A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of FTLD, FTD-ALS, and ALS. FTLD patients with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases).
FTLD; Schizophrenia; C9ORF72 repeat expansion; psychosis
Diagnosis of frontotemporal dementia (FTD) in the mental health setting and issues pertaining to longitudinal care of this population in a specialty clinic are reviewed. FTD is often misdiagnosed as a psychiatric disorder, most commonly as a mood disorder. FTD has features that overlap with those of major depression, mania, obsessive-compulsive disorder and schizophrenia. We describe these features and how to differentiate FTD from these psychiatric disorders. This paper also describes practical issues in the management of FTD, specifically the issues that clinicians, patients and their families face in managing this disease. Areas of clinical care along the continuum are explored; FTD care involves collaborative management of symptoms and disability, and assisting patients and families in adapting to the disease.
The study’s objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impairment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer’s disease (AD). 1,368 participants from the National Alzheimer’s Coordinating Center database with a diagnosis of probable AD (CDR 0.5–1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typical subgroup (n = 926) was defined as having a difference in language and memory performance of <1 SD. Compared with the memory subgroup, the language subgroup was 3.7 years older and more frequently self-identified as African American (OR = 3.69). Under a dominant genetic model, the language subgroup had smaller odds of carrying at least one APOEε4 allele relative to the memory subgroup. While this difference was present for all ages, it was more striking at a younger age (OR = 0.19 for youngest tertile; OR = 0.52 for oldest tertile). Compared with the memory subgroup, the language subgroup rose 35% faster on the Functional Assessment Questionnaire and 44% faster on CDR sum of boxes over time. Among a subset of participants who underwent autopsy (n = 98), the language, memory, and typical subgroups were equally likely to have an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. The study demonstrates that a language subgroup of AD has different demographics, genetic profile, and disease course in addition to cognitive phenotype.
African Americans; age of onset; Alzheimer’s disease; aphasia; apolipoprotein E4; focal onset Alzheimer’s disease; demographic factors; language; longitudinal studies; memory
The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options.
A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.
ALS; FTD; FUS; motor disease; proteinopathies; TAU; TDP-43; ubiquitin inclusions
There is growing study of the psychiatric features of essential tremor. Depressive symptoms occur in a considerable number of patients. Yet their impact, as a primary factor, has received almost no attention. We assessed whether, independent of tremor severity, patients with more depressive symptoms have more perceived tremor-related disability, lower tremor-related quality of life, and poorer compliance with tremor medication.
Based on their Center for Epidemiological Studies Depression Scale score, we stratified 70 essential tremor patients into three groups: 41 with minimal depressive symptoms, 24 with moderate depressive symptoms, and 5 with severe depressive symptoms. Importantly, the three groups had similar tremor severity on neurological examination. We assessed: self-reported tremor-related disability, tremor-related quality of life (Quality of Life in Essential Tremor Questionnaire), and medication compliance.
Cases with minimal depressive symptoms had the lowest quality of life scores, cases with moderate depressive symptoms had intermediate scores, and those with severe depressive symptoms had the highest scores (p<0.001). Depressive symptoms were a stronger predictor of tremor-related quality of life than was the main motor feature of ET itself (tremor). Self-reported medication compliance was lowest in cases with severe depressive symptoms and highest in cases with minimal depressive symptoms.
The physical disability caused by the tremor of ET has traditionally been regarded as the most important feature of the disease that causes distress, and it has received the most attention in the management of patients with this disease. Our data indicate that this may not be the case.
essential tremor; psychiatric; depression; disability; quality of life; medication; treatment; clinical
Frontotemporal lobar degeneration (FTLD) is an umbrella term for several different disorders. In behavioral variant frontotemporal dementia (bvFTD), patients show deterioration in cognition and social behavior. New diagnostic criteria proposed by the International Behavioral Variant FTD Consortium provide greater sensitivity in diagnosing bvFTD. Current pharmacological management of symptoms relies on medications borrowed from treating Alzheimer’s Disease (AD) and psychiatric disorders. The evidence for using AD medications such as acetylcholinesterase inhibitors is questionable. Psychiatric medications can be helpful. Trazodone or SSRIs can have some efficacy in reducing disinhibition, repetitive behaviors, sexually inappropriate behaviors, and hyperorality. Small doses of atypical antipsychotics may be helpful in decreasing agitation and verbal outbursts. Non-pharmacological management includes caregiver education and support and behavioral interventions. While symptomatic treatments are likely to remain important behavior management tools, targeting the underlying pathology of bvFTD with disease-modifying agents will hopefully be the future of treatment.
FTLD; frontotemporal lobar degeneration; bvFTD; frontotemporal dementia; diagnosis; differential diagnosis; treatment
Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.
The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model.
More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores.
The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.
Motor neuron disease; Executive function; Diffusion tensor imaging
In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 FTLD patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-FTD and 2 FTD-ALS) out of 53 patients and one neurologically normal control. Interestingly, two of the C9ORF72 expansion carriers also carried two novel missense mutations in GRN (Y294C) and in PSEN-2 (I146V). Further, one of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TDP-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD or FTD-ALS and occasional comorbid conditions such as Alzheimer’s disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
Apathy, defined as decreased goal-directed activity, has been observed in Parkinson's disease. A number of cognitive/psychiatric features have been documented in essential tremor, yet we are unaware of studies of apathy.
Using the Apathy Evaluation Scale (range = 18–72 [more apathy]), we compared 79 essential tremor cases, 20 dystonia cases, and 39 Parkinson's disease cases with 80 normal controls.
The score of the Apathy Evaluation Scale was higher in essential tremor, dystonia, and Parkinson's disease cases than controls (all P ≤ .04). Parkinson's disease cases had the highest scores. Analyses stratified by presence/absence of depressive symptoms indicated the presence of a group of apathetic but nondepressed cases.
Patients with Parkinson's disease, essential tremor, and dystonia had elevated apathy scores. Features of apathy seemed to occur in these conditions independent of depressive symptoms. The mechanistic basis for the apparent increased features of apathy in essential tremor and dystonia deserves further study.
apathy; depression; dystonia; essential tremor; non-motor; Parkinson's disease
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
A published predictor model in a single-site cohort study (questionable dementia, QD) that contained episodic verbal memory (SRT total recall), informant report of function (FAQ), and MRI measures was tested using logistic regression and ROC analyses with comparable measures in a second multisite cohort study (Alzheimer's Disease Neuroimaging Initiative, ADNI). There were 126 patients in QD and 282 patients in ADNI with MCI followed for 3 years. Within each sample, the differences in AUCs between the statistical models were very similar. Adding hippocampal and entorhinal cortex volumes to the model containing AVLT/SRT, FAQ, age and MMSE increased the area under the curve (AUC) in ADNI but not QD, with sensitivity increasing by 2% in ADNI and 2% in QD for a fixed specificity of 80%. Conversely, adding episodic verbal memory (SRT/AVLT) and FAQ to the model containing age, Mini Mental State Exam (MMSE), hippocampal and entorhinal cortex volumes increased the AUC in ADNI and QD, with sensitivity increasing by 17% in ADNI and 10% in QD for 80% specificity. The predictor models showed similar differences from each other in both studies, supporting independent validation. MRI hippocampal and entorhinal cortex volumes showed limited added predictive utility to memory and function measures.
Frontotemporal Dementia (FTD) is the second major cause of dementia in persons under the age of 65 after Alzheimer’s disease (AD). FTD is clinically, pathologically and genetically heterogeneous and has been associated with mutations in different genes located on chromosomes 17, 9 and 3. In our study we report a novel heterozygous g.26218G>A variant in exon 6 of Charged Multivesicular body Protein 2B (CHMP2B), predicted to cause the amino acid change p.Ser187Asn, in one patient diagnosed with FTD. We were not able to determine the mode of inheritance of the mutation since we did not have access to the genetically informative family members of the proband; those who were screened did not carry the variant. We didn’t find this variant in 273 Caucasian controls while we did find it in 6 of 94 African American controls. Most of the mutations in CHMP2B which are considered pathogenic lead to partial deletion of the C-terminus region of CHMP2B protein. Based on previous reports and on our current data, missense mutations seem unlikely to be pathogenic. The pathogenicity of CHMP2B mutations requires further investigation.
dementia; FTD; CHMP2B; gene; missense mutation
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis–Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. A better understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI.
Formal olfactory testing may be useful as a bedside tool to help differentiate between conditions such as atypical parkinsonism, dementia, and psychiatric conditions. However, the neural basis of olfactory dysfunction, the effect of concurrent cognitive deficits on olfactory testing results, and the exact prevalence of olfactory deficits in populations with corticobasal syndrome (CBS) and the frontal variant of frontotemporal dementia (FTD-FV) are to date unclear.
To assess the prevalence and the neural basis of olfactory recognition deficits in patients with a clinical diagnosis of CBS or FTD-FV.
Retrospective study of clinical, neuropsychological, and imaging data.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Twenty-five patients with CBS, 22 with FTD-FV, and 12 age-matched control subjects.
Main Outcome Measures
Results of neuropsychological evaluation, formal olfactory recognition testing (University of Pennsylvania Smell Identification Test [UPSIT]), and voxel-based morphometry analysis of structural magnetic resonance images of the brain.
Mean UPSIT percentile scores were 31.6% for the CBS group and 9.5% for the FTD-FV group. The voxel-based morphometry correlations between local gray matter and UPSIT scores showed a significant volume effect in the right midfrontal gyrus for the FTD-FV patients and in the right insula, right midfrontal gyrus, and bilateral inferior frontal gyrus for the patients with CBS. A linear regression analysis of the UPSIT scores revealed as significant predictors the general memory score of the Wechsler Memory Scale and the Boston Naming Test total score for the patients with FTD-FV and the Mattis Dementia Rating Scale total score for the patients with CBS.
Our data showed a more severe olfactory impairment for CBS patients than previously reported. We also showed a significant relationship between formal olfactory recognition testing scores and specific cognitive domains. These findings could be useful to clinically differentiate FTD-FV and CBS from other dementing illnesses and movement disorders.
Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined.
In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations.
We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination.
Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer’s disease.
Frontotemporal dementia spectrum disorders are a set of neurodegenerative disorders affecting the frontal and anterior temporal lobes. They are often fatal, and currently no medications have been shown to slow their progression. Recent developments in understanding these disorders may aid in developing treatments.
To discuss the development of drug therapies for frontotemporal dementia spectrum disorders, both those under current investigation and those that could be targets for future investigation.
This review is divided into four sections: First, a brief review of frontotemporal dementia spectrum disorders; second, a discussion of the challenges in the development of drug therapies third, a review of the current clinical trials; and finally a discussion of some recent discoveries, which have sparked new areas of investigation.
Hopefully, advances in understanding of frontotemporal dementia spectrum disorders and clinical trial design will aid the development of new treatments.
frontotemporal dementia; medication treatment; neurodegenerative disorders; neuroprotection
Although patients with frontotemporal dementia (FTD) are known to exhibit a wide range of cognitive and personality difficulties, some evidence suggests that there may be a degree of selectivity in their reasoning impairments. Based on a recent review of the neuroimaging literature on reasoning, the authors hypothesized that the presence or absence of familiar content may have a selective impact on the reasoning abilities of patients with FTD. Specifically, the authors predicted that patients with frontalvariant FTD would be more impaired when reasoning about transitive arguments involving familiar spatial environments than when reasoning about identical logical arguments involving unfamiliar spatial environments. As predicted, patients with FTD were less accurate than normal controls only when the content of arguments involved familiar spatial environments. These results indicate a degree of selectivity in the cognitive deficits of this patient population and suggest that the frontal-temporal lobe system may play a necessary role in reasoning about familiar material.
executive function; frontotemporal dementia; reasoning; semantic memory
To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS).
Case-control and cross-sectional study.
Forty-eight patients with CBS and 14 control subjects.
Administration of the Test of Oral and Limb Apraxia.
Main Outcome Measures
Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS.
Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, pre-motor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis.
In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.
Event knowledge is organized on the basis of goals that enable the selection of specific event sequences to organize everyday life activities. Although the medial prefrontal cortex represents event knowledge, little is known about its role in mediating event knowledge complexity. We used functional MRI to investigate the patterns of brain activation while healthy volunteers were engaged in the task of evaluating the complexity (i.e. numbers of events) of daily life activities selected on the basis of normative data. Within a left frontoparietal network, we isolated the medial frontopolar cortex as the only region that showed a linear relationship between changes in the blood oxygen level-dependent signal and changes in event knowledge complexity. Our results specify the importance of the medial frontopolar cortex in subserving event knowledge that is required to build and execute complex behavior.
frontopolar cortex; hierarchy; humans; prefrontal cortex; sequence
Schizophrenia has been linked to a region on chromosome 17q21 in Latino populations (Escamilla et al., 2009). Mutations of a gene at this location (GRN) are associated with frontotemporal dementia. A recent study demonstrated that patients with frontotemporal dementia who presented with symptoms of schizophrenia show neuropathological findings consistent with GRN mutations, but were not tested for GRN mutations (Velakoulis, Walterfang, Mocellin, Pantelis, & McLean, 2009). The current study describes a Latino family in which two siblings have schizophrenia and one has frontotemporal dementia. We sequenced GRN in one of the siblings with frontotemporal dementia and one of the siblings with schizophrenia. The siblings both have a loss-of-function GRN mutation. This finding, in conjunction with other studies (Escamilla et al., 2009; Velakoulis et al., 2009), suggests that there may be an association between schizophrenia, frontotemporal dementia, and GRN mutations in Latino populations that should be investigated further.
Frontotemporal dementia; Schizophrenia; Genetics; Progranulin; Psychiatric disorders
Inappropriate social behaviours are early and distinctive symptoms of the temporal and frontal variants of frontotemporal lobar degeneration (FTLD). Knowledge of social behaviour is essential for appropriate social conduct. It is unknown, however, in what way this knowledge is degraded in FTLD. In a recent functional MRI study, we have identified a right-lateralized superior anterior temporal lobe (aTL) region showing selective activation for ‘social concepts’ (i.e. concepts describing social behaviour: e.g. ‘polite’, ‘stingy’) as compared with concepts describing less socially relevant animal behaviour (‘animal function concepts’: e.g. ‘trainable’, ‘nutritious’). In a further fMRI study, superior aTL activation was independent of the context of actions and feelings associated with these social concepts. Here, we investigated whether the right superior sector of the aTL is necessary for context-independent knowledge of social concepts. We assessed neuronal glucose uptake using 18-fluoro-deoxy-glucose-positron emission tomography (FDG-PET) and a novel semantic discrimination task which probed knowledge of social and animal function concepts in patients with FTLD (n = 29) and corticobasal syndrome (n = 18). FTLD and corticobasal syndrome groups performed equally poorly on animal function concepts but FTLD patients showed more pronounced impairments on social concepts than corticobasal syndrome patients. FTLD patients with right superior aTL hypometabolism, as determined on individual ROI analyses, were significantly more impaired on social concepts than on animal function concepts. FTLD patients with selective impairments for social concepts, as determined on individual neuropsychological profiles, showed higher levels of inappropriate social behaviours (‘disinhibition’) and demonstrated more pronounced hypometabolism in the right superior aTL, the left temporal pole and the right lateral orbitofrontal and dorsomedial prefrontal cortex as compared with FTLD patients showing selective impairments of animal function concepts. Combining both FTLD subgroup analyses, based on anatomical and neuropsychological criteria, by using inclusive masks, revealed the right superior aTL as associated with selective impairments of social concepts in both analyses. These results corroborate the hypothesis that the right aTL is necessary for representing conceptual social knowledge. Further, we provide first evidence for the potential importance of conceptual social knowledge impairments as contributing to behavioural symptoms of FTLD.
frontotemporal dementia; semantics; social cognition; anterior temporal lobe; social behaviour
Social values are composed of social concepts (e.g., “generosity”) and context-dependent moral sentiments (e.g., “pride”). The neural basis of this intricate cognitive architecture has not been investigated thus far. Here, we used functional magnetic resonance imaging while subjects imagined their own actions toward another person (self-agency) which either conformed or were counter to a social value and were associated with pride or guilt, respectively. Imagined actions of another person toward the subjects (other-agency) in accordance with or counter to a value were associated with gratitude or indignation/anger. As hypothesized, superior anterior temporal lobe (aTL) activity increased with conceptual detail in all conditions. During self-agency, activity in the anterior ventromedial prefrontal cortex correlated with pride and guilt, whereas activity in the subgenual cingulate solely correlated with guilt. In contrast, indignation/anger activated lateral orbitofrontal-insular cortices. Pride and gratitude additionally evoked mesolimbic and basal forebrain activations. Our results demonstrate that social values emerge from coactivation of stable abstract social conceptual representations in the superior aTL and context-dependent moral sentiments encoded in fronto-mesolimbic regions. This neural architecture may provide the basis of our ability to communicate about the meaning of social values across cultural contexts without limiting our flexibility to adapt their emotional interpretation.
Major Depression; Semantics; Moral Emotions; Anterior Temporal Lobe; Subgenual Cingulate Cortex
The neuroanatomical correlates of depression remain unclear. Functional imaging data have associated depression with abnormal patterns of activity in prefrontal cortex (PFC), including the ventromedial (vmPFC) and dorsolateral (dlPFC) sectors. If vmPFC and dlPFC are critical neural substrates for the pathogenesis of depression, then damage to either area should affect the expression of depressive symptoms. Using patients with brain lesions we show that, relative to nonfrontal lesions, bilateral vmPFC lesions are associated with markedly low levels of depression, whereas bilateral dorsal PFC lesions (involving dorsomedial and dorsolateral areas in both hemispheres) are associated with substantially higher levels of depression. These findings demonstrate that vmPFC and dorsal PFC are critically and causally involved in depression, although with very different roles: vmPFC damage confers resistance to depression, whereas dorsal PFC damage confers vulnerability.
depression; emotion; prefrontal cortex; ventromedial; dorsolateral; neuropathology