Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

Investigating the impact of nutritional insufficiency on parahippocampal neurons in domestic chickens, Gallus gallus domesticus.

Over time, scientists have been fascinated by the complex connections among nutrition, brain development, and behavior. It's been well understood that the brain's peak performance relies on having the right nutrients available. Thus, nutritional insufficiency, where an organism lacks vital nutrients crucial for optimal growth and function, can upset the body's balance, potentially triggering stress responses. However, our grasp of how the brain reacts to insufficient nutrition, particularly in avian species like domestic chickens, has shown inconsistencies in our understanding. Domestic chickens have frequently served as subjects for studying memory and learning, primarily focusing on the hippocampus-a region highly responsive to environmental changes. Yet, another critical brain region, the parahippocampal region, integral to memory and spatial cognition, had received relatively little attention concerning the consequences of inadequate nutrition and hydration. To address this knowledge gap, our study sought to investigate the impact of stress induced by nutritional insufficiency on the neuronal cells within the region parahippocampalis in two distinct age groups of domestic chickens, Gallus gallus domesticus: fifteen and thirty days old. We employed the Golgi-Cox-Impregnation technique to explore whether the structural characteristics of neuronal cells, specifically the dendritic spines, underwent changes under transient stressful conditions during these crucial developmental stages. The results were intriguing. Stress evidently induced observable alterations in the dendritic spines of the parahippocampal neuronal cells, with the extent of these changes being age-dependent. In fifteen-day-old chickens, stress prompted substantial modifications in the dendritic spines of parahippocampal multipolar and pyramidal neurons. In contrast, among thirty-day-old chickens, the response to stress was less comprehensive, with only specific parahippocampal multipolar neurons displaying such alterations. These findings underscored the influential role of stress in reshaping the structure of parahippocampal neurons and emphasized the importance of considering age when studying the impact of stress on the brain. Through this research, we aim to enhance our understanding of the intricate interplay between stress, brain structure, and the critical role of adequate nutrition, especially during pivotal developmental stages. Our future research objectives include a deeper investigation into the intracellular events including cellular and molecular mechanisms precipitating these changes and determining whether these alterations have downstream effects on crucial brain functions like learning and memory.

Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer's disease.

The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer's disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aß) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aß and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aß deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11-16 and 18-22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11-14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD.

In vivo exploration of synaptic projections in frontotemporal dementia.

The purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer's disease (AD). Loss of synaptic projections was assessed with [18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, [18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in [18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes.

Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Neural biomarker of functional disability in major depressive disorder: A structural neuroimaging study.

BACKGROUND: Most patients with the major depressive disorder (MDD) have varying degrees of impaired social functioning, and functional improvement often lags behind symptomatic improvement. However, it is still unclear if certain neurobiological factors underlie the deficits of social function in MDD. The aim of this study was to investigate the biomarkers of social function in MDD using structural magnetic resonance imaging (MRI). METHODS: 3T anatomical MRI was obtained from 272 subjects including 46 high-functioning (high-SF, Sheehan Disability Scale (SDS) rating < 18) and 63 low-functioning (low-SF, SDS score ≥ 18) patients with MDD and 163 healthy controls (HC). Voxel-based morphometry (VBM) was employed to locate brain regions with grey matter (GM) volume differences in relation to social function in MDD. Regions showing GM differences in relation to social function at baseline were followed up longitudinally in a subset of 38 patients scanned after 12-week treatment. RESULTS: Volume of right parahippocampal gyrus (rPHG) was significantly reduced in low-SF patients with MDD when compared to high-SF ones (FDR-corrected p < 0.05). Over 12 weeks of follow-up, though SF improved overall, the high and low-SF subgroups continued to differ in their SF, but had no progressive changes in PHG volume. LIMITATIONS: Limited functional assessment, high drop-out rate and median-based grouping method. CONCLUSIONS: Greater GM volume (GMV) of the rPHG may mark better social function in patients with MDD.

Parahippocampal area three gray matter is reduced in first-episode schizophrenia spectrum: Discovery and replication samples.

Early course schizophrenia is associated with reduced gray matter. The specific structures affected first and how deficits impact symptoms and cognition remain unresolved. We used the Human Connectome Project multimodal parcellation (HCP-MMP) to precisely identify cortical areas and investigate thickness abnormalities in discovery and replication samples of first-episode schizophrenia spectrum individuals (FESz). In the discovery sample, T1w scans were acquired from 31 FESz and 31 matched healthy controls (HC). Thickness was calculated for 360 regions in Freesurfer. In the replication sample, high-resolution T1w, T2w, and BOLD-rest scans were acquired from 23 FESz and 32 HC and processed with HCP protocols. Thickness was calculated for regions significant in the discovery sample. After FDR correction (q < .05), left and right parahippocampal area 3 (PHA3) were significantly thinner in FESz. In the replication sample, bilateral PHA3 were again thinner in FESz (q < .05). Exploratory correlation analyses revealed left PHA3 was positively associated with hallucinations and right PHA3 was positively associated with processing speed, working memory, and verbal learning. The novel use of the HCP-MMP in two independent FESz samples revealed thinner bilateral PHA3, suggesting this byway between cortical and limbic processing is a critical site of pathology near the emergence of psychosis.

Dual/double pathology in neurocysticercosis causing drug resistant epilepsy - Chance association or causal?

INTRODUCTION: Neurocysticercosis (NCC) as cause of drug resistant epilepsy (DRE) is commonly reported from India. We reviewed the neuropathological findings in patients undergoing resective surgery for DRE due to NCC, to determine the pathomechanism of epileptogenesis. METHODS: Clinical, demographic and neuropathological findings of histologically confirmed cases of NCC causing DRE between 2005-2019 were reviewed. NeuN, GFAP, phosphorylated neurofilament, vimentin, CD34 for glial/ neuronal alterations, and Masson trichrome, Luxol Fast blue for evidence of fibrosis/ demyelination was used to determine cause of epileptogenesis. RESULTS: There were 12 cases of NCC associated with dual/ double pathology, which constituted 3.02 % (12/398) of all the operated DRE. [Age range: 17-37y, Male:Female = 1.4:1]. Seizure duration ranged from 3-32y, with seizure onset between 4-27y. On MRI, lesions were of variable signal intensity on T1 and isointense on T2 with blooming on GRE/ SWI, and CT revealed calcification. Majority (11/12) had associated hippocampal sclerosis (HS) type 1 (dual pathology), localised to the same side as cysticercal cyst, suggesting it may be involved in the pathogenesis of HS. Ten had single cysticercal lesion involving ipsilateral hippocampus in 6, parahippocampal gyrus in 2, amygdala and temporal lobe in 1 case each. One had multiple NCC located in bilateral frontal, parietal and ipsilateral hippocampus. Adjacent cortex around the NCC evaluated in 6 cases, revealed inflammation, gliosis, axonal disruption/ beading, and variable synaptic/ neuronal dystrophic changes. There was a single case of NCC with Focal cortical dysplasia (FCD) type IIb (double pathology). In 11/12 cases Engel's post-surgery outcome was available with all having class I outcome. CONCLUSION: HS was most common pathology associated with cysticercosis (Dual pathology), localised ipsilateral to the cysticercal cyst, suggesting that HS is a secondary/ epiphenomenon. Perilesional changes such as inflammation, gliosis, dystrophic synaptic and axonal pathology play a role in inducing or perpetuating the epileptiform activity. The association of FCD IIb with NCC in one case is likely to be a chance occurrence.

Automated Hippocampal Subfield Volumetric Analyses in Atypical Alzheimer's Disease.

BACKGROUND: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD. OBJECTIVE: To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD. METHODS: Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests. RESULTS: The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA. CONCLUSION: Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.

Longitudinal atrophy in early Braak regions in preclinical Alzheimer's disease.

A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1-weighted MRI of 337 participants were included, divided into amyloid-ß negative (Aß-) controls, cerebral spinal fluid p-tau positive (T+) and negative (T-) preclinical AD (Aß+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2-year-follow-up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T- preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross-sectional MTL measures, longitudinal cognitive measures (PACC, ADAS-Cog) and cross-sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross-sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.

Neuropathological findings in PINK1-associated Parkinson's disease.

INTRODUCTION: Biallelic mutations in PTEN-induced putative kinase 1 (PINK1) is a relatively common cause of autosomal recessive early-onset Parkinson's disease (PD). However, only three PINK1 patients with brain autopsy have been reported in the literature. METHODS: We describe the clinical and pathological characteristics of a patient with early-onset PD. We screened for copy number variants SNCA, PRKN, PINK1, DJ-1, ATP13A2, LPA and TNFRSF9 by multiplex ligation-dependent probe amplification (MLPA), and subsequently we performed whole-exome sequencing. RESULTS: Clinically the patient presented with typical parkinsonism that responded well to levodopa. After 23 years of disease she had a bilateral GPi deep brain stimulation (DBS) surgery. Genetic analyses revealed a heterozygous exon 4-5 deletion and a homozygous exon 1 [c. 230T > C (p.Leu77Pro)] mutation in PINK1. Post-mortem neuropathological examination after more than 30 years of disease revealed gliosis and a large loss of melanin-containing neurons in the substantia nigra. Lewy body pathology was evident in substantia nigra, temporal cortex, locus coeruleus and the parahippocampal region. CONCLUSION: We describe the first clinical and pathological characterization of a PINK1 patient with a typical disease presentation and long disease duration. Previous reports describe two patients with Lewy-related pathologies, albeit with differential distribution, and one patient with no Lewy-related pathology. Hence, it seems that only two patients with parkinsonism due to mutations in PINK1 are consistent with α-synucleinopathy distribution like that seen in the majority of cases with sporadic PD. Our data further extend the clinicopathological characterization of PINK1-associated PD.

The presubiculum links incipient amyloid and tau pathology to memory function in older persons.

OBJECTIVE: To identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD). METHODS: A total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education. RESULTS: Neocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden. CONCLUSIONS: The presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.

Hippocampal and parahippocampal volumes vary by sex and traumatic life events in children

Background: Childhood trauma is reliably associated with smaller hippocampal volume in adults; however, this finding has not been shown in children, and even less is known about how sex and trauma interact to affect limbic structural development in children. Methods: Typically developing children aged 9 to 15 years who completed a trauma history questionnaire and structural T1-weighted MRI were included in this study (n = 172; 85 female, 87 male). All children who reported 4 or more traumas (n = 36) composed the high trauma group, and all children who reported 3 or fewer traumas (n = 136) composed the low trauma group. Using multivariate analysis of covariance, we compared FreeSurfer-derived structural MRI volumes (normalized by total intracranial volume) of the amygdalar, hippocampal and parahippocampal regions by sex and trauma level, controlling for age and study site. Results: We found a significant sex × trauma interaction, such that girls with high trauma had greater volumes than boys with high trauma. Follow-up analyses indicated significantly increased volumes for girls and generally decreased volumes for boys, specifically in the hippocampal and parahippocampalregions for the high trauma group; we observed no sex differences in the low trauma group. We noted no interaction effect for the amygdalae. Limitations: We assessed a community sample and did not include a clinical sample. We did not collect data about the ages at which children experienced trauma. Conclusion: Results revealed that psychological trauma affects brain development differently in girls and boys. These findings need to be followed longitudinally to elucidate how structural differences progress and contribute to well-known sex disparities in psychopathology.

The striatum, the hippocampus, and short-term memory binding: Volumetric analysis of the subcortical grey matter's role in mild cognitive impairment.

BACKGROUND: Deficits in short-term memory (STM) binding are a distinguishing feature of preclinical stages leading to Alzheimer's disease (AD). However, the neuroanatomical correlates of conjunctive STM binding are largely unexplored. Here we examine the possible association between the volumes of hippocampi, parahippocampal gyri, and grey matter within the subcortical structures - all found to have foci that seemingly correlate with basic daily living activities in AD patients - with cognitive tests related to conjunctive STM binding. MATERIALS AND METHODS: Hippocampal, thalamic, parahippocampal and corpus striatum volumes were semi-automatically quantified in brain magnetic resonance images from 25 cognitively normal people and 21 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test. RESULTS: Hippocampal and parahippocampal gyrus volumes differed between MCI and control groups. Although the grey matter volume in the globus pallidus (r = -0.71, p < 0.001) and parahippocampal gyry (r = -0.63, p < 0.05) correlated with a STM binding task in the MCI group, only the former remained associated with STM binding deficits in MCI patients, after correcting for age, gender and years of education (ß = -0.56,P = 0.042) although with borderline significance. CONCLUSIONS: Loss of hippocampal volume plays no role in the processing of STM binding. Structures within the basal ganglia, namely the globus pallidus, could be part of the extrahippocampal network supporting binding. Replication of this study in large samples is now needed.

Scene construction impairments in frontotemporal dementia: Evidence for a primary hippocampal contribution.

The capacity to generate naturalistic three-dimensional and spatially coherent representations of the world, i.e., scene construction, is posited to lie at the heart of a wide range of complex cognitive endeavours. Clinical populations with selective damage to key nodes of a putative scene construction network of the brain have provided important insights regarding the contribution of medial temporal and prefrontal regions in this regard. Here, we explored the capacity for atemporal scene construction, and its associated neural substrates, in the behavioural-variant of frontotemporal dementia (bvFTD); a neurodegenerative brain disorder in which atrophy systematically erodes medial and lateral prefrontal cortices with variable medial temporal lobe involvement. Nineteen bvFTD patients were compared to 18 typical Alzheimer's Disease (AD), and 25 healthy older Control participants on a scene construction task. Relative to Controls, both patient groups displayed marked impairments in generating contextually detailed and spatially coherent scenes, with bvFTD indistinguishable from AD patients across the majority of task metrics. Voxel-based morphometry, based on structural brain MRI, revealed divergent neural substrates of scene construction performance in each patient group. Despite widespread medial and lateral prefrontal atrophy, the capacity to generate richly detailed and spatially coherent scenes in bvFTD was found to rely predominantly upon the integrity of right medial temporal structures, including the hippocampus and parahippocampal gyrus. Scene construction impairments in AD, by contrast, hinged upon the integrity of posterior parietal brain regions. Our findings in bvFTD resonate with a large body of work implicating the right hippocampus in the construction of spatially integrated scene imagery. How these impairments relate to changes in autobiographical memory and prospection in bvFTD will be an important question for future studies to address.

Comparisons of Voxel-Based Morphometric Brain Volumes of Individuals with Methamphetamine-Induced Psychotic Disorder and Schizophrenia Spectrum Disorder and Healthy Controls.

BACKGROUND: Several psychological and neurological pathways are described to explain the emergence and maintenance of psychiatric disorders, and changes in brain volumes and brain activity are observed as correlates of psychiatric disorders. In the present study, we investigated if and to what extent specific voxel-based morphometric brain volume differences could be observed among individuals with methamphetamine-induced psychosis (MAIP) and schizophrenia spectrum disorder (SSD) compared to healthy controls. METHODS: A total of 69 individuals took part in the present study. Of those, 26 were diagnosed with MAIP, 23 with SSD, and 20 were healthy controls. After a thorough psychiatric assessment, participants underwent brain volume measurement. RESULTS: Compared to healthy controls, participants with MAIP had smaller volumes for left caudate and left and right parahippocampal gyrus. Compared to healthy controls, participants with SSD had smaller volumes for the gray and white matter, left amygdala, left hippocampus, left parahippocampal gyrus, left putamen, and the total volume. Compared to individuals with MAIP, individuals with SSD had a lower white matter brain volume. CONCLUSIONS: The pattern of results suggests that individuals with MAIP and SSD showed specific and regional brain atrophies on the left hemisphere, always compared to healthy controls. Given the cross-sectional design, it remains undisclosed if specific and regional brain atrophies were the cause or the consequence of the psychiatric issues.

Voxel-wise lesion mapping of self-reported urinary incontinence in multiple sclerosis.

AIMS: Besides spinal lesions, urinary incontinence may be attributed to particular cerebral lesion sites in multiple sclerosis (MS) patients. We intended to determine the contribution of suprapontine lesions to urinary incontinence in MS using a voxel-wise lesion analysis. METHODS: In this retrospective study, we sought MS patients with documented urinary incontinence in a local database. We established a control group of MS-patients without documented urinary incontinence matched for gender, age, and disease severity. Patients with urinary incontinence due to local diseases of the urinary tract were excluded. The MS lesions were analyzed on T2-weighted magnetic resonance imaging scans (1.5 or 3T). After manual delineation and transformation into stereotaxic space, we determined the lesion overlap and compared the presence or absence of urinary incontinence voxel-wise between patients with and without lesions in a given voxel performing the Liebermeister test with 4000 permutations. RESULTS: A total of 56 patients with urinary incontinence and MS fulfilled the criteria and were included. The analysis yielded associations between urinary incontinence and MS in the frontal white matter, temporo-occipital, and parahippocampal regions. CONCLUSIONS: Our voxel-wise analysis indicated associations between self-reported urinary incontinence and lesions in the left frontal white matter and right parahippocampal region. Thus, our data suggest that dysfunction of supraspinal bladder control due to cerebral lesions may contribute to the pathophysiology of urinary incontinence in MS.

Disrupted functional network in patients with temporal lobe epilepsy with impaired alertness.

Cognitive impairment is common in patients with temporal lobe epilepsy (TLE). Alertness is an important subfunction of cognition, but it is poorly understood in TLE. We hypothesized that disruptions to underlying brain networks may affect alertness in patients with TLE. Patients with unilateral TLE were grouped into low-alertness and high-alertness groups, and they were matched with healthy controls (HCs) (n = 20 each). Functional magnetic resonance imaging (fMRI) was used to construct functional brain networks, and graph theory was used to identify topological parameters of the networks. At the global level, patients with low alertness had networks with less small-worldness and less normalized clustering than HCs. At the nodal level, patients with low alertness exhibited decreased centrality of the bilateral parahippocampal gyrus compared with HCs and increased centrality of the right postcentral gyrus compared with patients with high alertness. This study reveals a decreased separation, tending toward randomization, of the functional network in patients with TLE with impaired alertness. Our results also suggest that the parahippocampal gyrus may contribute to impaired alertness and the right postcentral gyrus plays an important role in the modulation of alertness in patients with TLE.

Understanding the effect of cognitive/brain reserve and depression on regional atrophy in early Alzheimer's disease.

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer's type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning.

Chronic tinnitus and the limbic system: Reappraising brain structural effects of distress and affective symptoms.

Chronic tinnitus has been associated with brain structural changes in both the auditory system as well as limbic system. While there is considerable inconsistency across brain structural findings, growing evidence suggests that distress and other non-auditory symptoms modulate effects. In this study we addressed this issue, testing the hypothesis that limbic changes in tinnitus relate to both disease-related distress as well as co-morbid psychopathology. We obtained high-resolution structural magnetic resonance imaging (MRI) scans from a total of 125 subjects: 59 patients with bilateral chronic tinnitus (29 with a co-morbid psychiatric condition, 30 without), 40 healthy controls and 26 psychiatric controls with depression/anxiety disorders (without tinnitus). Voxel-based morphometry with the CAT12 software package was used to analyse data. First, we analysed data based on a 2 × 2 factorial design (tinnitus; psychiatric co-morbidity), showing trend-level effects for tinnitus in ROI analyses of the anterior cingulate cortex and superior/transverse temporal gyri, and for voxel-based analysis in the left parahippocampal cortex. Multiple regression analyses showed that the parahippocampal finding was mostly predicted by tinnitus rather than (dimensional) psychopathology ratings. Comparing only low-distress tinnitus patients (independent of co-morbid conditions) with healthy controls also showed reduced left parahippocampal grey matter. Our findings demonstrate that depression and anxiety (not only subjective distress) are major modulators of brain structural effects in tinnitus, calling for a stronger consideration of psychopathology in future neurobiological and clinical studies of tinnitus.