Noncognitive Behavioral Changes Associated With Alzheimer's Disease: Implications of Neuroimaging Findings.

Alzheimer's disease (AD) is commonly associated with noncognitive behavioral changes (NCBCs). The authors systematically reviewed whether neuroimaging has helped with understanding the pathophysiology, diagnosis, or management of NCBCs associated with AD, including depression, aggression or agitation, anxiety, apathy, psychosis, and sleep disorder. The authors identified dissociable neural substrates with multimodal imaging: depression implicates the lateral and superior prefrontal cortex; apathy and agitation implicate the dorsal anterior cingulate; psychosis implicates right lateralized frontal and medial temporal areas; and anxiety implicates mesial temporal regions. Frontal white matter changes appear to underlie many NCBCs, emphasizing the preventative management of vascular risk factors. Further delineation of underlying neurocircuitry and pathophysiology in larger data sets might lead to biomarker identification for diagnosis and optimizing treatment targets.

Pharmacological management of persistent hostility and aggression in persons with schizophrenia spectrum disorders: a systematic review.

The incidence of aggressive behaviors is higher among persons with schizophrenia spectrum disorders (SSDs) than among persons without such disorders. This phenomenon represents a risk to the well-being of patients, their families, and society. The authors undertook a systematic review of the English language literature to determine the efficacy of neuropharmacological agents for the management of hostility and aggression among persons with SSDs. The search combined findings from the Medline, EMBASE, and PsycINFO databases. Ninety-two full text articles were identified that reported relevant findings. The American Academy of Neurology criteria were used to determine levels of evidence. Paliperidone-extended release is probably effective for the management of hostility among inpatients with SSDs who have not been preselected for aggression (Level B). Clozapine is possibly more effective than haloperidol for the management of overt aggression and possibly more effective than chlorpromazine for the management of hostility among inpatients with SSDs who have not been preselected for aggression (Level C). Clozapine is also possibly more effective than olanzapine or haloperidol for reducing aggression among selected physically assaultive inpatients (Level C). Adjunctive propranolol, valproic acid, and famotidine are possibly effective for reducing some aspects of hostility or aggression among inpatients with SSDs (Level C). Paliperidone-extended release currently appears to be the agent for the management of hostility among inpatients with SSDs for which there is the strongest evidence of efficacy.

Traumatic encephalopathy: review and provisional research diagnostic criteria.

OBJECTIVES: To determine the frequency of neurobehavioral signs and symptoms reported in every published case of traumatic encephalopathy with a view toward the development of clinical diagnostic criteria with predictive validity. INTRODUCTION: Cases of persistent or progressive neurological or neurobehavioral change following exposure to one or more head injuries have been reported since 1928. This condition is often referred to as traumatic encephalopathy (TE). To date, however, no diagnostic criteria have been advanced or accepted for the clinical diagnosis of TE. Provisional research diagnostic criteria are required not only for meaningful diagnosis but also to facilitate research to determine the epidemiology, etiology, course, prognosis, imaging and biomarkers, neuropathological features and potentially effective treatments of TE. METHODS: All 436 published cases of TE in all languages were reviewed. All symptoms and signs reported in these cases were classified and enumerated. RESULTS: Ninety-seven cases met inclusion criteria based on sufficient documentation of the history and neurobehavioral examination. Provisional research diagnostic criteria for clinically probable and clinically possible TE were developed based on the most frequently reported clinical features. CONCLUSION: The provisional diagnostic criteria for TE presented here are the first published criteria for this condition based upon a systematic analysis of its clinical characteristics. This is the first a step toward scientifically derived consensus criteria, which are essential to accelerate progress in the investigation of this important condition.

Support for religio-political aggression among teenaged boys in Gaza: part II: neuroendocrinological findings.

Hormones seem to play important roles in the regulation of human aggression. Multiple studies have confirmed that testosterone (T) levels exhibit complex relationships with aggression, dominance, and/or risk-taking behavior. Some evidence suggests that cortisol (CORT) interacts with T and may also be associated with aspects of mood and aggression. However, almost no research to date has investigated the possibility that these neuroendocrine factors are associated with variations in political attitudes or with political aggression. During the second intifada, we tested the hypothesis that morning salivary T and/or salivary CORT levels might be associated with self-rated aggression or with support for religio-political aggression (RPA) among 14-year-old Palestinian boys living in Gaza. We obtained and averaged weekly 09:00 hr salivary measures of T and CORT for more than 1 month. Averaged morning T levels did not correlate with self-rated aggression, but were positively associated with agreement with the statement "religious ends justify any means," (r = .355, P = .014) and marginally associated with a composite measure of support for RPA (r = .247, P = .094). Average CORT levels were inversely correlated with self-rated aggression (r = -.328, P = .037) and with anger (r = -.373, P = .016), but CORT levels were not associated with support for RPA or with the statement "religious ends justify any means." Acknowledging that a modest sample size and methodological issues necessarily limit confidence in our conclusions, these results may represent the first findings regarding neurobiological correlates of support for political aggression.

Support for religio-political aggression among teenaged boys in Gaza: Part I: psychological findings.

Politically aggressive militant groups usually rely on support from a larger community, although evidence suggests that only some members of that larger community support that aggression. A major subtype of political aggression is that associated with religious differences--or Religio-Political Aggression (RPA). Little previous research has explored demographic or psychological factors that might distinguish supporters from non-supporters of RPA. In an exploratory study, we investigated whether factors previously associated with aggression might correlate with support for RPA in the case of the Israeli/Palestinian conflict. During the second intifada, fifty-two 14-year-old Palestinian boys in Gaza completed self-report measures of life events, emotional status, and political attitudes. Teenaged boys who reported family members having been wounded or killed by the Israeli Defense Forces (IDF) expressed greater support for RPA (t(50) = -2.30, P = .026). In addition, boys who felt their group was treated unjustly reported greater support for RPA compared with those who did not (t(50) = -2.273, P = .027). Implications of these preliminary data are discussed.

Psychopharmacological neuroprotection in neurodegenerative disease: heuristic clinical applications.

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Childhood motor coordination and adult schizophrenia spectrum disorders.

OBJECTIVE: The authors examined whether motor coordination difficulties assessed in childhood predict later adult schizophrenia spectrum outcomes. METHOD: A standardized childhood neurological examination was administered to a sample of 265 Danish children in 1972, when participants were 10-13 years old. Adult diagnostic information was available for 244 members of the sample. Participants fell into three groups: children whose mothers or fathers had a psychiatric hospital diagnosis of schizophrenia (N=94); children who had at least one parent with a psychiatric record of hospitalization for a nonpsychotic disorder (N=84); and children with no parental records of psychiatric hospitalization (N=66). Psychiatric outcomes of the offspring were assessed through psychiatric interviews in 1992 when participants were 31-33 years of age, as well as through a scan of national psychiatric registers completed in May 2007. RESULTS: Children who later developed a schizophrenia spectrum disorder (N=32) displayed significantly higher scores on a scale of coordination deficits compared with those who did not develop a mental illness in this category (N=133). CONCLUSIONS: Results from this study provide further support for the neurodevelopmental hypothesis of schizophrenia and underscore the potential role of cerebellar and/or basal ganglia abnormalities in the etiology and pathophysiology of schizophrenia.

Understanding human aggression: New insights from neuroscience.

The present paper reviews and summarizes the basic findings concerning the nature of the neurobiological and behavioral characteristics of aggression and rage. For heuristic purposes, the types of aggression will be reduced to two categories - defensive rage (affective defense) and predatory attack. This approach helps explain both the behavioral properties of aggression as well as the underlying neural substrates and mechanisms of aggression both in animals and humans. Defensive rage behavior is activated by a threatening stimulus that is real or perceived and is associated with marked sympathetic output. This yields impulsivity with minimal cortical involvement. Predatory attack behavior in both animals and humans is generally planned, taking minutes, hours, days, weeks, months, or even years (with respect to humans) for it to occur and is directed upon a specific individual target; it reflects few outward sympathetic signs and is believed to require cortical involvement for its expression. Predatory attack requires activation of the lateral hypothalamus, while defensive rage requires activation of the medial hypothalamus and midbrain periaqueductal gray (PAG). Both forms of aggressive behavior are controlled by components of the limbic system, a region of the forebrain that is influenced by sensory inputs from the cerebral cortex and monoaminergic inputs from the brainstem reticular formation. Control of aggressive tendencies is partly modifiable through conditioning and related learning principles generated through the cerebral cortex.

Aggression, science, and law: The origins framework. Introduction.

Human societies have formalized instincts for compliance with reciprocal altruism in laws that sanction some aggression and not other aggression. Neuroscience makes steady advances toward measurements of various aspects of brain function pertinent to the aggressive behaviors that laws are designed to regulate. Consciousness, free will, rationality, intent, reality testing, empathy, moral reasoning, and capacity for self-control are somewhat subject to empirical assessment. The question becomes: how should law accommodate the wealth of information regarding these elements of mind that the science of aggression increasingly makes available? This essay discusses the evolutionary purpose of aggression, the evolutionary purpose of law, the problematic assumptions of the mens rea doctrine, and the prospects for applying the neuroscience of aggression toward the goal of equal justice for unequal minds. Nine other essays are introduced, demonstrating how each of them fits into the framework of the permanent debate about neuroscience and justice. It is concluded that advances in the science of human aggression will have vital, but biologically limited, impact on the provision of justice.

The psychology of suicide terrorism.

This paper reviews current understandings of the psychology of suicide terrorism for psychiatrists and other mental health professionals to help them better understand this terrifying phenomenon. After discussing key concepts and definitions, the paper reviews both group and individual models for explaining the development of suicide terrorists, with an emphasis on "collective identity." Stressing the importance of social psychology, it emphasizes the "normality" and absence of individual psychopathology of the suicide bombers. It will discuss the broad range of terrorisms, but will particularly emphasize terrorism associated with militant Islam. The article emphasizes that comprehending suicide terrorism requires a multidisciplinary approach that includes anthropological, economic, historical, and political factors as well as psychological ones. The paper concludes with a discussion of implications for research, policy, and prevention, reviewing the manner in which social psychiatric knowledge and understandings applied to this phenomenon in an interdisciplinary framework can assist in developing approaches to counter this deadly strategy.

What Should This Fight Be Called? Metaphors of Counterterrorism and Their Implications.

This monograph examines from a psychological perspective the use of metaphors in framing counterterrorism. Four major counterterrorism metaphors are considered, namely those of war, law enforcement, containment of a social epidemic, and a process of prejudice reduction. The war metaphor is as follows: Wars are fought by states; the enemy is thus an identifiable entity whose interests fundamentally oppose your own. The conflict is zero-sum-the outcome will be victory for one side or the other-and there is no compromise. The war metaphor is totalistic and extreme. Arguably, it was adopted in light of the immensity of damage and national hurt produced by the 9/11 attack. It has insinuated itself into the public discourse about counterterrorism, and it has guided policy, but it has also met challenges because of lack of fit and the availability of counteranalogies with different lessons of history. Some of the drawbacks of the war metaphor are addressable in the law enforcement metaphor of counterterrorism. Unlike war's special status and circumscribed duration, law enforcement is an ongoing concern that must compete for resources with other societal needs. A major advantage of law enforcement over warfare is its focused nature-targeting the actual terrorists, with less likelihood of injuring innocent parties. Yet despite its advantages, the law enforcement metaphor exhibits a partial mismatch with the realities of terrorism. Its complete and uncritical adoption may temporarily hamper terrorists' ability to launch attacks without substantially altering their motivation to do so. The public health epidemiological model was usefully applied to the epidemic of terror that followed the 9/11 attacks. It utilizes a partition between (a) an external agent, (b) a susceptible host, (c) an environment that brings them together, and (d) the vector that enables transmission of the disease. In the specific application to jihadist terrorism, the agent refers to the militant Islamist ideology, the susceptible host refers to radicalizable Muslim populations, the environment refers to conditions that promote the readiness to embrace such ideology, and the vectors are conduits whereby the ideology is propagated. The epidemiological metaphor has its own advantages over the war and law enforcement metaphors, but also limitations. Whereas the latter metaphors neglect the long-range process of ideological conversion and radicalization that creates terrorists, the epidemiological metaphor neglects the "here and now" of counterterrorism and the value of resolute strikes and intelligence-gathering activities needed to counter terrorists' concrete schemes and capabilities. Framing counterterrorism as the process of prejudice reduction addresses the interaction between two communities whose conflict may breed terrorism. This framing shifts the focus from a unilateral to a bilateral concern and acknowledges the contribution to intergroup tensions that the party targeted by terrorists may make. A major tool of prejudice reduction is the creation of positive contact between members of the conflicted groups. Efforts at prejudice reduction via positive contact need to take place in the context of a larger set of policies, such as those concerning immigration laws, educational programs, and foreign policy initiatives designed to augment the good-will-generating efforts of optimal-contact programs. For all its benefits, the prejudice-reduction framework is also not without its drawbacks. Specifically, the positive-contact notion highlights the benefits of mere human interaction; it disregards differences in ideological beliefs between the interacting parties, thereby neglecting an element that appears essential to producing their estrangement and reciprocal animosity. Too, like the epidemiological metaphor, the prejudice-reduction framing takes the long view, thereby neglecting the "here and now" of terrorism and the need to counter specific terrorist threats. Thus, each of the foregoing frameworks captures some aspects of counterterrorism's effects while neglecting others. Accordingly, an integrated approach to counterterrorism is called for, one that exploits the insights of each metaphor and avoids its pitfalls. Such an approach would maximize the likelihood of enlightened decision making concerning contemplated counterterrorist moves given the complex tradeoffs that each such move typically entails.

Prevalence of white matter hyperintensities in a young healthy population.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are bright objects observed in the white matter on brain magnetic resonance (MR) imaging. WMHs are often reported as "normal" findings but may represent pathological changes. The prevalence of WMHs appears to increase with increasing age although both the typical timing and clinical significance of their appearance among medically and neurologically healthy persons remains unclear. We assessed the prevalence of WMHs in a cohort of younger healthy subjects. METHODS: Our study comprised 243 healthy subjects ages 16-65 years from our prospective normative MR imaging database. MR scans were rated for presence of periventricular and centrum semiovale WMHs using a four-point visual semi-quantitative scale. RESULTS: WMHs occurred in 5.3% (13 of 243) of subjects. All WMHs were small (rating of 0.5) except one subject age 65 years who had large WMHs (ratings of 2). The median age for subjects with no WMHs was 34.5 years compared to 57.0 years for subjects with WMHs. There were no gender differences (P= .76). Older age correlated with presence of WMHs (r = 0.24; P= .01). Age greater than 55 years had a 10-fold increase in the prevalence of WMHs compared to age < or =55 years (odds ratio = 10.01; 95% confidence interval = 3.1-32.3; P < .001). CONCLUSION: WMHs were uncommon in a younger healthy population screened for comorbid diseases, but increased 10-fold in subjects over 55 years of age. When present, the WMHs are generally small (rating of 0.5). While large WMHs appear to be associated with cognitive deterioration, the optimum threshold for identification, clinical significance, and prognostic value of smaller white matter changes requires further research.

Clinical rating of cortical atrophy and cognitive correlates following traumatic brain injury.

We report on the utility of using a rapid, easy-to-use, visually based semi-quantitative neuroimaging atrophy rating scale in individuals with traumatic brain injury (TBI) and normal control subjects. Magnetic resonance (MR) scans were rated using a standardized semi-quantitative MR rating method. A four-point scale was used to rate each scan for atrophy in frontal, temporal, and parietal areas. Seventy-five TBI subjects (50 males, 25 females) and 75 age- and gender-matched control subjects were compared for atrophy ratings. Clinical atrophy ratings were also compared to a quantitative measure of atrophy, the ventricle-to-brain ratio, and with the TBI subjects' scores on standard neuropsychological tests. TBI patients had significantly higher clinical atrophy ratings in frontal and temporal lobe areas compared to controls. The clinical atrophy ratings significantly correlated with the ventricle-to-brain ratio, a quantitative measure of atrophy in the same TBI subjects. Higher clinical ratings of frontal and temporal atrophy correlated with deficits in memory and executive function. These findings indicate that clinical ratings of trauma-induced atrophy can be reliably performed and are associated with neuropsychological outcome and quantitative measures of cerebral atrophy.

Role of white matter lesions, cerebral atrophy, and APOE on cognition in older persons with and without dementia: the Cache County, Utah, study of memory and aging.

Neuropsychological, qualitative, and quantitative magnetic resonance imaging findings were examined in subjects with Alzheimer's disease (AD), non-AD dementia or mixed neuropsychiatric disorder, subjects characterized as mild/ambiguous, and controls, all with known apolipoprotein E (APOE) genotype. Neuropsychological tasks included an expanded Consortium to Establish a Registery for Alzheimer's Disease (J. T. Tschanz et al., 2000; K. A. Welsh, J. M. Hoffman, N. L. Earl, & M. W. Hanson 1994) battery and the Mini-Mental Status Examination (M. F. Folstein, S. E. Folstein, & P. R. McHugh, 1975). Periventricular white matter lesions were the most clinically salient, and generalized measures of cerebral atrophy were the most significant quantitative indicators. APOE genotype was unrelated to imaging or neuropsychological performance. Neuropsychological relationships with neuroimaging findings depend on the qualitative or quantitative method used.

White matter lesions, quantitative magnetic resonance imaging, and dementia.

The authors performed quantitative and qualitative image analysis on a sample of the elderly population of Cache County, Utah, relating neuroimaging findings to Mini-Mental Status Examination (MMSE) scores and the presence of the apolipoprotein E epsilon4 allele. Neuroimaging measures included white, gray, and hippocampal volumes; a ventricle-to-brain ratio (VBR); and qualitative ratings of white matter lesions (WMLs) in the periventricular (PV) and centrum semiovale (CS) regions. Subjects included 85 persons with possible and probable Alzheimer disease (AD), 21 with vascular dementia (VaD), 30 with cognitive symptoms classified as mild/ambiguous (M/A), a heterogenous group of 39 non-AD or VaD subjects but diagnosed with some form of neuropsychiatric disorder ("Mixed Neuropsychiatric" group), and 20 normal control subjects aged 65 years or older. Controlling for age, sex, and length of disease, the authors found that AD and VaD subjects differed significantly from control subjects on WMLs, but only the VaD subjects significantly differed from M/A subjects. The two dementia groups also displayed, as expected, significant cerebral atrophy. The WMLs generally increased with age and severity of dementia. PV WMLs were significantly but only modestly associated with white matter volume loss and greater impairment on the MMSE. Modest correlations were also present between the quantitative measures of cerebral structure and MMSE performance. However, when degree of cerebral atrophy was controlled by using the VBR measure, WML effects on MMSE performance became nonsignificant, with the only significant relationship remaining being that between hippocampal volume and MMSE performance. There were no significant qualitative or quantitative findings related to presence of the epsilon4 allele and MMSE performance. The role of WMLs in aging and dementia is discussed.