Neurological Soft Signs as Early Psychosis Predictors

1. Neurological Soft Signs as Early Psychosis Predictors Alison Carr Neuropsychology Spring 2007

2. Neurological Soft Signs �[�]non-normative performance on a motor or sensory test; [�] the individual shows abnormalities, but none of the features of a fixed localizable neurological disorder. Bender, Fink, and Green (1947) If an individual has an obvious pathological lesion anywhere in their brain, this was referred to as �hard,� or definite. In contrast, the term Neurological �SOFT� signs is used to describe deficits that cannot be explained by such an obvious lesion. Basically, these are best described as nonspecific �Neurological Exam Abnormalities.� To qualify as a soft sign, there cannot be any association between the observed behavioral abnormalities and any history of neurological disease or trauma There are 100+ neurological soft signs which have been identified (Spreen et al, 1983) Bender L, Fink N, Green M: Childhood schizophrenia: clinical study of 100 schizophrenic children. Am J Orthopsychiatry 1947; 17:40�56 These individuals found NSS in childhood scizophrenics; symptoms progressed as the course of the disease progressed. What is important to note, that although we have been studying Neurological soft signs for 60 years now, we don�t understand them very well. It has yet to be concretely established as to whether neurological soft signs result from specific or diffuse brain structure abnormalities, or even whether they are a cause or effect of psychological disorder. If an individual has an obvious pathological lesion anywhere in their brain, this was referred to as �hard,� or definite. In contrast, the term Neurological �SOFT� signs is used to describe deficits that cannot be explained by such an obvious lesion. Basically, these are best described as nonspecific �Neurological Exam Abnormalities.� To qualify as a soft sign, there cannot be any association between the observed behavioral abnormalities and any history of neurological disease or trauma There are 100+ neurological soft signs which have been identified (Spreen et al, 1983) Bender L, Fink N, Green M: Childhood schizophrenia: clinical study of 100 schizophrenic children. Am J Orthopsychiatry 1947; 17:40�56 These individuals found NSS in childhood scizophrenics; symptoms progressed as the course of the disease progressed. What is important to note, that although we have been studying Neurological soft signs for 60 years now, we don�t understand them very well. It has yet to be concretely established as to whether neurological soft signs result from specific or diffuse brain structure abnormalities, or even whether they are a cause or effect of psychological disorder.

3. Physiological Reasons for NSS Dazzan et al. (2004) One of the FIRST studies looking at the actual brain occurrences in patients with NSS. Dazzaan, Morgan, Orr, Hutchinson, Chitnis, Suckling, Fearon, Salvo, McGuire, Mallett, Jones, Leff, and Murray found that (by studying 77 first episode psychotics, that higher rates of NSS are associated with a reduction of grey matter within the subcortical structures (namely the putamen, globus pallidus, and thalamus). Higher levels of sensory integration were strongly associated with a volume reduction within the precentral, superior, and middle temporal lobes, as well as lingual gyri. MOST IMPORATNLY, NSS and their associated brain structure changes were independent of level of exposure to neuroleptics. One of the FIRST studies looking at the actual brain occurrences in patients with NSS. Dazzaan, Morgan, Orr, Hutchinson, Chitnis, Suckling, Fearon, Salvo, McGuire, Mallett, Jones, Leff, and Murray found that (by studying 77 first episode psychotics, that higher rates of NSS are associated with a reduction of grey matter within the subcortical structures (namely the putamen, globus pallidus, and thalamus). Higher levels of sensory integration were strongly associated with a volume reduction within the precentral, superior, and middle temporal lobes, as well as lingual gyri. MOST IMPORATNLY, NSS and their associated brain structure changes were independent of level of exposure to neuroleptics.

4. Measuring NSS Neurological Evaluation Scale (NES) (Buchanan and Hendrichs, March 1989)

5. NSS* Integrative sensory function deficits may be the result of Parietal Lobe dysfunction. These symptoms may include impaired integration of audio and visual sensory input, Agraphaesthesia, bilateral extinction, Astereognosis, and right-left confusion. Motor coordination deficits may include intention tremors, finger-thumb opposition, randem alk, rapid alternating movements, rhythmic tapping, and an inability to successfully complete the finger-nose test. Motor sequencing deficits are theorized to stem from frontal lobe deficits, namely coming from abnormalities in the basal ganglia circuitry. These symptoms may include an inability to engage in repetitive hand tasks, Integrative sensory function deficits may be the result of Parietal Lobe dysfunction. These symptoms may include impaired integration of audio and visual sensory input, Agraphaesthesia, bilateral extinction, Astereognosis, and right-left confusion. Motor coordination deficits may include intention tremors, finger-thumb opposition, randem alk, rapid alternating movements, rhythmic tapping, and an inability to successfully complete the finger-nose test. Motor sequencing deficits are theorized to stem from frontal lobe deficits, namely coming from abnormalities in the basal ganglia circuitry. These symptoms may include an inability to engage in repetitive hand tasks,

6. MRI in NSS patients Dazzaan et al., 2004 This is an MRI of NSS patients. In the upper slide, you can see grey matter deficits highlighted in blue. In the lower slide, you can see grey matter excess. These two changes were present in patients showing high motor coordination deficits.This is an MRI of NSS patients. In the upper slide, you can see grey matter deficits highlighted in blue. In the lower slide, you can see grey matter excess. These two changes were present in patients showing high motor coordination deficits.

7. MRI in NSS patients Dazzaan et al., 2004 In this slide, we see grey matter deficits highlighted in blue. These deficits were present in patients who scored high for sensory integration NSS signs.In this slide, we see grey matter deficits highlighted in blue. These deficits were present in patients who scored high for sensory integration NSS signs.

8. MRI in NSS patients Dazzaan et al., 2004 Finally here, we see excess white matter, present in individuals scoring high for sensory integration NSS symptoms.Finally here, we see excess white matter, present in individuals scoring high for sensory integration NSS symptoms.

9. NSS in the Normative Population Kinney et al., 1986 Ardilla and Roselli, 1996 Individual occurrence rates of NSS are lower in the average population than in the psychologically impaired population. Individual occurrence rates of NSS are lower in the average population than in the psychologically impaired population.

10. Cause or Effect? If NSS are a cause� If NSS are an effect� A big question was, when do Neurological Soft Signs appear? The first possibility is that they are a comorbid or even precursor disorder to schizophrenia, a consequence of the degenerative process that occurs in schizophrenic patients, or if it is the result of long term pharmacological treatment A big question was, when do Neurological Soft Signs appear? The first possibility is that they are a comorbid or even precursor disorder to schizophrenia, a consequence of the degenerative process that occurs in schizophrenic patients, or if it is the result of long term pharmacological treatment

11. Why Schizophrenia? Schizophrenia is a debilitating and Schizophrenia is a debilitating and

12. NSS = Cause Studies looking at NSS in first-episode psychosis patients Scottish Schizophrenia Research Group, 1987 Browne et al, 2000 Scottish = 20%, used the Northwick Park Brief Neurological Assessment Browne=97.1% used the more validated scales (Neurological Evaluation Scale and Condensed Neurological Examination)Scottish = 20%, used the Northwick Park Brief Neurological Assessment Browne=97.1% used the more validated scales (Neurological Evaluation Scale and Condensed Neurological Examination)

13. NSS = Result Gupta et al., 1995 King et al., 1991 Smith et al., 1999 Neuroleptic drugs include Gupta, Andreasen, Arndt, Flaum, Schultz, Hubbard, and Smith looked at the differences in NSS in subjects; 1/3 normative, 1/3 schizophrenics who have not been administered neuroleptics, and 1/3 who have been prescribed long term neuroleptics. Soft signs were present in 4% of the normative population, 23% of neuroleptic na�ve patients, 46% of medicated patients King, et al. did an in depth longitudinal study of patients as they progressed with their psychological treatment. There was a significant difference between neuroleptic na�ve patients and patients who received long term neuroleptics; the conclusion drawn was that neuroleptics may contribute to NSS, but NSS are NOT simply a side effect. Smith, Hussain, Chowdhury, and Stearns did a longitudinal study of chronically hospitalized patients with schizophrenia.They found that NSS scores were stable over time, and found no change even in patients who were being treated with neurolepticsNeuroleptic drugs include Gupta, Andreasen, Arndt, Flaum, Schultz, Hubbard, and Smith looked at the differences in NSS in subjects; 1/3 normative, 1/3 schizophrenics who have not been administered neuroleptics, and 1/3 who have been prescribed long term neuroleptics. Soft signs were present in 4% of the normative population, 23% of neuroleptic na�ve patients, 46% of medicated patients King, et al. did an in depth longitudinal study of patients as they progressed with their psychological treatment. There was a significant difference between neuroleptic na�ve patients and patients who received long term neuroleptics; the conclusion drawn was that neuroleptics may contribute to NSS, but NSS are NOT simply a side effect. Smith, Hussain, Chowdhury, and Stearns did a longitudinal study of chronically hospitalized patients with schizophrenia.They found that NSS scores were stable over time, and found no change even in patients who were being treated with neuroleptics

14. NSS in Patients with Mental Disorder Flyckt et al. (1999) Rochford et al. (1970) Flyckt- compared first episode schizophrenics, chronic schizophrenics, and normative individuals. Found no difference between chronic schizophrenics and first episode patients. These two groups were significantly different from the normative patient groups. Rochford- This 1970 study found that NSS rates were comparable in schizophrenic and in personality disorder patients Flyckt- compared first episode schizophrenics, chronic schizophrenics, and normative individuals. Found no difference between chronic schizophrenics and first episode patients. These two groups were significantly different from the normative patient groups. Rochford- This 1970 study found that NSS rates were comparable in schizophrenic and in personality disorder patients

15. NSS in Normative vs. Disordered Patients We have established that NSS are present in early disordered patients. What does this mean for patients at a high risk for developing psychosis? Fellick et al, 2001, found that 12% of presumably normal children show Neurological soft signs. Interesting to note is that this study also looked at children who had suffered from meningococcal disease in childhood; these children showed a 44% increase in Neurological soft signs, which will be discussed later. Cannon et al., 1999, found that there was a significant difference in both adolescent and adult schizophrenic patients, compared to their peers. These researchers also studied the incidence of NSS in normative versus �high risk� persons, and found a significantly higher Illowsky et al were studying NSS in early-onset schizophrenic patients. They did longitudinal studies of children, and found that while young children had some NSS, those individuals who were going to go on to develop early onset schizophrenia showed an increase in symptoms, whereas other children �grew out of them,� so to speak. We have established that NSS are present in early disordered patients. What does this mean for patients at a high risk for developing psychosis? Fellick et al, 2001, found that 12% of presumably normal children show Neurological soft signs. Interesting to note is that this study also looked at children who had suffered from meningococcal disease in childhood; these children showed a 44% increase in Neurological soft signs, which will be discussed later. Cannon et al., 1999, found that there was a significant difference in both adolescent and adult schizophrenic patients, compared to their peers. These researchers also studied the incidence of NSS in normative versus �high risk� persons, and found a significantly higher Illowsky et al were studying NSS in early-onset schizophrenic patients. They did longitudinal studies of children, and found that while young children had some NSS, those individuals who were going to go on to develop early onset schizophrenia showed an increase in symptoms, whereas other children �grew out of them,� so to speak.

16. NSS as a predictor? Simon et al. (2005) Semerci et al. (2004) Fellick et al. (2001) Simon AE; Roth B; Zmilacher S; Isler E; Umbricht D Developing services for the early detection of psychosis: a critical consideration of the current state of the art. A 2004 study by Semerci et al. Looked at NSS in children with Tourrette�s syndrome. This study found that 57.5% of all children and adolescents with Tourrette�s also displayed NSS and EEG abormalities As you may remember, the Fellick study from 2001, in addition to looking at normative populations, also looked at children who had suffered from meningococcal disease. They found that of students tested and were found to have persistent NSS, they scored 38% lower than peers on cognitive tasks, 42% lower on coordination tasks, and were 35% more likely to have attention deficit disorder. This study shows that perhaps NSS may be a result as well as an indicator of early brain damage.Simon AE; Roth B; Zmilacher S; Isler E; Umbricht D Developing services for the early detection of psychosis: a critical consideration of the current state of the art. A 2004 study by Semerci et al. Looked at NSS in children with Tourrette�s syndrome. This study found that 57.5% of all children and adolescents with Tourrette�s also displayed NSS and EEG abormalities As you may remember, the Fellick study from 2001, in addition to looking at normative populations, also looked at children who had suffered from meningococcal disease. They found that of students tested and were found to have persistent NSS, they scored 38% lower than peers on cognitive tasks, 42% lower on coordination tasks, and were 35% more likely to have attention deficit disorder. This study shows that perhaps NSS may be a result as well as an indicator of early brain damage.

17. Conclusion Where research is now Future NSS research We are at a crossroads for NSS research. Clearly they are strongly connected with many mental disorders, from meningococcal disease to schizophrenia. We have not been able to firmly establish whether NSS are a cause, a symptom, or a result of these disorders. Future research on NSS will likely be targeted at MRIs, particularly in high-risk patients. Hopefully this will make us able to give MRIs to future high-risk patients to establish their risk for schizophrenia. While we already have connected NSS with schizophrenia, it is not a concrete predictor. Hopefully MRIs will be able to reveal the source of the NSS, and as a result be a more reliable predictor.We are at a crossroads for NSS research. Clearly they are strongly connected with many mental disorders, from meningococcal disease to schizophrenia. We have not been able to firmly establish whether NSS are a cause, a symptom, or a result of these disorders. Future research on NSS will likely be targeted at MRIs, particularly in high-risk patients. Hopefully this will make us able to give MRIs to future high-risk patients to establish their risk for schizophrenia. While we already have connected NSS with schizophrenia, it is not a concrete predictor. Hopefully MRIs will be able to reveal the source of the NSS, and as a result be a more reliable predictor.