- Email: [email protected]
Abnormal corticolimbic circuitry in schizophrenia
2245
BIOL. PSYCHIATRY 1997;42:15-2975
In the &teady state SPEM particularly with low gain (e.g. Holzman et aI 1973). However, since the steady state SPEM Is Influenced by many factors. It is necessary to examine SPEM in the open-loop period (i.e. the period needed to generate SPEM without visual feedback). A step-rarT1l SPEM task is appropriate for this purpose, since It allows us to examine initial eye movement responses during the open loop period in addition to the steady state SPEM in a later period. Using the step-ramp SPEM task, we examined In the present study, peak eye velocity and acceleration in the open loop period of SPEM in schizophrenics, and compared the results with those in the antisaccade• and memory-guided saccade- tasks. We have also examined effects of antipsychotic drugs and dinlcal symptoms on the task performance In schizophrenics when they were not medicated and also when they received the same medication. Methods: SUbjects Included in this study were patients who fulfilled DSM-IIIR criteria for schizophrenia (ages 1841) and other patients with localized frontal lesions due to cerebral vascular accidents and age-matched normal controls. Subjects were seated In the dark with their head fixed in front of a screen. Eye movement was recorded using an infrared oculography. The antisaccade- and memolY-guided saccade- tasks were used as described previously. In the SPEM task, a target was presented by a laser beam in a step-ramp fashion at a speed of 10, 15 and 20 °ls with an amplitude of 100. Latency, peak eye velocity and peak eye acceleration during the open loop period (<120 ms of initial eye response) were measured together with average eye velocity during the steady state. Results: In both antisaccade- and memorylIuided saccade- tasks, schI• zophrenics as well as the frontal patients showed more errors to the reflexive target, longer latencies and lower peak eye velocities in initiating and per• forming correct saccades to the invisible target, although they showed normal results in the simple saccade task similar to our previous studies (Fukushima et aI. 1988. 1990). The frontal patients with lesions covering the FEF and prefrontal cortex showed significantly higher error rates In the antisaccade task compared to the age-matched controls; In the memory-gulded saccade task. they showed all errors. In the SPEM task, schizophrenics showed longer latencies and lower Initial peak eye velocities. They also showed lower peak eye acceleration In a late component of initial eye acceleration In addition to a decrease In average eye velocity i(l the steady state. The schizophrenics examined In the drug controlled study showed abnormalities repeatedly in the error rate In the antisaccade task and inillal peak velocity and acceleration in the open loop period of SPEM, while their latencies and the average eye velocities in the steady state improved In the SPEM task as their clinical symptoms imprOVed. The medication did not deteriorate any eye movement parameters in these patients. These results Indicate that schizophrenics as well as the frontal patients show abnormalities In suppression of reflexive saccades, initiation and execution of correct pur• poseful saccades. In addition, schizophrenics showed abnormalities In the Initiation and maintenance of SPEM. All together, these abnormalities can be explained by dysfunction of the frontal eye movement-related areas in schizophrenics.
183-21 Neurological soft-signs In schizophrenia M.O. Krebs. C. Spadone. J.M. Vanelle, J. Dischamps, H. Loa. J.P. Olie, M.F. Poirier. S·H-U. Hopital Sainte-Anne, 1 TUe Cabanls. Paris. France The currently prevalent hypothesis of schizophrenia being an heterogeneous syndrom has Increased the Interest for markers improving the character• ization of these patients. In this view, neurological symptoms have been recently pointed out as a possible marker of a subtype of schizophrenia Identified neurologic syndroms, as extra-pyramidal syndroms or more seldom cerebellar syndroms, are sometimes observed even In neuroleptic• naive schizophrenic patients, but more often are the neurological anomalies unspec~ic and qualified as "neurological soft signs' (NSS). This term des• Ignates various symptoms, generally regarded as evidence for non specific brain damage. Most of the studies of the literature bring consistent results about the frequence of NSS in schizophrenic patients and their relatives. However. the condition of evaluation (patients under treatment or not, neuroleptic naive patients). the population tested (gender. age, inclusion of schizoaffective disorders...) and the nature of the evaluated Items (gait and balance, motor coordination, developmentaJ reflexes. perceptive disorders...) vary in the different works and the preclse clinical slgn~icance of these symptoms remain unclear. Several authors have proposed scales evaluating these symptoms. How• ever. their current use by non-neurologlsts In schizophrenic patients remain difficult due to a lack of standardization, necessity of advanced training,
Physical and functional quantitative traits in schizophrenia
lack Of description of cotation level or long duration. Moreover. the possible Interference of treatments require a concomitant evaluation of extra-pyram;. daI symptoms. Finally. the distinct cotation of each side of the body could bring Interesting Informations, since asymetric cerebral dysfunction as been suggested In schizophrenia. We have elaborated a 15-20 minutes standardized examination leading to the assessment of a selection of Items Including gait and balance, rapid altemative movements, Iaterallzation, complex perceptive Integration. This scheduled examination also allow the reting of Abnormal Involuntary Movements scale (AIMS), Simpson and Angus' scale (adapted for distinct rating Of left and right side) and Bames Akathisia scale. In preliminary results, we found that neuroleptic-free schizophrenics (NFS, n • 17 Including 9 neuroleptic-naive patients) had significant higher scores than sax- and age-matched healthy volunteers (n .. 15): NFS: 19.7 ± 3.2 (mean ± sam) va controls: 7.26 ± 1, suggesting that neurological soft-Signs could be related to the disease Itself. However, treated schizophrenics (TS. n • 12) had significantly higher scores (TS: 31.8 ± 4.2) as compared to neuroleptic-free schizophrenics. These populations were comparable for gender and age (NFS: 33.1 ± 9; TS: 32.5 ± 7; C: 32.7 ± 4). Treated and untreated schizophrenics did not differ for age of onset and severity of symptomatology evaluated with PANSS, GAF and CGI. A slightly revised version of this scale Is currently evaluated on differ• ent psychiatric populations (schizophrenic and bipolar patients) and non psychiatric patients for validation. Results will be presented In the Oral communication. In our hands, this scale is an useful and convenient tool facilitating the neurological assessment of schizophrenic patients. A more systematic char• acterization Of neurological function of these patients In works studying cognitive, oculo-molor function or neuroimaglng in schizophrenia should, In tum, bring Interesting Informations about the dinical significance of neu• rological soft-signs and more generally should help to distingUish clinical subtypes of this disease.
183-31 anomalies Developmental stability and minor physical In schizophrenic patients R. Joober '.2. S. Abid ' , S. Ben Zineb 1, K. Tabbene ' , J. Taktak'. S. Doukl '. ' ~rtmsnt of Psychiatry, Faculte dB M9dsclT/6 dB Tunis, Tunis, Tunlsis, Douglas Hospital Rssearch Csnlre, McGill University, Montreal, Quebec, Canada
Minor Physical Anomalies (MPA) have been reported to be over represented In schizophrenic patients compared to normal control subjects. They have equally been reported to be more frequent In a myriad of other behavioral disorders like mental retardation, hyperactive, psychotic and autistic disor• ders. Although these anomalies are thought to reflect eariy disturbances In the development, their significance remains unknown. In this presentation we will discuss the potential signlflcance of MPA using the developmentai stability model. This model hypothesizes that the stability of the normal de• ployment of the developmental scheme Is, at least partially, under the control of genetic factors. It Is also thought that these genetic factors are related to the level of overall homozygoclty of the genome. To test this hypothesis, we are comparlng MPA and developmentel stability Indicators In schizophrenic patients: (1) born to first cousins. (2) bom to parents with no consangUinity and (3) In normal controls bom to first cousin parents. •
183-41 Abnormal cortlcollmbic circuitry In schizophrenia
F.M. Benes. McLsan Hospital and Harvard Medical School. Boston. MA USA •
It Is now believed that schizophrenia (SZ), Is not due to a typical degenerative process, but rather to a more subtle neurodevelopmental one that begins early In life and requires normal maturetlonal changes during adolescence to "trigger" lts onsel A variety of studies have suggested that a defect of GABAergic transmission may playa central role in SZ. Since this system interacts extensively with cortical dopamine (DA) projections. a ralative shift of OA Inputs from pyramidal neurons to GABA cells. even in the absence of any absolute changes of DA activity. could result In a significant alteration of the neural circuitry In corticolimblc regions such as clngulate cortex. A recent study has demonstrated thai normal development Involves a progressive increase until the start Of the early adult period In the degree to Which DA fibers form contacts with GABA neurons. Thus, a latent defect of GABAe 'c transmission could become manifest when a critical level of DA Inputsrg:s attained during adolescence. A model of this type also has Implications for
Melatonin: Clinical perspectives in psychiatric disorders
BIOI.. PSYCHIATRY
225S
1997:42:1$-297$
why SZ Is exacerbated by stress and why neuroleptic drugs can help to alleviate the effect of stress on patients willllllis disorder. Supported by NIMH grants MH00423, MH42261, MH31154 and awards from the Scottish Rite and the Stanley Foundation.
JMemoryoffunctions and schizophrenia: a specific Impairment?
[83-5
pattern
J.-M. Danian, P. Salama. IN5ERM U405, Department of Psychiatry. StrasboUrg. France
It Is now well that memory Impairments are a major aspect of the cognitive diSturbanCeS observed In patients with schizophrenia The magnitude of the memory deficit varies from one patient to another, some of them exhibiting a mar1
In: PsychophalTllllClOlogy, The Fourth
G_ratlon 01 Progress, F.E.
BIOOl11 and O.J. Kupfer (EdltOl'8). New York, Raven Press, pp. 1245-t257.
84. Melatonin: Clinical perspectives in psychiatric disorders
[!4- D Melatonin: From basic science to clinical application L Wetterberg. Department of Clinical Neuroscience. Section of Psychiatry. Karolinska Institute, 5·11281 Stockholm, Sweden The pineal hormone melatonin Is of great Interast for Its circadian regulation of a variety of physiological and neuroendoclme processes and specially regulation of the sleep-wake cycle In health and disease. The synthesis of melatonin and Its production at night Is controlled by a circadian clock within the hypothalamic suprachiasmatlc nucleus and Is synchronized by environmental fight. At the faU of dar1
own production of melatonin. e 9 postoperatively of pinealectomy or some patients on high doses of adrenergic beta-blockers suffers Insomnia and night mares and are often tired In daytime. For such patients sUpplementation with melatonin at night is a proper treatment. It may also be used In delayed-sleep-phase syndrome and as remedy In Jet lag. In some countries melatonin Is sold as a "dietary sUppiemenr, In other It is available only on doctors prescription and In still other countries only In controlled clinical trial. No one yet knows the possible long term risks and side effects of melatonln. A proper dose finding study is also lacking. The use of melatonin as a lay man therapeutic agent has Olrtpaced research on the fundamental physiological and phannaoological actions. The presentation will focus on some of the fundamental aspects of melatonin, Its genetic regulation, seasonal variation, control by light through the human eye and pharmacological aspects with the overall main aim to diagnose low melatonin patients. The production of the pineal hormone melatonin has been shown to be under genetic control (Wettertlerg et aI. 1983). In a further study melatonin has been examined in the night portion of urine In more than 300 apparentiy healthy Individuals for each month of the year under standardized conditions. The statistical analyses show a three component model fitted distribution of the total sample with the mean of urinary melatonin concentration of 0.15, 0.26 and 0.36 nmolesll. Patients with affective disorders, duodenal ulcer, alcoholisms showed melatonin values in the low component with statistically higher frequency. Further genetic analysis combining melatonln concentration with platelet monoamineoxiclase activity and post-dexamethasone suppression test of serum cortisol may be useful In the diagnosis of subgroups of depressed patients taking both the trait and state of the affective disease into considera• tion. The result of new sUbgroups of affective patients with different levels of melatonin will be discussed In light of melatonin as a mar1
order1 using platelet rnon:lSmlne oxidase activity, serum melatonin and post-dexam•
elllasoneeottlaol. Acta PsychiatrScand9131~1 13] Thakln B-E. Merkrld L, I
184-21 secretion and disorders
use of melatonin In circadian rhythm
Josephine Arendt, Debra Skene. University of Surrey, GUJldford, GU25XH, UK The pineal hormone melatonin appears to serve similar functions In all verte~rates. By Its pattem of secretion It conveys information about phase, duratlOA and strength of the daily photoperiod for the organisation of seasonal and circadian physiology. In humans melatonin, suitably timed, will phase shift the endogenous melatonin rtlythm and core body temperature. validated mar1
BIOL. PSYCHIATRY 1997;42:15-2975
In the &teady state SPEM particularly with low gain (e.g. Holzman et aI 1973). However, since the steady state SPEM Is Influenced by many factors. It is necessary to examine SPEM in the open-loop period (i.e. the period needed to generate SPEM without visual feedback). A step-rarT1l SPEM task is appropriate for this purpose, since It allows us to examine initial eye movement responses during the open loop period in addition to the steady state SPEM in a later period. Using the step-ramp SPEM task, we examined In the present study, peak eye velocity and acceleration in the open loop period of SPEM in schizophrenics, and compared the results with those in the antisaccade• and memory-guided saccade- tasks. We have also examined effects of antipsychotic drugs and dinlcal symptoms on the task performance In schizophrenics when they were not medicated and also when they received the same medication. Methods: SUbjects Included in this study were patients who fulfilled DSM-IIIR criteria for schizophrenia (ages 1841) and other patients with localized frontal lesions due to cerebral vascular accidents and age-matched normal controls. Subjects were seated In the dark with their head fixed in front of a screen. Eye movement was recorded using an infrared oculography. The antisaccade- and memolY-guided saccade- tasks were used as described previously. In the SPEM task, a target was presented by a laser beam in a step-ramp fashion at a speed of 10, 15 and 20 °ls with an amplitude of 100. Latency, peak eye velocity and peak eye acceleration during the open loop period (<120 ms of initial eye response) were measured together with average eye velocity during the steady state. Results: In both antisaccade- and memorylIuided saccade- tasks, schI• zophrenics as well as the frontal patients showed more errors to the reflexive target, longer latencies and lower peak eye velocities in initiating and per• forming correct saccades to the invisible target, although they showed normal results in the simple saccade task similar to our previous studies (Fukushima et aI. 1988. 1990). The frontal patients with lesions covering the FEF and prefrontal cortex showed significantly higher error rates In the antisaccade task compared to the age-matched controls; In the memory-gulded saccade task. they showed all errors. In the SPEM task, schizophrenics showed longer latencies and lower Initial peak eye velocities. They also showed lower peak eye acceleration In a late component of initial eye acceleration In addition to a decrease In average eye velocity i(l the steady state. The schizophrenics examined In the drug controlled study showed abnormalities repeatedly in the error rate In the antisaccade task and inillal peak velocity and acceleration in the open loop period of SPEM, while their latencies and the average eye velocities in the steady state improved In the SPEM task as their clinical symptoms imprOVed. The medication did not deteriorate any eye movement parameters in these patients. These results Indicate that schizophrenics as well as the frontal patients show abnormalities In suppression of reflexive saccades, initiation and execution of correct pur• poseful saccades. In addition, schizophrenics showed abnormalities In the Initiation and maintenance of SPEM. All together, these abnormalities can be explained by dysfunction of the frontal eye movement-related areas in schizophrenics.
183-21 Neurological soft-signs In schizophrenia M.O. Krebs. C. Spadone. J.M. Vanelle, J. Dischamps, H. Loa. J.P. Olie, M.F. Poirier. S·H-U. Hopital Sainte-Anne, 1 TUe Cabanls. Paris. France The currently prevalent hypothesis of schizophrenia being an heterogeneous syndrom has Increased the Interest for markers improving the character• ization of these patients. In this view, neurological symptoms have been recently pointed out as a possible marker of a subtype of schizophrenia Identified neurologic syndroms, as extra-pyramidal syndroms or more seldom cerebellar syndroms, are sometimes observed even In neuroleptic• naive schizophrenic patients, but more often are the neurological anomalies unspec~ic and qualified as "neurological soft signs' (NSS). This term des• Ignates various symptoms, generally regarded as evidence for non specific brain damage. Most of the studies of the literature bring consistent results about the frequence of NSS in schizophrenic patients and their relatives. However. the condition of evaluation (patients under treatment or not, neuroleptic naive patients). the population tested (gender. age, inclusion of schizoaffective disorders...) and the nature of the evaluated Items (gait and balance, motor coordination, developmentaJ reflexes. perceptive disorders...) vary in the different works and the preclse clinical slgn~icance of these symptoms remain unclear. Several authors have proposed scales evaluating these symptoms. How• ever. their current use by non-neurologlsts In schizophrenic patients remain difficult due to a lack of standardization, necessity of advanced training,
Physical and functional quantitative traits in schizophrenia
lack Of description of cotation level or long duration. Moreover. the possible Interference of treatments require a concomitant evaluation of extra-pyram;. daI symptoms. Finally. the distinct cotation of each side of the body could bring Interesting Informations, since asymetric cerebral dysfunction as been suggested In schizophrenia. We have elaborated a 15-20 minutes standardized examination leading to the assessment of a selection of Items Including gait and balance, rapid altemative movements, Iaterallzation, complex perceptive Integration. This scheduled examination also allow the reting of Abnormal Involuntary Movements scale (AIMS), Simpson and Angus' scale (adapted for distinct rating Of left and right side) and Bames Akathisia scale. In preliminary results, we found that neuroleptic-free schizophrenics (NFS, n • 17 Including 9 neuroleptic-naive patients) had significant higher scores than sax- and age-matched healthy volunteers (n .. 15): NFS: 19.7 ± 3.2 (mean ± sam) va controls: 7.26 ± 1, suggesting that neurological soft-Signs could be related to the disease Itself. However, treated schizophrenics (TS. n • 12) had significantly higher scores (TS: 31.8 ± 4.2) as compared to neuroleptic-free schizophrenics. These populations were comparable for gender and age (NFS: 33.1 ± 9; TS: 32.5 ± 7; C: 32.7 ± 4). Treated and untreated schizophrenics did not differ for age of onset and severity of symptomatology evaluated with PANSS, GAF and CGI. A slightly revised version of this scale Is currently evaluated on differ• ent psychiatric populations (schizophrenic and bipolar patients) and non psychiatric patients for validation. Results will be presented In the Oral communication. In our hands, this scale is an useful and convenient tool facilitating the neurological assessment of schizophrenic patients. A more systematic char• acterization Of neurological function of these patients In works studying cognitive, oculo-molor function or neuroimaglng in schizophrenia should, In tum, bring Interesting Informations about the dinical significance of neu• rological soft-signs and more generally should help to distingUish clinical subtypes of this disease.
183-31 anomalies Developmental stability and minor physical In schizophrenic patients R. Joober '.2. S. Abid ' , S. Ben Zineb 1, K. Tabbene ' , J. Taktak'. S. Doukl '. ' ~rtmsnt of Psychiatry, Faculte dB M9dsclT/6 dB Tunis, Tunis, Tunlsis, Douglas Hospital Rssearch Csnlre, McGill University, Montreal, Quebec, Canada
Minor Physical Anomalies (MPA) have been reported to be over represented In schizophrenic patients compared to normal control subjects. They have equally been reported to be more frequent In a myriad of other behavioral disorders like mental retardation, hyperactive, psychotic and autistic disor• ders. Although these anomalies are thought to reflect eariy disturbances In the development, their significance remains unknown. In this presentation we will discuss the potential signlflcance of MPA using the developmentai stability model. This model hypothesizes that the stability of the normal de• ployment of the developmental scheme Is, at least partially, under the control of genetic factors. It Is also thought that these genetic factors are related to the level of overall homozygoclty of the genome. To test this hypothesis, we are comparlng MPA and developmentel stability Indicators In schizophrenic patients: (1) born to first cousins. (2) bom to parents with no consangUinity and (3) In normal controls bom to first cousin parents. •
183-41 Abnormal cortlcollmbic circuitry In schizophrenia
F.M. Benes. McLsan Hospital and Harvard Medical School. Boston. MA USA •
It Is now believed that schizophrenia (SZ), Is not due to a typical degenerative process, but rather to a more subtle neurodevelopmental one that begins early In life and requires normal maturetlonal changes during adolescence to "trigger" lts onsel A variety of studies have suggested that a defect of GABAergic transmission may playa central role in SZ. Since this system interacts extensively with cortical dopamine (DA) projections. a ralative shift of OA Inputs from pyramidal neurons to GABA cells. even in the absence of any absolute changes of DA activity. could result In a significant alteration of the neural circuitry In corticolimblc regions such as clngulate cortex. A recent study has demonstrated thai normal development Involves a progressive increase until the start Of the early adult period In the degree to Which DA fibers form contacts with GABA neurons. Thus, a latent defect of GABAe 'c transmission could become manifest when a critical level of DA Inputsrg:s attained during adolescence. A model of this type also has Implications for
Melatonin: Clinical perspectives in psychiatric disorders
BIOI.. PSYCHIATRY
225S
1997:42:1$-297$
why SZ Is exacerbated by stress and why neuroleptic drugs can help to alleviate the effect of stress on patients willllllis disorder. Supported by NIMH grants MH00423, MH42261, MH31154 and awards from the Scottish Rite and the Stanley Foundation.
JMemoryoffunctions and schizophrenia: a specific Impairment?
[83-5
pattern
J.-M. Danian, P. Salama. IN5ERM U405, Department of Psychiatry. StrasboUrg. France
It Is now well that memory Impairments are a major aspect of the cognitive diSturbanCeS observed In patients with schizophrenia The magnitude of the memory deficit varies from one patient to another, some of them exhibiting a mar1
In: PsychophalTllllClOlogy, The Fourth
G_ratlon 01 Progress, F.E.
BIOOl11 and O.J. Kupfer (EdltOl'8). New York, Raven Press, pp. 1245-t257.
84. Melatonin: Clinical perspectives in psychiatric disorders
[!4- D Melatonin: From basic science to clinical application L Wetterberg. Department of Clinical Neuroscience. Section of Psychiatry. Karolinska Institute, 5·11281 Stockholm, Sweden The pineal hormone melatonin Is of great Interast for Its circadian regulation of a variety of physiological and neuroendoclme processes and specially regulation of the sleep-wake cycle In health and disease. The synthesis of melatonin and Its production at night Is controlled by a circadian clock within the hypothalamic suprachiasmatlc nucleus and Is synchronized by environmental fight. At the faU of dar1
own production of melatonin. e 9 postoperatively of pinealectomy or some patients on high doses of adrenergic beta-blockers suffers Insomnia and night mares and are often tired In daytime. For such patients sUpplementation with melatonin at night is a proper treatment. It may also be used In delayed-sleep-phase syndrome and as remedy In Jet lag. In some countries melatonin Is sold as a "dietary sUppiemenr, In other It is available only on doctors prescription and In still other countries only In controlled clinical trial. No one yet knows the possible long term risks and side effects of melatonln. A proper dose finding study is also lacking. The use of melatonin as a lay man therapeutic agent has Olrtpaced research on the fundamental physiological and phannaoological actions. The presentation will focus on some of the fundamental aspects of melatonin, Its genetic regulation, seasonal variation, control by light through the human eye and pharmacological aspects with the overall main aim to diagnose low melatonin patients. The production of the pineal hormone melatonin has been shown to be under genetic control (Wettertlerg et aI. 1983). In a further study melatonin has been examined in the night portion of urine In more than 300 apparentiy healthy Individuals for each month of the year under standardized conditions. The statistical analyses show a three component model fitted distribution of the total sample with the mean of urinary melatonin concentration of 0.15, 0.26 and 0.36 nmolesll. Patients with affective disorders, duodenal ulcer, alcoholisms showed melatonin values in the low component with statistically higher frequency. Further genetic analysis combining melatonln concentration with platelet monoamineoxiclase activity and post-dexamethasone suppression test of serum cortisol may be useful In the diagnosis of subgroups of depressed patients taking both the trait and state of the affective disease into considera• tion. The result of new sUbgroups of affective patients with different levels of melatonin will be discussed In light of melatonin as a mar1
order1 using platelet rnon:lSmlne oxidase activity, serum melatonin and post-dexam•
elllasoneeottlaol. Acta PsychiatrScand9131~1 13] Thakln B-E. Merkrld L, I
184-21 secretion and disorders
use of melatonin In circadian rhythm
Josephine Arendt, Debra Skene. University of Surrey, GUJldford, GU25XH, UK The pineal hormone melatonin appears to serve similar functions In all verte~rates. By Its pattem of secretion It conveys information about phase, duratlOA and strength of the daily photoperiod for the organisation of seasonal and circadian physiology. In humans melatonin, suitably timed, will phase shift the endogenous melatonin rtlythm and core body temperature. validated mar1