Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical ß-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered ß-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and ß-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Strong synaptic transmission impact by copy number variations in schizophrenia.

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

The future of the Affective Neuroscience Personality Scales: A reflection on seven pressing matters.

The Affective Neuroscience Personality Scales (ANPS) were designed to provide researchers in the mental sciences with an inventory to assess primary emotional systems according to Pankseppian Affective Neuroscience Theory (ANT). The original ANPS, providing researchers with such a tool, was published in 2003. In the present brief communication, about 20 years later, we reflect upon some pressing matters regarding the further development of the ANPS. We touch upon problems related to disentangling traits and states of the primary emotional systems with the currently available versions of the ANPS and upon its psychometric properties and its length. We reflect also on problems such as the large overlap between the SADNESS and FEAR dimensions, the disentangling of PANIC and GRIEF in the context of SADNESS, and the absence of a LUST scale. Lastly, we want to encourage scientists with the present brief communication to engage in further biological validation of the ANPS.

Microarray database mining and cell differentiation defects in schizophrenia.

The causes of schizophrenia remain unknown, but a key role of oligodendrocytes and of the myelination process carried out by them has gained increasing support. The adult human brain parenchyma contains a relatively large population of progenitor cells that can generate oligodendrocytes. Defects in these adult oligodendrocyte progenitor cells (OPCs) or in their proliferation/differentiation have received little attention as potential causes of schizophrenia yet. We compared the set of genes whose expression is modified in schizophrenia, as revealed by our microarray studies, with genes specifically expressed in stem cells, as revealed by studies on human embryonic stem cells. We also evaluated the genes that are upregulated when stem cells engage in differentiation programs. These genes can be viewed as fingerprints or signatures for differentiation processes. The comparisons revealed that a substantial fraction of the genes downregulated in the brains of persons with schizophrenia belong to the differentiation signature. A plausible interpretation of our observations is that a cell differentiation process, possibly of adult OPCs to oligodendrocytes, is perturbed in schizophrenia. These observations constitute an incentive for a new direction of study, aimed at investigating the potential role of OPCs in schizophrenia.

The Roles of Primary Emotional Systems and Need Satisfaction in Problematic Internet and Smartphone Use: A Network Perspective.

Problematic Internet and smartphone use (PIU and PSU, respectively) have received significant attention over the past years. In the current work, we studied the associations between PIU and PSU, primary emotional systems, and need satisfaction. The effective sample comprised 399 people who responded to scales measuring these variables. Bivariate correlation analysis showed that both PSU and PIU were positively associated with negative primary emotion traits (FEAR, ANGER, SADNESS) as well as lower scores on most of the need satisfaction factors. Network analysis showed that while PIU and PSU have a strong association with each other, in general, there were not many significant correlations between PSU, PIU, and other variables in the network. The associations being present were rather weak. Network analysis showed that PSU was positively associated with FEAR, ANGER, PLAY primary emotional systems. Both PSU and PIU had a negative association with safety and security and physiological needs satisfaction. Moreover, PSU had a positive link with belongingness need satisfaction, while higher PIU was associated with lower esteem and self-actualization need satisfaction. Addressing those unmet needs may be helpful in reducing problematic technology use, but further research testing this would be necessary.

A comprehensive review of studies using the Affective Neuroscience Personality Scales in the psychological and psychiatric sciences.

Jaak Panksepp's Affective Neuroscience Theory (ANT) belongs to the most prominent emotion theories in the psychological and psychiatric sciences. ANT proposes the existence of seven primary emotional systems deeply anchored in the mammalian brain. These emotional/motivational systems have been shaped by evolutionary processes and function as tools for survival in mammalian species. The systems are called SEEKING, LUST, CARE, and PLAY, as well as ANGER, FEAR, and SADNESS. Panksepp carved out these emotional systems via means of deep brain stimulation, brain lesion and pharmacological manipulation studies. Davis et al. (2003) designed the Affective Neuroscience Personality Scales (ANPS) against the background of findings from ANT. This self-report inventory is meant to enable researchers to assess individual differences in primary emotional systems. Seventeen years have passed since the first version of the ANPS has been published. Therefore, we now provide a comprehensive overview on studies using the ANPS including work from personality science, psychiatry and the neurosciences.

The Affective Neuroscience Personality Scales: Linking the adjective and statement-based inventories with the Big Five Inventory in English and German-speaking samples.

Jaak Panksepp's Affective Neuroscience Theory is of high relevance not only for a better understanding of affective brain disorders but also in personality research. To make Panksepp's theory more accessible for psychologists and psychiatrists, Davis, Panksepp, and Normansell (2003) developed the Affective Neuroscience Personality Scales (ANPS). These scales assess the manifestation of the primary emotional traits in humans based on a personality trait approach. Given their putative foundation in old subcortical areas in the brain, these primary emotional traits (assessed via the ANPS) could represent the evolutionarily oldest manifestations of personality (but this notion is still a matter of a debate). However, the ANPS inventories were based on using contextual items (e.g., about specific attitudes, behaviors, and feelings in specific situations). Recently, an adjective-based ANPS (ANPS-Adjective Ratings or ANPS-AR) was developed for a less context-dependent and more efficient assessment of Panksepp's primary emotional systems in humans for use by both individuals and independent observer raters. The present work introduces the first German version of the ANPS-AR. Moreover, the current work investigates the original and ANPS-AR versions of the ANPS and their associations with the Big Five personality traits in two independent English- and German-speaking samples. The results show that the ANPS measures are very similarly correlated with the Big Five personality traits across different samples and scales. This work replicates the previous findings in an English version, and demonstrates the reliability and validity of the adjective-based German ANPS-AR.

A meta-analysis on individual differences in primary emotional systems and Big Five personality traits.

The Affective Neuroscience Personality Scales (ANPS) were constructed as a self-report assessment to measure individual differences in Jaak Panksepp's cross-species primary emotional systems: SEEKING, PLAY, CARE (positive emotions) and FEAR, SADNESS, ANGER (negative emotions). Beginning with the first published work on the ANPS in 2003, individual differences on the ANPS measures of these six primary emotional systems have been consistently linked to Big Five personality traits. From a theoretical perspective, these primary emotional systems arising from subcortical regions, shed light on the nature of the Big Five personality traits from an evolutionary perspective, because each of these primary emotional systems represent a tool for survival endowing mammalian species with inherited behavioral programs to react appropriately to complex environments. The present work revisited 21 available samples where both ANPS and Big Five measures have been administered. Our meta-analytical analysis provides solid evidence that high SEEKING relates to high Openness to Experience, high PLAY to high Extraversion, high CARE/low ANGER to high Agreeableness and high FEAR/SADNESS/ANGER to high Neuroticism. This seems to be true regardless of the ANPS inventory chosen, although much more work is needed in this area. Associations between primary emotional systems and Conscientiousness were in the lower effect size area across all six primary emotions, thereby supporting the idea that Conscientiousness rather seems to be less directly related with the subcortical primary emotions and likely is the most cognitive/cortical personality construct out of the Big Five. In sum, the present work underlines the idea that individual differences in primary emotional systems represent evolutionarily ancient foundations of human personality, given their a) meaningful links to the prominent Big Five model and b) their origins lying in subcortical areas of the human brain.

Linking individual differences in satisfaction with each of Maslow's needs to the Big Five personality traits and Panksepp's primary emotional systems.

Maslow's hierarchy of needs is one of the most impactful theories in motivation psychology and personality science. Therefore, it is surprising that studies linking individual differences in a person's current satisfaction with each of Maslow's needs to the Big Five personality traits are rare. In the present study of 850 participants, associations between the Need Satisfaction Inventory and the Big Five personality traits were examined for the first time. In addition, the administration of the Affective Neuroscience Personality Scales provided an evolutionary framework for the present research. Individual differences in the Need Satisfaction Inventory were assessed, but participants were also asked about the current importance of each of Maslow's needs in their lives. This latter approach to viewing Maslow's needs (general rated importance of each need in the life of a person) showed strong deviations from Maslow's proposed order in the classic pyramid depicting the hierarchy of needs.

Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei.

Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei.

A Tribute to Jaak Panksepp (1943-2017).

This article gives a short overview on the life and achievements of Jaak Panksepp. Jaak Panksepp dedicated his life to the study of mammalian emotions. By means of electrical stimulation of the brain and psychopharmacological challenges he carved out seven primary emotional systems being highly conserved across different species of mammals including homo sapiens. The primary emotional systems are called SEEKING, CARE, LUST, PLAY (positive emotions), and FEAR, RAGE, SADNESS (negative emotions). While his early career was characterized by the direct study of these primary emotions in mammals, in his late career he invested more and more time in applying his knowledge to different fields of psychology including personality neuroscience and psychiatry.

Affective Neuroscience Theory and Personality: An Update.

The present work gives a short overview of central aspects of Jaak Panksepp's Affective Neuroscience Theory (AN theory) and its relevance for modern personality neuroscience. In contrast to the widely used Big Five approach to studying and understanding human personality, AN theory provides researchers with a distinct roadmap to the biological basis of personality, including molecular and neuroanatomical candidates, to understand individual differences in human behavior. Such molecular and neuroanatomical brain candidates have been derived by means of electrical brain stimulation and pharmacological challenges, while investigating primary emotional systems anchored in the subcortical mammalian brain. Research results derived from the study of emotions in mammals are also of relevance for humans because ancient layers of our minds-those layers where primary emotions originate-have been homologously conserved across species. From an evolutionary perspective, this makes sense because primal emotions represent "built-in tools for survival" for all mammals. In this context, Montag and Panksepp recently illustrated a potential ancient neurobiological effect by carving out robust associations between individual differences in primary emotions (assessed via self-report) and the Big Five in a cross-cultural study with data from the United States, Germany, and China. These associations together with some ideas derived from MacLean's Triune Brain concept highlighted (a) that primary emotions likely represent the phylogenetically oldest parts of human personality and (b) that primary emotions influence human personality in a bottom-up fashion given their localization in ancient subcortical brain regions. A comment on the work by Montag and Panksepp asked for insights on putative links between primary emotions and facets of the Big Five. Therefore, we provide some first insights into such associations from recent Germany data. In addition, the present work provides a new short version of the Affective Neuroscience Personality Scales to assess individual differences in primary emotions.

Selected Principles of Pankseppian Affective Neuroscience.

In the early nineties of the twentieth century Jaak Panksepp coined the term "Affective Neuroscience" (AN) today being accepted as a unique research area in cross-species brain science. By means of (i) electrical stimulation, (ii) pharmacological challenges, and (iii) brain lesions of vertebrate brains (mostly mammalian), Panksepp carved out seven primary emotional systems called SEEKING, CARE, PLAY, and LUST on the positive side, whereas FEAR, SADNESS, and ANGER belong to the negative affects. Abundant research into human clinical applications has supported the hypothesis that imbalances in these ancient primary emotional systems are strongly linked to psychiatric disorders such as depression. The present paper gives a concise overview of Panksepp's main ideas. It gives an historical overview of the development of Panksepp's AN thinking. It touches not only areas of neuroscience, but also shows how AN has been applied to other research fields such as personality psychology. Finally, the present work gives a brief overview of the main ideas of AN.

Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia.

Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n=41) and a comparison group (n=34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n=31) and unmedicated (n=10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia.

Diffusion tensor imaging in schizophrenia.

BACKGROUND: Alignment of white matter axons as inferred from diffusion tensor imaging has indicated changes in schizophrenia in frontal and frontotemporal white matter. METHODS: Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired in 64 patients with schizophrenia and 55 normal volunteers. Anatomical images were acquired with a magnetization prepared rapid gradient echo sequence, and diffusion tensor images used a pulsed gradient spin-echo acquisition. Images were aligned and warped to a standard brain, and anisotropy in normal volunteers and patients was compared using significance probability mapping. RESULTS: Patients showed widespread areas of reduced anisotropy, including the frontal white matter, the corpus callosum, and the frontal longitudinal fasciculus. CONCLUSIONS: These findings, which are consistent with earlier reports of frontal decreases in anisotropy, demonstrate that the effects are most prominent in frontal and callosal areas and are particularly widespread in frontal white matter regions.

The human homolog of the QKI gene affected in the severe dysmyelination "quaking" mouse phenotype: downregulated in multiple brain regions in schizophrenia.

OBJECTIVE: The authors sought to understand the origins of oligodendrocyte/myelin gene expression abnormalities in the brains of persons with schizophrenia. METHOD: Twelve cortical regions (Brodmann's areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7, and 17) and three noncortical regions (caudate, hippocampus, and putamen) of 16 elderly schizophrenia patients and 14 matched comparison subjects were examined using 450 separate microarrays. The mRNA levels of QKI and its isoforms were then measured in a larger cohort by using quantitative real-time polymerase chain reaction (qPCR) in the cingulate cortex of schizophrenia subjects and matched comparison subjects. RESULTS: Expression of QKI mRNA was decreased in seven cortical regions and the hippocampus in the schizophrenia subjects. QKI gene expression deficits detected by microarray were validated by qPCR in the cingulate cortex, where the expression of isoforms QKI-5, QKI-6, and QKI-7 were profoundly perturbed in schizophrenia. CONCLUSIONS: Since QKI plays a fundamental role in oligodendrocyte differentiation and in myelination, its underexpression may be pivotal to, and upstream of, other myelin-associated gene expression abnormalities in schizophrenia. Given the role of QKI in determination of oligodendrocyte fate, these results not only confirm oligodendrocyte-related gene expression abnormalities in schizophrenia but suggest that the physiology of glial progenitor cells may be altered in schizophrenia.

Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: retrospective comparison of first generation and second generation antipsychotics.

INTRODUCTION: Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity. METHODS: This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N=97) or second generation (N=78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment x time. RESULTS: Cognitive functions (Mini Mental State Examination time effect estimate=-.41, p<.001; ADAS-L Cog time effect estimate=.64, p<.001) and self-care skills (ADAS-L Self-Care time effect estimate=.65, p<.001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time. CONCLUSION: This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.

Seasonality effects on schizophrenic births in multiplex families in a tropical island.

Many studies have found that individuals with schizophrenia have been born in winter months in disproportionately high numbers. Temperature and weather effects, such as hot summers or cold winters, have been among the suggested explanations for this seasonality effect. We studied the relationship between schizophrenia and season of birth in Puerto Rico, a tropical island with mild seasonal variation of temperature and virtually no cold periods. Our sample consisted of 132 subjects (57 with schizophrenia, 75 without) from 24 multiplex families. Schizophrenic family members were significantly more likely to be born during the winter months (21/57; 36.8%) than their unaffected relatives (16/75; 21.3%). These results suggest that extreme temperatures are not a sufficient explanation for the seasonality effect and that other factors associated with seasonality may have an effect on the later development of schizophrenia. The fact that a seasonality effect was found in a group likely to have an increased genetic loading for schizophrenia suggests that seasonality may be associated with a second, environmental "hit" in a "two-hit hypothesis" of schizophrenia.

Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin.

OBJECTIVE: While both thalamic abnormalities and dopaminergic dysregulation have been separately implicated in the pathophysiology of schizophrenia, little is known about the possible dysfunction of molecules associated with dopaminergic neurotransmission in the thalamus in this illness. In this study, the authors studied this question by measuring in postmortem brain the expression of molecules associated with dopaminergic neurotransmission. METHOD: Using in situ hybridization and receptor autoradiography, the authors determined in schizophrenia and comparison subjects 1) thalamic expression of the transcripts encoding the five dopamine receptors; 2) binding to the dopamine D(1), D(2), and D(3) receptors; 3) monoaminergic innervation as assessed by binding to the vesicular monoamine transporter; and 4) transcripts encoding three dopamine receptor-associated intracellular proteins (calcyon, spinophilin, and DARPP-32) that mediate integration of dopaminergic signaling with other neurotransmitter systems. RESULTS: Both calcyon and spinophilin transcripts were significantly elevated in schizophrenia subjects. Monoaminergic innervation, as well as dopamine receptor transcripts and binding sites, were unaffected in this illness. CONCLUSIONS: These data indicate that there are dopaminergic abnormalities in the thalamus in schizophrenia but that they are at the level of intracellular integration of dopamine signaling with other neurotransmitter systems, likely including glutamate, in thalamic neurons.