Keys: Affective Bipolar Disorders

This paper reports the neurofunctional findings in a cohort of 44 patients with a diagnosis of affective bipolar disorder divided in two groups one of early onset and the other, of late onset of  disease. The emphasis of this study concentrates on finding neuro-functional markers of the clinical condition of bipolar disease.

  Lately reports of International Diagnostic Classification Systems have emphasized, for better understanding of  Unipolar and Bipolar affective disorders, that these are two different clinical entities in their clinical presentation and also in evolution. This diagnostic perspective has demonstrated its validity in different studies that have been replicated and that are essential at the time of defining therapeutic strategies.

Epidemiology

Bipolar Affective Disorder is present in all cultures and races with a similar prevalence of 1.6% [23]. However, studies that considered all the range of bipolar spectrum, report a lifetime prevalence fluctuating between 3.7% and 6% [19]. On the other hand, the female/male affected ratio varies from 1.3 to 2.1 respectively. Although bipolar disorder can develop at any age, the peak period of onset is between the ages of 15 and 19 years. More interesting, 59% of a studied sample experienced their first bipolar symptoms during childhood or adolescence [8, 25].

Clinical Manifestations

Bipolar affective disorder is defined as a group of diseases with a common factor of one manic or hypomanic episode during its evolution and episodes of opposite affective polarity. Therefore, the classical description of Falret and Kraepelin recognizes the presence of clinical differences in depression, mania, hypomania, mixed phases and asymptomatic interphases of remission.

DSM-IV describes 4 types of Bipolar Affective Disorders:

Bipolar Affective Disorder I

Corresponds to the classically described disease of manic-depressive psychosis. The characteristic is at least one manic episode associated or not associated to episodes of hypomania, depression or mixed phases. Mania is defined as a psychopathological state characterized by 3 central elements: Pathologically elevated mood, increased motor activity and grandiosity ideas. Parallel to these, it is frequent to observe acceleration in the speed of speech and thoughts, loss of subtle clues that are necessary for social interaction, increased sexual arousal, hyperphagia, insomnia and psychotic manifestations. From the affective point of view it is also possible to observe irritability and rage following minimal stimulation. Two characteristics of importance in the majority of manic episodes is the loss of insight and impairment of social and labour relations. This situation implies serious consequences to the patient and its environment.

Bipolar Affective Disorder II

Describes the group of patients that present major recidivant depressive episodes alternating with hypomanic phases of at least 4 days duration.  By definition, Bipolar Affective Disorders II do not present periods of mania nor mixed phases. The concept of hypomania refers to a phase characterized by pathologically elevated mood of minor to moderate intensity, increase of energy and physical activity and optimistic mood not frequently seen in the patient. During the episode of hypomania there is preservation of insight without an impairment of social or labour performance [18].

Ciclotimic Disorders

It refers to a group of patients that present cyclical variations of mood characterized by numerous periods of hypomanic symptoms of less than 4 days duration, alternating with periods of depressive symptoms that are not severe enough to constitute a major depressive episode [3]. The first descriptions by Kraepelin considered ciclotimia as a form of temperament that predisposed patients to frequent fluctuations of their psychic state.

Non specified Bipolar Affective Disorders

Includes abnormalities characteristic of bipolar disorders that do not comply strictly with criteria defined by the 3 types of bipolar disorders previously described.

Recent development in molecular genetics, in particular linkage studies, offered possibilities of identification of the gene associated with the ethiopathology of bipolarity. This possibility has not materialized. However, in spite of the previous statement there is reliable information stating that there are genetic links basis for this disorder. This evidence originates in family studies, adoption studies and findings in mono and dizygotic twins. Family members in first degree of relationship with bipolar patients have an 8% probability of developing Bipolar Affective Disorders and concordance of monozygotes versus dizygotes is 61% vs a 23% respectively. There is, however, lack of a mathematical inheritance model that explains the distribution of Bipolar Affective Disorders in the numerous families studied. However, linkage studies have not been able to demonstrate chromosomic locations that can be associated in a reproducible way with Bipolar Affective Disorders. The following are chromosomic locations with contradictory linkage types: Xq28, 11p15, 18p, 18q, Xq27, 5q35, 21q22, 12q23, 16p13 and 4p16. [22, 33, 5, 1, 7, 31].

Neurochemical and neuroendocrine factors of bipolar affective disorders.

All research reports in bipolar disorders suggest that the physiopathology of this disease could be extraordinarily complex and dependent on multiple interactions of neurochemical and/or neuroendocrinological nature. The great symptomatic variability of pathology has rendered the etiopathogenic study difficult. More than 90% of biological signs that have been replicated correspond to status markers (signs that are detectable only during symptomatic episodes).

A more detailed description of research findings and etiopathogenical hypothesis in bipolar disorder are beyond the objectives of this paper. However, we will mention only the biological systems that are more frequently involved.  (Table I) [1, 37].

Table I. 
Neurochemical and endocrine changes associated to the
physiopathology of Bipolar Affective Disorders

Involvement of neurological circuitry

There is little direct evidence in relation to the neurofunctional impairment that is responsible for the pathogenic changes of ABD. However, there is a series of theoretical models designed on the basis of clinical and experimental findings that allow the hypothesis that there are neurocircuitry probably involved in this disorder. The most current model related to the neuro-biology of affectivity was defined by Cummings in 1993 and consists of a series of cortical and subcortical structures with highlighted participation of the prefrontal cortex, striatum and thalamus (figure 1) [12]. Detailed descriptive studies have demonstrated psychopathological changes that are induced by selective lesions of the different components of the general affectivity circuitry (Table II). In these structures most probably we will find the functional substratum of bipolarity and F. Varela, neurobiologist, has defined the most probable mechanism of affective phenomena. His hypothesis is widely known as the “neuronal synchronicity and large-scale integration” [36]. The central concept of his theory describes the functioning of mental phenomena as non-directional processes that have been described as “emergent properties”. At any time affective phenomena would emerge starting with a simultaneous action of different neuronal circuits synchronized in a scale of milliseconds. And according to this theoretical model only the synchronic action of a series of neuro-anatomical-functional structures would determine the appearance of an affective moment. Therefore, an impairment or damage to one segment of an affective synchronic segment would determine a clinical picture with similar psychopathological characteristics.

Table II
Clinical correlation of neuro- anatomical selective impairment

NeuroSPECT findings in bipolar disorder

Research studies that address homogeneous bipolar disorders population, report on similar findings. These papers report on at least two coincidental concepts: 1) Abnormalities of Tc99m HMPAO uptake in frontal cortex, subgenual region, anterior cingulate gyrus and superior temporal gyrus and 2) NeuroSpect findings appear to be dependant on the dominant clinical features during the acquisition of NeuroSPECT and appear to be, therefore, markers of the Clinical State. The phases that have been evaluated correspond to depression or mania, without information on periods of eutimic mood. In table III we describe some of the findings reported and the imaging techniques that were used [28, 15, 32, 20, 9, 35].

Table III.
NeuroSPECT functional findings in BD

2) Define regions of interest (ROI) that present with statistically significant functional differences with respect to a normal control population.

3) To suggest the existence of neuro-anatomical structures involved in the physiopathology of bipolar disorder considering levels of macro-organizational circuitry in the brain.

Subjects

We studied a cohort of 44 patients with clinical diagnosis of ABD according to DSM IV criteria. We established the following inclusion criteria: absence of psychiatric comorbidity in axis I (Unipolar depression, schizophrenia, attentional deficit and organic states among others), absence of neurological comorbidity, evolution of a period of at least six months by a clinical psychiatrist and treatment with psychopharmacological drugs for a period shorter (less) than one year. The total cohort study consisted of two groups of 22 patients each differente only on the age of presentation. We distinguished a group of early onset (mean age = 15.1 years; distribution by sex 41% males, 59% females) and a second group of late onset (mean age = 38.4 years, distribution by sex 36% males, 64% females). There was no difference in the distribution by sex (p > 0.05). There was, however, a statistically significant difference in the distribution by age (p < 0.05). The patients studied corresponded clinically to bipolar disorder type I and II. Here, the clinical status of the patient at the moment of neuroSPECT was Eutimia, namely their animic state was preserved. Clinical analysis of this cohort was performed by two clinical psychiatrists. Quantitative imagenological analysis and also the data analysis were performed by two blinded investigators with respect to the identification of patients and its characteristics.

NeuroSPECT

Preparation of the Patient

Patient discontinued psychotropic medication at least 5 days before the performance of the NeuroSPECT test and 24 hours before, discontinued also consumption of tea, coffee, chocolate and cola beverages. Besides these limitations, the NeuroSPECT examination is performed under normal dietary conditions.

Contraindication of NeuroSPECT. Test can not be performed in pregnant women or in women suspected of the possibility of pregnancy.

TECHNIQUE

Injection of the radiopharmaceutical

30mCi of HMPAO Tc-99m (Ceretec Amersham) (1110 mBq) in basal conditions are injected intravenously with the patient in dorsal decubitus in a room with ambient noise and light under control, the patient has the eyes opened and the injection is performed into an antecubital vein that is cannulated 10 minutes before. The intravenous injection is given in an approximate volume of 2 ml. followed by a bolus of normal saline of 10 ml. 60 to 90 minutes after the injection, the NeuroSPECT images are gathered.

Acquisition Technique

The patient lies on whole body table with the head fixed in a head holder of special design with pillows under his knees, arms at the side of his trunk and the head is supported with a Velcro band on the forehead and chin.

For the SPECT acquisition we use a NeuroSPECT Sophy DSX (SMV, Ohio, USA) system with rectangular head and Ultra High Resolution collimator; we use an energy window 140 Kev with a window width of 20%. The matrix is 64 x 64 with a circular orbit and Step&Shoot motion with 64 steps and 360 degrees rotation. The time of acquisition per projection is 30 seconds with a zoom factor of 1.66 and at the end of acquisition we verify the possibility of a motion artifact in a Cine mode and the Sinogram will demonstrate the existence of patient motion. If there is patient motion, the acquisition is repeated without the necessity of reinjecting the patient.

NeuroSPECT Image Processing

The acquisition is tridimensionally reconstructed by back projection by means of a Butterworth filter 4.25, delimiting non-useful information by means of an elliptic ROI. We perform oblique reorientation for transaxial, coronal, and sagittal planes with a volume zoom of 35%.

The reconstructed tridimensional raw images are transferred in a M03 format to a PC computer in order to reprocess, quantify and normalize their volume.

a) Normalization of HMPAO brain uptake.

The computer performs an analysis of voxel by voxel brain uptake of HMPAO, the results are normalized and expressed as percentage of maximal uptake observed in the cerebellum for cortica analysis and in the brain for basal ganglia analysis,  the results are displayed by means of a color scale that defines as normal values the ones observed between a range of 72% + 5 in red color, values above the normal mean, in silver color values above 82%, values below 60% (larger than 2 standard deviations below normal mean) expressed in color yellow, 50% of maximum in color green and below 40% in color blue.

Volume Normalization

We use the technique of Talairach (Arcila et al Alasbimn, Lima 1997) (NEUROGAM, SEGAMI Corp. Maryland USA). We reorient the tridimensional volume of the brain defining a line that fits the inferior pole of the occipital lobe and the inferior edge of the frontal lobe; this line is automatically rendered horizontal. We correct for lateral deviations defining a line above the interhemisphere fissure and automatically orienting this line in the vertical plane. In this reoriented image we define the intermediate level of the pons and anterior plane of the temporal lobes. We limit the volume of analysis in the lateral planes, superior and inferior planes of the brain. With this information, the Talairach technique renders the brain volume into a normalized volume and allows therefore, a voxel by voxel comparison of the HMPAO uptake in the brain cortex with a normal data base, corrected also volumetrically, for normal children age 6 to 15 years and young  normal individuals at the age of 18 to 45 yeas. In this tridimensional image, we define a new color scale that represents in color red values above the normal mean and two standard deviations above the normal mean in color Silver, all values below the normal mean, in color green and all values below two standard deviations below the normal mean, in color BLUE. We define, therefore, areas of abnormal hypoperfusion that have 95% of probability of being hypoperfused and demonstrated in color BLUE and areas of hyperperfusion in color SILVER that have 95% probability of being hyperperfused in comparison with the normal database (Segami Corp., Maryland, USA).

The intraobserver reproducibility of these measurements was reported at the Alasbimn Meeting in Lima, Peru, 1997 and has a mean of reproducibility of 3.6 mm. that is considered acceptable for this type of technology.

In order to define with high reproducibility the exact localization of areas of hypoperfusion observed in Major Depression and of hyperperfusion observed in Bipolar Disorders, we produced a template of 11 areas of Brodmann in each cortical hemisphere that are involved with behavioral activities by means of the program CORELDRAW 8. We used the Brodmann areas as reference for clinical and experimental functional cerebral and pathological reported information. All these behavioral Brodmann areas are projected automatically by the computer on the anterior, left and right lateral and both para-sagittal images of the three dimensional images of the brain. The projection of this template is automatic and therefore the reproducibility of the results is 100%.

Analysis of Basal Ganglia Uptake of Tc99m HMPAO. The same acquisitions used for analysis  cortical distribution of HMPAO Tc99m uptake were used for further evaluation of basal Ganglia uptake. For this purpose Images were corrected in first place for attenuation by Chang's first order method (attenuation coefficient µ=0.09cm-1). Latter on uptake was normalized to maximal uptake in the brain and images were displayed with the + 2 Standard Deviations color scale and later on compared against the matched normal database and results expressed in standard deviations above and below the normal mean.

Quantification of extension of hypoperfusion in each cortical Brodmann area. By consensus of two of the investigators, we estimated the percentage of sub-regions o hypoperfusion demonstrated by means of blue color in the colorimetric scale.

Statistical analysis

A voxel by voxel comparative analysis with a normal age matched control group was performed and cortical perfusion values were expressed as Standard Deviation (SD) above or below the normal mean for this age group. ROIs were defined by cortical   Brodmann Areas and our system determined the maximal perfusion level in each ROI. We considered as abnormally increased perfusion only with maximal perfusion values above 2 SD of the normal mean perfusion. For each of 15 ROIs studied, we calculated the mean of the SDs of this sample. We considered that the absolute SD was a continuous variable, and therefore we applied an unpaired Student t test for the intracomparisson of pairs of ipsilateral ROIs in each study group.

Cortical structures.

Analyses of these results demonstrate the following:

1) Presence of increased perfusion in both groups of the study in subregions of areas 8, 9 and 10 of Brodmann (executive area), also in area 7 of Brodmann, (posterior parietal lobe). All these areas presented a maximal uptake > 2 standard deviations above the mean of the normal controls. Fig 2, 3, 4, 6 and 7.

2) Presence of relative hypoperfusion in areas 24 and 32 (internal frontal lobe), area: 25, (affective area) and area 21, 22, and 38, (temporal lobe). Fig 6 and 7

3) There were statistically significant differences among the two groups of this study in the following subregions of interest for the maximal uptake: area 24 left, area 25 right, area 11 right, 22 left, 38 left. In all these areas, the group of long lasting evolution of disease presented hypoperfusion significantly more marked than the group of short evolution (p < 0.005). Only in subregion 32 right maximal uptake was significantly increased in the group of long lasting evolution versus the short evolution. Fig 7

Subcortical Structures

Analyses of all results demonstrate the following:

1) The three sub-cortical structures analysed (thalamus, caudate and lentiform nucleus) demonstrated increased perfusion in both groups studied with values larger than 3 standard deviations above the normal control (Fig 5).

2) There were no statistical differences among the different areas in the two groups studied (Table V).

Table IV.
Comparison of values of cortical perfusion between early onset group
and late  onset group expressed by means of maximum SD

Table V. 
Comparison of values of sub-cortical perfusion between early onset group and
late onset group expressed by means of maximum SD

There is currently agreement that affective states have a somatic component of emotions related to sub-cortical structures and also a conscious or sentiment component related to neo-cortical structures. Papez and later on MacLean, proposed the neurobiological and anatomo-physiological bases for cortical representation of sentiment, defined as the conscious sensation of emotions [29, 26]. The cerebral structures involved in this process are: pre-frontal cortex, associative cortex, hippocampus, corpus amigdaloideum, hypothalamus, and anterior thalamic nuclei. These structures would mediate different affective states through complex interactions. Furthermore, there is experimental evidence demonstrating that lesions in orbito-frontal and anterior cyngulate gyrus reduce aggressiveness following withdrawal of reward and also increase resistance to pain. These behavioural responses are part of the classical model of depression known as ¨learned hopelessness¨. Also, irritative lesions of anterior cyngulate gyrus are followed by rage and unmotivated or after irrelevant stimuli, aggressive reactions.  The corpus amigdaloideum would participate in the coordination of neo-cortical and sub-cortical structures involved in neuromodulation of affective states [14, 13, 2, 21]. This nucleus is located in the dorso-medial temporal lobe and has efferent fibres to caudate and thalamus through the Stria Terminalis [10].

Our NeuroSPECT findings have identified a group of cerebral structures related to affective activity, standing out executive cortex, internal frontal region, thalamus, lentiform nucleus and caudate. Furthermore, the increased HMPAO uptake in posterior parietal region (area 7 of Brodmann) would be the result of its multiple sensitive modalities integration for motor planning decisions. Neo-cortical quantitative results would support the existence of functional modules or groups of Brodmann areas functionally integrated. These modules would have the capability of similar response in their quantitative functional expression. This phenomenon of functional integration has been thoroughly described in pre-frontal cortex both in healthy human volunteers and primates [16].

Finally, our results indicate that the fisiopathology of Bipolar Disorders is explained by participation of different structures related to affective modulation. Of particular interest is the hyperperfusion of executive area (area 8, 9 and 10 of Brodmann), thalamus, caudate and lenticular nucleous as segments of a complex circuit of neo-cortical and sub-cortico-limbic structures. This results must be considered in the context of Varela’s theory of phase synchronization and large-scale integration [36].

Acknowledgements. The authors wish to thank the collaboration of Pedro Torres, MD, in the study of patients with bipolar disorder, of Ms. Leila De Souza Coelho for technical assistance and of Ms. Paola Bucchi and Miss Ximena Sepulveda in the preparation of this manuscript.