Frontal Cortex Gray Matter Research Articles

Methylphenidate as a treatment option for substance use disorder: a transdiagnostic perspective.

A transition in viewing mental disorders from conditions defined as a set of unique characteristics to one of the quantitative variations on a collection of dimensions allows overlap between disorders. The overlap can be utilized to extend to treatment approaches. Here, we consider the overlap between attention-deficit/hyperactivity disorder and substance use disorder to probe the suitability to use methylphenidate as a treatment for substance use disorder. Both disorders are characterized by maladaptive goal-directed behavior, impaired cognitive control, hyperactive phasic dopaminergic neurotransmission in the striatum, prefrontal hypoactivation, and reduced frontal cortex gray matter volume/density. In addition, methylphenidate has been shown to improve cognitive control and normalize associated brain activation in substance use disorder patients and clinical trials have found methylphenidate to improve clinical outcomes. Despite the theoretical basis and promising, but preliminary, outcomes, many questions remain unanswered. Most prominent is whether all patients who are addicted to different substances may equally profit from methylphenidate treatment.

The relationship between glutamate, dopamine, and cortical gray matter: A simultaneous PET-MR study

Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [11C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D2/3R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D2/3R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D2/3R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D2/3R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D2/3R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations.

Altered abundances of human immunoglobulin M and immunoglobulin G subclasses in Alzheimer\u2019s disease frontal cortex

The immune system has been described to play a role in the development of Alzheimer’s disease (AD), but the distribution of immunoglobulins and their subclasses in brain tissue has not been explored. In this study, examination of pathologically diagnosed frontal cortex gray matter revealed significantly higher levels of IgM and IgG in late-stage AD (Braak and Braak stages V and VI) compared to age-matched controls. While levels of IgG2 and IgG4 constant region fragments were higher in late-stage AD, concentration of native–state IgG4 with free Fc regions was increased in AD III and VI. RNA analysis did not support parenchymal B-cell production of IgG4 in AD III and V, indicating possible peripheral or meningeal B-cell involvement. Changes in the profile of IgM, IgG and IgG subclasses in AD frontal cortex may provide insight into understanding disease pathogenesis and progression.

Common disbalance in the brain parenchyma of dementias: Phospholipid profile analysis between CADASIL and sporadic Alzheimer's disease

Sporadic Alzheimer's disease (SAD) is the most common form of dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary ischemic small vessel disease of the brain. Relevant biomarkers or specific metabolic signatures could provide powerful tools to manage these diseases. Therefore, the main goal of this study was to compare the postmortem frontal cortex gray matter, white matter and cerebrospinal fluid (CSF) between a cognitively healthy group and CADASIL and SAD groups. We evaluated 352 individual lipids, belonging to 13 lipid classes/subclasses, using mass spectrometry, and the lipid profiles were subjected to multivariate analysis to discriminate between the dementia groups (CADASIL and SAD) and healthy controls. The main lipid molecular species showing greater discrimination by partial least squares-discriminant analysis (PLS-DA) and a higher significance multivariate correlation (sMC) index were as follows: phosphatidylserine (PS) PS(44:7) and lysophosphatidylethanolamine (LPE) LPE(18:2) in gray matter (GM); phosphatidylethanolamine (PE) PE(32:2) and phosphatidylcholine PC PC(44:6) in white matter (WM), and ether PE (ePE) ePE(38:2) and ether PC (ePC) ePC(34:3) in CSF. Common phospholipid molecular species were obtained in both dementias, such as PS(44:7) and lyso PC (LPC) LPC(22:5) in GM, PE(32:2) in WM and phosphatidic acid (PA) PA(38:5) and PC(42:7) in CFS. Our exploratory study suggests that phospholipids (PLs) involved in neurotransmission alteration, connectivity impairment and inflammation response in GM, WM and CSF are a transversal phenomenon affecting dementias such as CADASIL and SAD independent of the etiopathogenesis, thus providing a possible common prodromal phospholipidic biomarker of dementia.

Social subordination alters estradiol-induced changes in cortico-limbic brain volumes in adult female rhesus monkeys

Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17β-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of social subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic social stress to modulate these effects on brain structure.

The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease.

Tau becomes excessively phosphorylated in Alzheimer's disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.

Frontal cortex gray matter volume alterations in pathological gambling occur independently from substance use disorder.

Neuroimaging in pathological gambling (PG) allows studying brain structure independent of pharmacological/neurotoxic effects occurring in substance addiction. Because of high comorbidity of PG with substance use disorder (SUD), first results on structural deficits in PG are controversial. The current investigation is the first to examine gray matter (GM) volume alterations in PG controlling for the impact of SUD by comparing non-comorbid (PGPURE ) and two comorbid (PGALCOHOL and PGPOLY ) groups. Two hundred and five individuals were included in the analysis: 107 patients diagnosed with PG and 98 healthy controls (HCs). We employed voxel-based morphometry to look for GM volume differences between the groups controlling for age, smoking and depression. GM decreases in the superior medial and orbital frontal cortex occur independently of substance use in PGPURE compared with HCs. The frontal pattern of GM decrease was comparable with PGALCOHOL group where additionally GM volume was decreased in the anterior cingulate but increased in the amygdala. Moreover, regions in PGALCOHOL + POLY with reduced GM volume were the medial frontal, anterior cingulate and occipital lobe regions. PGALCOHOL + POLY not only exhibited structural deficits in comparison with HCs but also relative to PGPURE in the precuneus and post-central gyrus. We demonstrated specific frontal cortex GM deficits in PG without SUD comorbidities. Whereas some target regions reported in earlier studies might result from comorbid substance abuse, there seems to be a core set of frontal alterations associated with addicted gambling behaviour independent of toxic substance effects.

R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study.

The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; P = .04 and vs 0.033 [0.013] for control individuals; P < .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all patients with AD (AD: 2.5, R47H_AD: 2.7, and control: 1.0; P < .01). Our results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.

Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer's disease subjects.

We undertook a non-targeted lipidomics analysis of post-mortem cerebrospinal fluid (CSF), frontal cortex grey matter, and subjacent white matter to define potential biomarkers that distinguish cognitively intact subjects from those with incipient or established dementia. Our objective was to increase our understanding of the role of brain lipids in pathophysiology of aging and age-related cognitive impairment. Levels of 650 individual lipids, across 26 lipid subclasses, were measured utilising a high-resolution mass spectrometric analysis platform. Monoacylglycerols (MAG), diacylglycerols (DAG), and the very-long-chain fatty acid 26:0 were elevated in the grey matter of the mild cognitive impairment (MCI) and old dementia (OD) cohorts. Ethanolamine plasmalogens (PlsEtn) were decreased in the grey matter of the young dementia (YD) and OD cohorts while and phosphatidylethanolamines (PtdEth) were lower in the MCI, YD and OD cohorts. In the white matter, decrements in sulphatide levels were detected in the YD group, DAG levels were elevated in the MCI group, and MAG levels were increased in the YD and OD groups. The parallel changes in grey matter MAGs and DAGs in the MCI and OD groups suggest that these two cohorts may have a similar underlying pathophysiology; consistent with this, MCI subjects were more similar in age to OD than to YD subjects. While PlsEtn and phosphatidylethanolamine were decreased in the YD and OD groups they were unaltered in the MCI group indicating that alterations in plasmalogen synthesis are unlikely to represent an initiating event in the transition from MCI to dementia.

VSNL1 Co-Expression Networks in Aging Include Calcium Signaling, Synaptic Plasticity, and Alzheimer's Disease Pathways.

The visinin-like 1 (VSNL1) gene encodes visinin-like protein 1, a peripheral biomarker for Alzheimer disease (AD). Little is known, however, about normal VSNL1 expression in brain and the biologic networks in which it participates. Frontal cortex gray matter obtained from 209 subjects without neurodegenerative or psychiatric illness, ranging in age from 16 to 91, was processed on Affymetrix GeneChip 1.1 ST and Human SNP Array 6.0. VSNL1 expression was unaffected by age and sex, and not significantly associated with SNPs in cis or trans. VSNL1 was significantly co-expressed with genes in pathways for calcium signaling, AD, long-term potentiation, long-term depression, and trafficking of AMPA receptors. The association with AD was driven, in part, by correlation with amyloid precursor protein (APP) expression. These findings provide an unbiased link between VSNL1 and molecular mechanisms of AD, including pathways implicated in synaptic pathology in AD. Whether APP may drive increased VSNL1 expression, VSNL1 drives increased APP expression, or both are downstream of common pathogenic regulators will need to be evaluated in model systems.

EPA-1217 – A systematic review of MRI differences between psychotic & non-psychotic depression

Psychotic depression is widely accepted as a specific subtype of unipolar major depression. Magnetic resonance imaging studies have begun to investigate the neurobiological changes that differentiate this subtype of major depression from non-psychotic depression. Any differences may eventually be useful in aiding diagnosis. This review collates the currently available evidence, with the aim of directing future study. A systematic search of the Medline, PubMed & Embase databases was used to identify all articles comparing structural or functional magnetic resonance imaging (MRI) differences between psychotic and non-psychotic depression. The results were then collated and organised according to brain region. Decreased frontal cortex grey matter volumes and, to a lesser degree, insula cortex volumes differentiate psychotic from non-psychotic depression. fMRI studies show associations between altered activity in these two regions and cognitive impairments in patients with psychotic depression. The volumes of putative emotional processing regions including the amygdala, hippocampus and anterior cingulate show no difference between psychotic and non-psychotic depression. Structural and functional changes in the higher associative regions of the frontal and insula cortices differentiate between psychotic and nonpsychotic depression to a greater degree than changes in putative emotional processing regions. The numbers of studies available and the sample sizes involved are both small but future studies aimed at understanding the neurobiology of psychotic depression may benefit from a more detailed assessment of these two regions.

Genes encoding heterotrimeric G-proteins are associated with gray matter volume variations in the medial frontal cortex.

G-protein–coupled signal transduction mediates most cellular responses to hormones and neurotransmitters; this signaling system transduces a large variety of extracellular stimuli into neurons and is the most widely used mechanism for cell communication at the synaptic level. The heterotrimeric G-proteins have been well established as key regulators of neuronal growth, differentiation, and function. More recently, the heterotrimeric G-protein genes group was associated with general cognitive ability. Although heterotrimeric G-proteins are linked to both cognitive ability aond neuron signaling, it is unknown whether heterotrimeric G-proteins are also important for brain structure. We tested for association between local cerebral gray matter volume and the heterotrimeric G-protein genes group in 294 subjects; a replication analysis was performed in an independent sample of 238 subjects. Voxel-based morphometry revealed a strong replicated association between 2 genes encoding heterotrimeric G-proteins with specific local increase in medial frontal cortex volume, an area known to be involved in cognitive control and negative affect. This finding suggests that heterotrimeric G-proteins might modulate medial frontal cortex gray matter volume. The differences in gray matter volume due to variations in genes encoding G-proteins may be explained by the role of G-proteins in prenatal and postnatal neocortex development.

Preliminary Evidence for Sensitive Periods in the Effect of Childhood Sexual Abuse on Regional Brain Development

Preliminary Evidence for Sensitive Periods in the Effect of Childhood Sexual Abuse on Regional Brain Development

Preliminary Evidence for Sensitive Periods in the Effect of Childhood Sexual Abuse on Regional Brain Development

Volumetric MRI scans from 26 women with repeated episodes of childhood sexual abuse and 17 healthy female comparison subjects (ages 18-22 years) were analyzed for sensitive period effects on hippocampal and amygdala volume, frontal cortex gray matter volume and corpus callosum area. Hippocampal volume was reduced in association with childhood sexual abuse at ages 3-5 years and ages 11-13 years. Corpus callosum was reduced with childhood sexual abuse at ages 9-10 years, and frontal cortex was attenuated in subjects with childhood sexual abuse at ages 14-16 years. Brain regions have unique windows of vulnerability to the effects of traumatic stress.

Relationship between Alzheimer’s disease clinical stage and Gq/11 in subcellular fractions of frontal cortex

Alzheimer's disease (AD) is associated with impaired coupling of cell surface muscarinic cholinergic receptors to G proteins of the Gq/11 class in brain. This alteration may contribute to progression of cognitive impairment during the course of the disease. We hypothesized that increasing severity of cognitive impairment would be related to decreased levels of Gq/11 detected in key subcellular fractions made from postmortem brain tissue. In this study, we used Western blotting to determine the quantity of Gq/11alpha in P2, synaptic plasma membrane, cytoplasm, microsomal membrane, and lipid raft fractions prepared from superior frontal cortex gray matter of 25 patients with clinical AD confirmed by post-mortem examination. Multiple linear regression analysis that adjusted for age, sex, and education showed a linear relationship between frontal cortex synaptic plasma membrane Gq/11alpha levels and severity of cognitive impairment determined by Mini Mental State score measured proximate to death.

Brain ganglioside and glycoprotein sialic acid in breastfed compared with formula-fed infants

The concentration of sialic acid in brain gangliosides and glycoproteins has been linked to learning ability in animal studies. Human milk is a rich source of sialic acid-containing oligosaccharides and is a potential source of exogenous sialic acid. The aim of the study was to compare the sialic acid concentration in the brain frontal cortex of breastfed and formula-fed infants. Twenty-five samples of frontal cortex derived from infants who died of sudden infant death syndrome were analyzed. Twelve infants were breastfed, 10 infants were formula-fed, and 1 infant was mixed-fed; the feeding status of the remaining 2 infants was unknown. Ganglioside-bound and protein-bound sialic acid were determined by HPLC. Ganglioside ceramide fatty acids were also analyzed to determine the relation between sialic acid and long-chain polyunsaturated fatty acids. After adjustment for sex with age at death as a covariate, ganglioside-bound and protein-bound sialic acid concentrations were 32% and 22% higher, respectively, in the frontal cortex gray matter of breastfed infants than in that of formula-fed infants (P < 0.01). Protein-bound sialic acid increased with age in both groups (P = 0.02). In breastfed but not in formula-fed infants, ganglioside-bound sialic acid correlated significantly with ganglioside ceramide docosahexaenoic acid and total n-3 fatty acids. Higher brain ganglioside and glycoprotein sialic acid concentrations in infants fed human milk suggests increased synaptogenesis and differences in neurodevelopment.

Neuronal nitric oxide synthase (nNOS) mRNA expression and NADPH-diaphorase staining in the frontal cortex, visual cortex and hippocampus of control and Alzheimer's disease brains

Neuronal nitric oxide synthase (nNOS) mRNA levels and NADPH diaphorase (NADPH-d) staining were compared in the frontal cortex, visual cortex and hippocampus (dentate gyrus and CA subfields of Ammon's horn) of five Alzheimer's disease (AD) and six control brains. The cellular abundance of nNOS mRNA was quantified by in-situ hybridisation using 35S-labelled antisense oligonucleotides complementary to the human nNOS sequence. Although the mean level of nNOS expression was decreased in all three regions in AD cases as compared to controls, it did not reach significance. Neurones positively labelled for nNOS mRNA and neurones positive for NADPH-d histochemistry displayed similar distributions in control and AD cases. In AD brains the density of neurones having detectable levels of nNOS mRNA was significantly decreased in the white matter underlying the frontal cortex ( P < 0.05) but not in the frontal cortex gray matter; no change was observed in the gray or white matter of the visual cortex in AD. The number of cells expressing detectable levels of nNOS mRNA in the hippocampus was also significantly decreased ( P < 0.05) in AD. The density of NADPH-d-positive cells was not significantly decreased in the gray or white matter of the frontal or visual cortices in AD compared to controls; however, the number of NADPH-d-positive cells was significantly decreased in the hippocampus ( P < 0.01). These data indicate that although the cellular abundance of nNOS mRNA is not significantly decreased in these three regions in AD, there is significant decrease in the number of cells expressing detectable levels of nNOS mRNA in the white matter underlying the frontal cortex and in the dentate gyrus and CA subfields of the hippocampus in AD. Futhermore, there was also a significant decrease in the number of NADPH-d-positive cells in the dentate gyrus and CA subfields of the hippocampus in AD as compared to controls. These results suggest specific populations of nNOS/NADPH-d cells in the white matter underlying the frontal cortex and in the hippocampus are vulnerable in AD. The implications of these findings are discussed.

Somatostatin messenger rna-containing neurons in Alzheimer's disease: An in situ hybridization study in hippocampus, parahippocampal cortex and frontal cortex

The level of expression of somatostatin messenger RNA-containing neurons in human brain was visualized and quantified by in situ hybridization with a 35S-labelled oligonucleotide complementary to amino acids 96–111 of the preprosomatostatin complementary DNA sequence. The analysis was carried out in the frontal and parahippocampal cortices and hippocampus of six age- and post mortem delay-matched Alzheimer's disease and control brains. By northern blot analysis, in frontal cortex samples, 18S rRNA degradation was identical in control and Alzheimer brains and somatostatin messenger RNAs migrated as a single band of 1 kb. By in situ hybridization, specificity was demonstrated by abolition of the signal using either an excess of unlabelled antisense probe or using a labelled sense probe. Somatostatin messenger RNA-containing neurons displayed a similar regional and subregional distribution in control subjects and patients with Alzheimer's disease, being more abundant in the frontal cortex, followed by the hippocampus and the parahippocampal cortex. An overall reduction of labelled cell density was observed in patients with Alzheimer's disease (frontal cortex gray matter: −41%; white matter: −66%; hippocampus: −44%; parahippocampal cortex white matter: −40%). Due to a great variation between brains, this decrease only reached significance in the parahippocampal cortex ( − 59%, P<0.05). A significantly lower level of expression of somatostatin messenger RNA per somatostatinergic cell was observed in the hippocampus of Alzheimer's disease patients ( − 47%, P < 0.05), but not in frontal cortex gray (−17%) and white (−36%) matter and parahippocampal cortex gray (−42%) and white ( − 29%) matter. These data are in accordance with the distribution of somatostatin cells as visualized by immunohis-tochemistry in human brain. They indicate that the ability of cortical cells to express somatostatin messenger RNA is partially preserved in Alzheimer disease brains and that the decrease in the amount of somatostatin messenger RNA per cell is restricted to the hippocampal formation.