Severe hippocampal atrophy is not associated with depression in temporal lobe epilepsy.

Depression in temporal lobe epilepsy (TLE) is common, is a strong predictor of subjective disability, and may have unique pathophysiological characteristics. Previous studies showed that reduced hippocampal volume is associated with significant depressive symptoms in patients with TLE. We utilized regions of interest analysis of high-resolution brain MRI and a reliable and valid measure of depressive symptoms to evaluate 28 consecutive adult subjects with video-EEG-confirmed TLE. Regions of interest were based on prior human and animal studies of mood and behavioral dysfunction. Forty-three percent of the entire group had significant symptoms of depression, defined by a Beck Depression Inventory (BDI) score of greater than 15. Total hippocampal volumes were significantly smaller in the group with BDI<15, (p<0.007). None of the subjects in the quartile with the smallest left hippocampal volume had a BDI score greater than 15 compared with 57% of the subjects in the upper three quartiles (p<0.008). No other limbic brain structures (amygdala, subcallosal gyrus, subgenual gyrus, gyrus rectus), or total cerebral volume were associated with depressive symptoms. Adequate hippocampal integrity may be necessary to maintain depression symptoms in mesial temporal lobe epilepsy. This finding also supports the possibility of a unique mechanism for depression in mesial temporal lobe epilepsy, such as hyperexcitable neuronal influence on the limbic network.

Neuropathological and neuromorphometric abnormalities in bipolar disorder: view from the medial prefrontal cortical network.

The question of whether BD is primarily a developmental disorder or a progressive, neurodegenerative disorder remains unresolved. Here, we review the morphometric postmortem and neuroimaging literature relevant to the neuropathology of bipolar disorder (BD). We focus on the medial prefrontal cortex (mPFC) network, a key system in the regulation of emotional, behavioral, endocrine, and innate immunological responses to stress. We draw four main conclusions: the mPFC is characterized by (1) a decrease in volume, (2) reductions in neuronal size, and/or changes in neuronal density, (3) reductions in glial cell density, and (4) changes in gene expression. These data suggest the presence of dendritic atrophy of neurons and the loss of oligodendroglial cells in BD, although some data additionally suggest a reduction in the cell counts of specific subpopulations of GABAergic interneurons. Based on the weight of the postmortem and neuroimaging literature discussed herein, we favor a complex hypothesis that BD primarily constitutes a developmental disorder, but that additional, progressive, histopathological processes also are associated with recurrent or chronic illness. Conceivably BD may be best conceptualized as a progressive neurodevelopmental disorder.

Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: a preliminary PET study.

Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole's antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[(18)F]-fluoro-3,4-dihydroxy-l-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; 11 responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity.

Subdivisions and connectional networks of the lateral prefrontal cortex in the macaque monkey.

Neuroanatomical studies have long indicated that corticocortical connections are organized in networks that relate distinct sets of areas. Such networks have been emphasized by development of functional imaging methods for correlating activity across the cortex. Previously, two networks were recognized in the orbitomedial prefrontal cortex, the "orbital" and "medial" networks (OPFC and MPFC, respectively). In this study, three additional networks are proposed for the lateral prefrontal cortex: 1) a ventrolateral network (VLPFC) in and ventral to the principal sulcus; 2) a dorsal network (DPFC) in and dorsal to the principal sulcus and in the frontal pole; 3) a caudolateral network (CLPFC) in and rostral to the arcuate sulcus and the caudal principal sulcus. The connections of the first two networks are described here. Areas in each network are connected primarily with other areas in the same network, with overlaps around the principal sulcus. The VLPFC and DPFC are also connected with the OPFC and MPFC, respectively. Outside the prefrontal cortex, the VLPFC connects with specific areas related to somatic/visceral sensation and vision, in the frontoparietal operculum, insula, ventral bank/fundus of the superior temporal sulcus, inferior temporal gyrus, and inferior parietal cortex. In contrast, the DPFC connects with the rostral superior temporal gyrus, dorsal bank of the superior temporal sulcus, parahippocampal cortex, and posterior cingulate and retrosplenial cortex. Area 45a, in caudal VLPFC, is unique, having connections with all the networks. Its extrinsic connections resemble those of the DPFC. In addition, it has connections with both auditory belt/parabelt areas, and visual related areas.

Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression.

BACKGROUND: Vagus nerve stimulation (VNS) has antidepressant effects in treatment resistant major depression (TRMD); these effects are poorly understood. This trial examines associations of subacute (3 months) and chronic (12 months) VNS with cerebral metabolism in TRMD. OBJECTIVE: (17)Fluorodeoxyglucose positron emission tomography was used to examine associations between 12-month antidepressant VNS response and cerebral metabolic rate for glucose (CMRGlu) changes at 3 and 12 months. METHODS: Thirteen TRMD patients received 12 months of VNS. Depression assessments (Hamilton Depression Rating Scale [HDRS]) and PET scans were obtained at baseline (pre-VNS) and 3/12 months. CMRGlu was assessed in eight a priori selected brain regions (bilateral anterior insular [AIC], orbitofrontal [OFC], dorsolateral prefrontal [DLPFC], and anterior cingulate cortices [ACC]). Regional CMRGlu changes over time were studied in VNS responders (decreased 12 month HDRS by ≥50%) and nonresponders. RESULTS: A significant trend (decreased 3 month CMRGlu) in the right DLPFC was observed over time in VNS responders (n = 9; P = 0.006). An exploratory whole brain analysis (P(uncorrected) = 0.005) demonstrated decreased 3 month right rostral cingulate and DLPFC CMRGlu, and increased 12 month left ventral tegmental CMRGlu in responders. CONCLUSIONS/LIMITATIONS: VNS response may involve gradual (months in duration) brain adaptations. Early on, this process may involve decreased right-sided DLPFC/cingulate cortical activity; longer term effects (12 months) may lead to brainstem dopaminergic activation. Study limitations included: a) a small VNS nonresponders sample (N = 4), which limited conclusions about nonresponder CMRGlu changes; b) no control group; and, c) patients maintained their psychotropic medications.

Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: a potential marker for response?

BACKGROUND: Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD). METHODS: Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥ 50% reduction in HDRS from baseline. RESULTS: Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n=11) from nonresponders (n=4) and correlated with HDRS change (r=.64, p=.01). In a regression analysis, lower anterior insular cortex CMRGlu (p=.004) and higher orbitofrontal cortex CMRGlu (p=.047) together predicted HDRS change (R(2)=.58, p=.005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r=.78, p=.001). LIMITATIONS: Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled. CONCLUSIONS: This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.

Neural circuits underlying the pathophysiology of mood disorders.

Although mood disorders constitute leading causes of disability, until recently little was known about their pathogenesis. The delineation of anatomical networks that support emotional behavior (mainly derived from animal studies) and the development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood disorders have enabled significant advances towards elucidating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). In this review, we integrate insights from human and animal studies, which collectively suggest that MDD and BD involve dysfunction within an extended network including the medial prefrontal cortex and anatomically-related limbic, striatal, thalamic and basal forebrain structures.

Brain blood-flow change with acute vagus nerve stimulation in treatment-refractory major depressive disorder.

BACKGROUND: Existing neuroimaging studies of vagus nerve stimulation (VNS) in treatment resistant major depression (TRMD) suggest that many brain regions (eg, prefrontal cortex, thalamus, cingulate cortex, insular cortex) associated with mood disorders undergo alterations in blood flow/metabolism. OBJECTIVE/HYPOTHESIS: Positron emission tomography (PET oxygen-15 labeled water or PET [(15)O] H(2)O) was used to identify changes in regional cerebral blood flow (rCBF) in response to immediate VNS in 13 subjects with TRMD. We hypothesized rCBF changes along the afferent pathway of the vagus and in regions associated with depression (eg, orbitofrontal cortex, amygdala, insular cortex). METHODS: Six 90-second PET [(15)O] H(2)O scans were performed on 13 subjects in a VNS off-on sequence. After normalization for global uptake and realignment to standard atlas space, statistical t images (P < .005) were used to evaluate rCBF change. RESULTS: VNS induced significant rCBF decreases in the left and right lateral orbitofrontal cortex and left inferior temporal lobe. Significant increases were found in the right dorsal anterior cingulate, left posterior limb of the internal capsule/medial putamen, the right superior temporal gyrus, and the left cerebellar body. Post hoc analysis found small-to-moderate correlations between baseline acute change in rCBF and antidepressant response after 12 months of VNS. CONCLUSIONS: Regions undergoing rCBF change in response to acute VNS are consistent with the known afferent pathway of the vagus nerve and models of brain network in depression. Larger studies assessing the correlation between acute stimulation patterns and antidepressant outcomes with VNS are needed.

APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aß42.

Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-ß (Aß) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aß plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aß plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.

Olfactory deficit detected by fMRI in early Alzheimer's disease.

Alzheimer's disease (AD) is accompanied by smell dysfunction, as measured by psychophysical tests. Currently, it is unknown whether AD-related alterations in central olfactory system neural activity, as measured by functional magnetic resonance imaging (fMRI), are detectable beyond those observed in healthy elderly. Moreover, it is not known whether such changes are correlated with indices of odor perception and dementia. To investigate these issues, 12 early stage AD patients and 13 nondemented controls underwent fMRI while being exposed to each of three concentrations of lavender oil odorant. All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale-2 (DRS-2), and the Clinical Dementia Rating Scale (CDR). The blood oxygen level-dependent (BOLD) signal at primary olfactory cortex (POC) was weaker in AD than in HC subjects. At the lowest odorant concentration, the BOLD signals within POC, hippocampus, and insula were significantly correlated with UPSIT, MMSE, DRS-2, and CDR scores. The BOLD signal intensity and activation volume within the POC increased significantly as a function of odorant concentration in the AD group, but not in the control group. These findings demonstrate that olfactory fMRI is sensitive to the AD-related olfactory and cognitive functional decline.

Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus.

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks--the cognitive control network, default mode network, and affective network--were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks--decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation--could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect "hot wiring" networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.

Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication.

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55 x 0.55 x 0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11+/-10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

Neurocircuitry of mood disorders.

This review begins with a brief historical overview of attempts in the first half of the 20th century to discern brain systems that underlie emotion and emotional behavior. These early studies identified the amygdala, hippocampus, and other parts of what was termed the 'limbic' system as central parts of the emotional brain. Detailed connectional data on this system began to be obtained in the 1970s and 1980s, as more effective neuroanatomical techniques based on axonal transport became available. In the last 15 years these methods have been applied extensively to the limbic system and prefrontal cortex of monkeys, and much more specific circuits have been defined. In particular, a system has been described that links the medial prefrontal cortex and a few related cortical areas to the amygdala, the ventral striatum and pallidum, the medial thalamus, the hypothalamus, and the periaqueductal gray and other parts of the brainstem. A large body of human data from functional and structural imaging, as well as analysis of lesions and histological material indicates that this system is centrally involved in mood disorders.

Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease.

OBJECTIVE: To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals. DESIGN: Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. SETTING: Washington University Alzheimer's Disease Research Center. PARTICIPANTS: Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years). RESULTS: About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. CONCLUSIONS: Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

The default mode network and self-referential processes in depression.

The recently discovered default mode network (DMN) is a group of areas in the human brain characterized, collectively, by functions of a self-referential nature. In normal individuals, activity in the DMN is reduced during nonself-referential goal-directed tasks, in keeping with the folk-psychological notion of losing one's self in one's work. Imaging and anatomical studies in major depression have found alterations in both the structure and function in some regions that belong to the DMN, thus, suggesting a basis for the disordered self-referential thought of depression. Here, we sought to examine DMN functionality as a network in patients with major depression, asking whether the ability to regulate its activity and, hence, its role in self-referential processing, was impaired. To do so, we asked patients and controls to examine negative pictures passively and also to reappraise them actively. In widely distributed elements of the DMN [ventromedial prefrontal cortex prefrontal cortex (BA 10), anterior cingulate (BA 24/32), lateral parietal cortex (BA 39), and lateral temporal cortex (BA 21)], depressed, but not control subjects, exhibited a failure to reduce activity while both looking at negative pictures and reappraising them. Furthermore, looking at negative pictures elicited a significantly greater increase in activity in other DMN regions (amygdala, parahippocampus, and hippocampus) in depressed than in control subjects. These data suggest depression is characterized by both stimulus-induced heightened activity and a failure to normally down-regulate activity broadly within the DMN. These findings provide a brain network framework within which to consider the pathophysiology of depression.

Paraventricular thalamic nucleus: subcortical connections and innervation by serotonin, orexin, and corticotropin-releasing hormone in macaque monkeys.

The present study examines subcortical connections of paraventricular thalamic nucleus (Pa) following small anterograde and retrograde tracer injections in cynomolgus monkeys (Macaca fascicularis). An anterograde tracer injection into the dorsal midline thalamus revealed strong projections to the accumbens nucleus, basal amygdala, lateral septum, and hypothalamus. Retrograde tracer injections into these areas labeled neurons specifically in Pa. Following a retrograde tracer injection into Pa, labeled neurons were found in the hypothalamus, dorsal raphe, and periaqueductal gray. Pa contained a remarkably high density of axons and axonal varicosities immunoreactive for serotonin (5-HT) and orexin/hypocretin (ORX), as well as a moderate density of fibers immunoreactive for corticotropin-releasing hormone (CRH). A retrograde tracer injection into Pa combined with immunohistochemistry demonstrated that ORX and 5-HT axons originate from neurons in the hypothalamus and midbrain. Pa-projecting neurons were localized in the same nuclei of the hypothalamus, amygdala, and midbrain as CRH neurons, although no double labeling was found. The connections of Pa and its innervation by 5-HT, ORX, and CRH suggest that it may relay stress signals between the midbrain and hypothalamus with the accumbens nucleus, basal amygdala, and subgenual cortex as part of a circuit that manages stress and possibly stress-related psychopathologies.

Progressive deformation of deep brain nuclei and hippocampal-amygdala formation in schizophrenia.

BACKGROUND: Progressive decreases in cortical gray matter volume have been reported in schizophrenia. However, studies of progressive change in deep brain nuclei and hippocampal-amygdala formation have not yielded consistent findings. METHODS: Two high-resolution, T1-weighted magnetic resonance images were collected 2 years apart in 56 schizophrenia and 62 control subjects. Large-deformation high-dimensional brain mapping was used to generate surfaces for deep brain nuclei and hippocampal-amygdala formation at baseline and follow-up. Repeated-measures analysis of variance was used to test for longitudinal changes in volume and shape. RESULTS: The pattern of progressive changes in the deep brain nuclei and hippocampal-amygdala formation in schizophrenia and control subjects was variable. Of the structures that receive direct projections from the cortex, the thalamus, caudate nucleus, nucleus accumbens, and hippocampus showed changes specific to subjects with schizophrenia, and changes in the amygdala and putamen were similar in both groups. Although different at baseline, no progressive change was observed in the globus pallidus, which does not receive direct projections from the cortex. CONCLUSIONS: These findings suggest that the disease process of schizophrenia is associated with progressive effects on brain structure and that brain structures that receive direct, excitatory connections from the cortex may be more likely to show progressive changes, compared with brain structures that receive indirect, inhibitory connections from the cortex. These findings are also somewhat consistent with the hypothesis that overactivity of excitatory pathways in the brain may contribute to the neural degeneration that occurs in at least a subgroup of individuals with schizophrenia.

Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.

The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.

What does it take to stay healthy past 100?: Commentary on "No disease in the brain of a 115-year-old woman".

The description of an 115-year-old woman without dementia or Alzheimer's disease (AD) is remarkable, but fits well with previous accounts of aging and AD. Several similar non-demented cases aged 85-105 years have been reported previously, who had neurofibrillary tangles in the medial temporal lobe, but no deposition of amyloid plaques. Together with observations on other aging and very mild AD cases, these can be related to a model of aging and AD. In this model, tangles develop independently but relatively slowly during aging; these represent neurodegeneration, but by themselves may not represent AD. In contrast, amyloid may be the driving factor in AD, exacerbating neurofibrillary changes and other neurodegeneration. There is a pre-clinical period when the process has begun but has not produced sufficient degeneration to produce clinical symptoms. Critical questions raised by the present report include what genetic or other factors allowed healthy survival to age 115 year, and whether anti-amyloid therapies will allow more general survival in good mental health beyond age 100?