Negative symptoms: A review of schizophrenia, melancholic depression and Parkinson's disease

Negative symptoms generally refer to a reduction in normal functioning. In schizophrenia they encompass apathy, anhedonia, flat affect, avolition, social withdrawal and, on some accounts, psychomotor retardation. Negative symptoms have been identified in other psychiatric disorders, including melancholic depression, and also in neurological disorders, such Parkinson's disease. Achieving a better understanding of negative symptoms constitutes a priority in mental health. Primarily, negative symptoms represent an unrelenting, intractable and disabling feature for patients, often amounting to a severe burden on families, carers and the patients themselves. Identifying and understanding subgroups within disorders may also contribute to the clinical care and scientific understanding of the pathophysiology of these disorders. The purpose of this paper is to review the current literature on negative symptoms in schizophrenia and explore the idea that negative symptoms may play an important role not only in other psychiatric disorders such as melancholic depression, but also in neurological disorders, such as Parkinson's disease. In each disorder negative symptoms manifest with similar motor and cognitive impairments and are associated with comparable neuropathological and biochemical findings, possibly reflecting analogous impairments in the functioning of frontostriatal-limbic circuits.     

Negative symptoms, depression and Alzheimer's disease

OBJECTIVES: To apply the negative symptoms (NS) concept used in schizophrenia to patients with AD, to compare the results with the frontal lobe perfusion in ethyl cysteinate dimmer (ECD) single-photon emission computed tomography (SPECT) and with the apolipoprotein E genotype. METHOD: 32 patients with a diagnosis of probable AD were assessed by the Positive and Negative Symptoms Scale (PANSS-N), the Montgomery and Asberg Depression Scale (MADRS), the NeuroPsychiatric Inventory (NPI), and the Mini-Mental Status Examination (MMSE). Each patient underwent ECD SPECT and APO E genotyping. PANSS-N, MADRS, NPI, and MMSE were administered to 19 normal elderly control subjects. RESULTS: The mean PANSS-N score for AD patients (20.56, SD: 8, range: 7-40) was significantly higher (p < 0.001) than that of controls (7, SD: 0). MADRS scores were not significantly different (p = 0.75) between AD patients (9.03, SD: 6.14, range: 0-25) and controls (6.2, SD: 3.61, range: 1-15). The NPI apathy score (0-12) was correlated with PANSS-N (p < 0.001). Correlation between prominent frontal hypoperfusion (six cases) and NS was at the limit of significance. No relation was found between epsilon E4 and NS. CONCLUSION: This consideration is important in distinguishing between depression and AD.     

A multivariate exploration of basic symptoms

Little is known about the relationship between the different categories of basic symptoms (BS). Researchers of the Bonn School have accurately described the progression from second-level BS (relatively characteristic BS) to first-rank Schneiderian symptoms. Using a multiple regression model, the present study tried to investigate which kind of dynamic deficiencies (DDs; uncharacteristic first-level BS) mostly lead to each type of second-level BS. A group of 108 patients with a DSM-III-R diagnosis of schizophrenia completed an inventory on BS, with all items in strict accordance with those of the Bonn Scale. Five dependent variables (cognitive thought disorders, cognitive perception disorders, cognitive action disorders, increased impressionability, cenesthesias) and four independent variables (DDs with direct negative symptoms, DDs with indirect negative symptoms, affective DDs, relational DDs) were considered. Among the significant findings, a widespread contribution of DDs with indirect negative symptoms to most of the dependent variables, and the special role of DDs with direct negative symptoms as a predictor of cognitive thought disorders, must be emphasized. Suggestions for further multivariate studies in the field of BS are presented.     

Negative symptoms: future developments of the concept

The concept of negative symptoms has become increasingly important since it was reintroduced into psychiatric thinking several years ago. As the possible significance of negative symptoms has become clarified, the complexity of this concept has also become apparent. In dealing with this complexity, major progress has been made in describing negative symptoms more reliably and in taking steps toward identifying possible biological correlates. But two other particularly important directions also need to be pursued. First, psychosocial factors need to be explored further both in terms of their etiological contributions to negative symptoms and in the way these symptoms influence psychosocial aspects of the evolution of disorder and recovery. Secondly, more attention must be focused on the potential that negative symptoms have for providing an understanding of the interface between biological, psychological, and social processes in psychiatric disorder. In these ways the study of negative symptoms may contribute major clues to the nature of psychopathology, its etiologies, and its course.     

Negative symptoms: the 'pathology' of motivation and goal-directed behaviour

In many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia, symptoms are present that appear to reflect an essential absence of normal movement, cognition and emotional states. These negative symptoms might reflect fundamental impairments in basic brain mechanisms that underlie goal-directed behaviour. Knowledge of the pathology and pathophysiology of these diseases, combined with evidence from basic science, offers opportunities for understanding the neurobiological basis of goal-directed behaviour, particularly the interaction between limbic structures and striato-thalamo-cortical circuits. The study of patients with negative symptoms also provides opportunities for testing cognitive models of goal-directed behaviour, and eventually to map such models onto the neurobiology of both normal and abnormal behaviour.     

Needle electromyography: basic concepts and patterns of abnormalities

Needle electromyography (EMG) records electrical signals generated from muscle fibers and interprets the signals to characterize underlying pathologic changes that are occurring in motor units within muscles. Different types of spontaneously firing waveforms and motor unit potential changes occur with different neuromuscular disorders. The performance of reliable EMG studies depends on the technical skills of the physician in inserting, moving, recording with a needle electrode, and analyzing electric signals recorded from muscle. This article reviews the technique of needle EMG and recognition and interpretation of various EMG waveforms. The author presents several demonstrative videos at www.neurologic.theclinics.com.     

First rank symptoms: concepts and diagnostic utility

First Rank Symptoms (FRS) were first defined by Schneider as diagnostic of schizophrenia. Since then, there has been an immense debate on their diagnostic and prognostic utility. This review attempts to understand the concepts of FRS as depicted over the years and the diagnostic and prognostic implications of FRS in mental illnesses including schizophrenia. Review of relevant material showed that there are wide variations in the concepts of FRS which may be classified according to broad and narrow definitions. These variations have also led to the differences in the diagnostic systems currently being used. Although the diagnostic utility of FRS in schizophrenia remains, it is not clearly so with other mental illnesses in which these symptoms may also be observed. In addition there is controversy over the prognostic implications with evidence divided between poor and no influence on outcome.     

Nerve conduction studies: basic concepts and patterns of abnormalities

As a fundamental component of the electrodiagnostic evaluation, nerve conduction studies provide valuable quantitative and qualitative insights into neuromuscular function. Nerve conduction studies are useful in the identification and characterization of several neuromuscular disorders, particularly disorders of peripheral nerve. Abnormalities of nerve conduction studies may anticipate specific pathologic processes, such as demyelination or axonal loss, and may provide precise localization of focal nerve lesions. As with other elements of the electrodiagnostic evaluation, nerve conduction studies must be performed with careful attention to technique and must be interpreted in a clinical context.     

Rett syndrome: the state of clinical and basic research, and future perspectives

To clarify the pathophysiology of brain and spinal cord impairment in Rett syndrome (RTT), we report on the current status of research on Rett syndrome and review the abnormalities reported in neurotransmitters, neuromodulators and other biological markers in patients with RTT. We have previously investigated the levels of various factors in the blood, plasma, and cerebrospinal fluid (CSF) of RTT patients, including biogenic amines, lactate, melatonin, pyruvate and other citric acid cycle intermediates, substance P, β-endorphin and other neuropeptides, and a neuromodulator of β-phenylethylamine. In addition, we have performed near-infrared spectroscopy of the cerebral cortices in patients with RTT and genetic studies of the methyl-CpG-binding protein 2 (MECP2) in these patients. Taken together, the multiple abnormalities we and other authors have revealed in the various neurotransmitters/neuromodulator systems explain the pervasive effects of Rett syndrome. We also discuss the possible role of plasma ghrelin and present the results of our mouse study of the MECP2-null mutation using ES cells. Finally, we consider the potential for future analyses using our recently developed iPS cell system and discuss the future perspectives for the treatment and management of this disease.     

Animal models of behavioral dysfunctions: basic concepts and classifications, and an evaluation strategy

In behavioral neurosciences, such as neurobiology and biopsychology, animal models make it possible to investigate brain-behavior relations, with the aim of gaining insight into normal and abnormal human behavior and its underlying neuronal and neuroendocrinological processes. Different types of animal models of behavioral dysfunctions are reviewed in this article. In order to determine the precise criteria that an animal model should fulfill, experts from different fields must define the desired characteristics of that model at the neuropathologic and behavioral level. The list of characteristics depends on the purpose of the model. The phenotype-abnormal behavior or behavioral dysfunctions-has to be translated into testable measures in animal experiments. It is essential to standardize rearing, housing, and testing conditions, and to evaluate the reliability, validity (primarily predictive and construct validity), and biological or clinical relevance of putative animal models of human behavioral dysfunctions. This evaluation, guided by a systematic strategy, is central to the development of a model. The necessity of animal models and the responsible use of animals in research are discussed briefly.     

Self-centrality, basic symptoms model and psychopathology in schizophrenia

The study's aim was to empirically derive the psychopathological constellation associated with self-centrality (i.e. non-delusional self-referential attitude) by seeking an interpretation in the light of the 'Basic Symptoms Model' of schizophrenic psychopathology. Eighty-four patients with an established schizophrenic illness receiving maintenance treatment at the Psychiatry Section of the Parma University Neuroscience Department were examined. The Scales for the Assessment of Positive and Negative Symptoms, the Calgary Depression Scale and the Toronto Alexithymia Scale were administered to all subjects to determine levels of positive, disorganized, negative and depressive symptoms, as well as alexithymia. Subjective experiences, including non-delusional self-centrality, were explored by means of the Bonn Scale for the Assessment of Basic Symptoms. Logistic regression detected three different psychopathological domains (delusional, alexithymic, and basic body symptoms) strongly associated with self-centrality. Among these the most influential independent variable was basic body symptoms. These results suggest that impaired lived body experience (i.e. protopathic body disattunement) is a psychopathologic condition concomitant with the emergence of autocentric polarization of experience (i.e. self-centrality).     

Negative symptoms,cognitive dysfunction,tardive akathisia and tardive dvskinesia

This study examined the relationship of neuropsychological deficits and negative symptoms with tardive akathisia in chronic schizophrenic patients. Consecutive volunteers (n= 100) were recruited from Community Health Centres with a DSM-III-R diagnosis of schizophrenic disorder, chronic and on stable medication. Subjects were subgrouped into tardive akathisia (TA), tardive dyskinesia (TD) and control groups using four sets of criteria. Detailed single examinations were performed using the following measures: sociodemographic, illness-related and treatment-related variables, Negative Symptom Rating Scale (NSRS), Abnormal Involuntary Movement Scale (AIMS), Rating Scale for Extrapyramidal Side-Effects (EPSE), Akathisia Rating Scale, Barnes Akathisia Rating Scale, and a brief neuropsychological test battery. Group comparisons and logistic regression analyses were performed in order to test the significance of findings. TA ratings showed a significant association with NSRS subscale scores, and with some neuropsychological test scores (Symbol Digits Modalities Test, and to a lesser extent Trail Making Test and Finger Tapping Test). TD scores showed a consistent association with age, and a less consistent association with gender, and their association with NSRS subscale scores and neuropsychological dysfunction was positive but less significant. Higher EPSE scores predicted TA and limb-truncal (LT) dyskinesia. In conclusion, TA showed a more significant association with some clinical indices of organic brain dysfunction than the oral-lingual-buccal-facial dyskinetic syndrome. Prospective studies are necessary to determine whether organicity is a vulnerability factor for TA. Both our data and the published literature suggest that the movement disorder seen in TA and TD is but one feature of complex syndromes that include motor and cognitive features.     

Duration of untreated negative symptoms and duration of active negative symptoms: proof of concepts

Aim: Negative symptoms are responsible for enormous burden in schizophrenia; yet they remain under‐recognized and under‐treated. There is mounting evidence that early intervention is crucial and that response to treatment falls away with chronicity. Current measures of illness duration fail to adequately capture the true time course of negative symptoms and new concepts are required to correct this and to focus clinical attention. The aim of this paper is to introduce accurate measures of negative symptom duration. Methods: Two new concepts, the duration of untreated negative symptoms (DUNS) and the duration of active negative symptoms (DANS), were trialled in a first‐episode sample with primary negative symptoms. Results: The new measures were easy to calculate and more accurately reflected the total duration of negative symptoms than currently available measures. The mean duration of untreated psychosis was 23 weeks, whereas the DUNS was 93.79 weeks. Conclusions: Applicability of the concepts needs confirming by replication with a larger cohort. Introduction of these concepts may have widespread implications for the timely and efficient treatment of negative symptoms and the reduction of the total burden of illness of schizophrenia within society.     

Mental state examination: the elicitation of symptoms

The general rules for elicitation of symptoms during the Mental State Examination (MSE) are not usually emphasized during the training of mental health professionals. This paper discusses principles which can be used to elicit and establish symptoms. The issues include the gold standard, demarcation of abnormalities, screening and confirmation, changes in population characteristics, prevalence and predictive values. The Bayesian framework is elaborated. The principles of elicitation should be emphasised during the training so that trainees have a more rational basis for the use of the MSE.