comparison between self-related and non self-related conditions revealed that SRE mainly activated the cortical midline system, especially the MPFC, in both groups. Additionally, in older adults and regardless of the condition, greater activity was found in a fronto-parietal network. Overall, correlations were noted between source memory performance and activity in the MPFC (irrespective of age) and visual areas (mediated by age). Thus, the present findings expand evidence of the role of the MPFC in self-referential processing in the context of source memory benefit in both young and older adults using incidental encoding via semantic autobiographical memory. However, our finding suggests that its role is less effective in aging.

Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia.

Repetitive transcranial magnetic stimulation (rTMS) over the left temporo‐parietal region has been proposed as a treatment for resistant auditory verbal hallucinations (AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology.