We study a sample of 18 patients in basal conditions and 31 patients with diagnosis of Borderline Personality Disorder (DSM-IV Criteria) during cortical activation by means of the Wisconsin card sorting test and assessing function/cerebral blood flow by means of HMPAO Tc 99m NeuroSPECT.

The results of changes of cerebral blood flow are shown statistically in a parametric image expressing standard deviations above or below the means of a normative data base for the corresponding age of the patient. We consider only as having significance levels below 2 standard deviations of the normal means . Over this parametric map we project a matrix of Brodmann areas developed by our group in order to precisely localize the areas of abnormality observed. We express our results as percentages of the areas of Brodmann that demonstrates hypoperfusion and we compare the results in a population studied in basal conditions (n=18) and (n=31) during activation by means of the Wisconsin card sorting test.

In our results we highlight, in order of importance areas of paradoxical hypoperfusion in conditions of activation versus basal measurements in anterior cyngulate gyrus (Area 24) in both hemispheres. This is followed in importance by Subgenual area (Area 25), area 40 and area 32 in the left hemisphere, and area 28 in the right hemisphere, then followed by area 28 and area 36 in the left hemisphere, area M* and area 44 in both hemispheres, and areas 32, 9 and 46 of Brodmann in the right hemisphere.

We concluded that there is a dysfunctional correlation of frontal function in borderline personality disorder. Particularly noticeable is the lack of motivation when there are changes in plans and conduct, lack of pleasure and loss of the meaning of a task during the cortical stimulation.

In particular, the Brodmann areas 24, 25 and 32, linked to motivation show a wider involvement when they are exposed to changes in planning and in coping strategies, as it happens during the Wisconsin Test. Areas involved in the executive ability and intelligence also show, but not as noticeable, special change under these circumstances. Both facts can be clinically observed and also in the biography of the Borderline Patient.

INTRODUCTION

Psychiatric semiology began to consider borderline personality disorders as early as 1801 (Pinel), however it was Kraepelin in 1905 and Kurt Schneider in 1923 that defined the concept of psychopathic personalities and abnormal personalities, formally considering the diagnosis of what would later on be viewed as personality disorders.

There is a semi-consensus among many investigators that these clinical entities have not been investigated in depth in Neuroscience (1) (2) because they are part of axis II of DSM-IV. It is for this reason that in this paper we are attempting to contribute to the biological aspects of these pathological entities.

There are valuable consensus documents (3, 4) that allow in many occasions to deepen the understanding of the personality disorders such as DSM-IV (Diagnostic and Statistical Manual of Mental Disorders). The terminology of borderline personality disorders in DSM-IV is a phenomenological-descriptive criteria based on investigations by Gunderson et al. It has the advantage of being a list of descriptive symptoms, easily diagnosable and useful for operational definitions and empirical research.

The prevalence of borderline personality disorders according to the DSM-IV is as high as 2% of the general population, it increases to 10% in out-patient psychiatric consultations and 20% of in-patient psychiatric consultations. This fact justifies the need of progress from different approaches in the assessment of this type of pathology that produces severe suffering of these patients and their families.

Apparently, there is an important genetic trait; as this type of diagnosis is 5 times as prevalent among relatives of first biological degree than in the general population. In these families there is also a frequent diagnosis of antisocial personality, mood disorders, symptomatology secondary to the use of psychoactive substances. Table I describes the diagnostic features for Borderline Personality.

A more biologically mediated Physiopathology of this clinical entity leads us to consider the neurotransmission system of the brain and there we have outlined the behavioral features that are shared by different pathologies such as personality disorders described in class B of DSM-IV and Major Depression. Both entities show a high correlation between suicidal attempts and a low response to phenfluramine (There is a significant diminution of the prolactine secretion after phenfluramine administration). These observations correlate with CSF levels of 5HIAA (metabolite of serotonine) where low levels are associated with suicidal attempts, more than depression. However, both features suggest a low serotoninergic activity associated with a behavioral pattern (5). Other studies concerned with a poor response of prolactine demonstrate the presence of antisocial aggressive behavior (auto and heteroaggression such as inflicting cuts and knifing, etc.) and irritability but not anxiety, or other pathological symptoms.

These facts explain why patients with dysfunctional serotoninergical systems have a higher frequency of auto and heteroaggression, this is frequently observed in patients with borderline personality disorders. Also noradrenaline participates in aggressiveness, it mediates the reactivity of a person with his/her environment, and noradrenaline make our environment more sharp in its perception, increasing contrasts. There are animal studies that demonstrate that it is necessary for the noraderenergic system to be intact in order to observe an increase in aggressiveness due to a low serotoninergic level (6).

When an individual is disconnected from the environment and turns into himself such as in sleep, feeding or grooming, the noradrenergic system is shut down, demonstrating that this system is a regulator of rhythms.

The studies of the noraderenergic system were defined by means of growth hormone released after an administration of clonidine (patients with depression produce less growth hormone versus normal controls after administration of clonidine).

Considering these facts one could define a relationship described in Table II that analyses the interrelation of two neurotransmission system, noradrenergic and seretoninergic with hyporeactive to both in-patients with severe depression and high risk of suicide. Both noradrenergic and serotoninergic functions are diminished and loss of control of aggressive behavior that cannot be addressed to the environment (due to low NA) and self-punishment can emerge (Upper left quadrant).

Another clinical condition can be related to the presence of high Norepinephrine levels and low Serotonine levels determining that patients will interact intensively with the environment, (the borderline patient will respond with idealization-devalorization or manipulation), and all the responses are coupled with loss of control of aggressiveness.

TABLE II

The right superior quadrant could correspond to the presence of excessive autoprotection (obsessive-compulsive actions of body protection). The right inferior quadrant is associated with high intensity reactivity to the environment with anxiety symptoms and personality traits (Otto Kernberg describes this as "borderline panneurosis") (8).

One has to consider also the participation of dopamine, particularly before the D4 receptor that is linked to behavioral feature of "Searcher of Novelty", described by Cloninger (9), that is frequently observed in borderline disorder patients.

Finally it is important to consider the participation of the cholinergic system, this influences the animal behavior inhibiting exploratory behavior that present with intense and sudden changes of mood, these are normalized with Physostigmine injections simulating the cholinergic system by enzymatic inhibition (5).

In the present paper we will analyze three of the five frontal subcortical circuits that correspond to the prefrontal dorsolateral circuit associated to higher intelligence function, the anterior cyngulate circuit associated to cognitive and motor motivation and the orbital frontal subcortical that is associated to mood changes.

The description of the different circuits and their physiological meanings has been described in ^*http://www.alasbimnjournal.cl/revistas/3/pradoia.htm "Cerebral functional changes in major depression demonstrated by Neurospect under basal and frontal stimulation conditions".

The purpose of this paper is to correlate functional changes observed in the basal state and during frontal activation by means of the Wisconsin test demonstrated by Neurospect of cerebral perfusion.

The sample comprised two mixed groups with ages between 18 – 50 years, 18 patients (Mean Age 35 y), 12 were males ( Mean Age 32 y.) and 6 were females (Mean Age 37 y.). These patients had Neurospect with HMPAO Tc99m in basal conditions (Group I). 31 patients (Mean Age 34 y.), 21 males ( Mean Age 31 y) and 10 females (Mean Age 36 y.) had the same Neuro Imaging examination performed during cortical activation by means of the Wisconsin Card Sorting Test (10) (Group II). The Wisconsin Card Sorting Test was performed using a computer.

4 sessions were performed: one included information from third party.

These interviews are given by psychiatrists considering the semiology outlined in Table I from the DSM-IV and selecting the descriptive aspects of the initial interview, investigating the symptoms that lead the patient to treatment.

A structural interview is not performed due to risk of psychotic reaction of the patient (O.Kernberg).

We have taken into account the recommendation of CIE-10; namely the evaluation has to consider as many sources of information as possible, and this leads in more than one occasion to multiple interviews and collection of an anamnestic information from several sources. The DSM-IV stresses that the diagnosis of borderline personality disorder requires an assessment of behavioral patterns over long periods of time. Special considerations were given to the stability of personality traits along time and different circumstances.

We keep in mind the hypotheses of Gazzaniga (11) in relation to "false remembrances" and the continuous assessments of facts performed by the left hemisphere, sometimes erroneously maintaining the psychic homeostasis of the subject. In these patients this is an important feature.

We keep in mind also that these patients in many aspects perform in psychiatric offices like patients with organic-frontal impairment, mainly, without reporting behavioral abnormality and these are appreciated in the life outside of a medical office in relation to imitation conducts. (12).

For diagnostic purposes we performed this projective test (13 - 20). The patient provides information naively, (without knowing what he is revealing with his answers) concerning specific behavior, modality that can be related to frontal function. The Rorschach Test assesses qualitative and quantitative information that suggests personality traits and allows in an indirect form to observe general aspects related to organic brain damage, intelligence and provides the capability of observing tendencies related to "orality" or impulsive conduct. It allows to detect patients that fulfill the exclusion criteria.

The test is applied by a psychologist, expert in Rorschach, blinded to the diagnosis of the patients which are included in a large population of patients suffering also from other pathologies.

We excluded patients that had additional diagnosis of major depression, schizophrenia and organic mental changes due to medical causes or induced by drugs, mental deficiency, manic depressive disease, dementia, pre-menstrual syndrome and stational depression. We exclude also personality traits of Group A and C of DSM-IV.

During the Spect examination we applied the Card Sorting Test to 31 patients (10-21). It consists of a maximum of 128 questions in series of 10 consecutive correct answers, after which at the completion of each series the strategy is modified and has to be assessed and redefined by the patient.

The selection of cards is made by computers, also the velocity of response is recorded and the results are compared with a normative data base of the same age, sex, dexterity and academic level defined by the program.

In our study the test was used to stimulate the patient by means of frustrating him/her. This was met by changing the planning and strategies which solved the problems. The goal was to replace or imitate the events which actually take place in the patient’s daily life. The radiopharmaceutical was given as an I.V. injection just at the moment when the first change in the planning strategies is presented by the computer.

The techniques of injection of the HMPAO Tc99m radiopharmaceutical and image acquisition and processing of Neurospect was done according to criteria utilized in previous publication ^*http://www.alasbimnjournal.cl/revistas/3/pradoia.htm.

In order to define with high reproducibility the exact localization of areas of hypoperfusion observed in borderline personality disorder we developed a matrix by means of program Corel Draw 8, that defines 24 areas of Brodmann in each hemispheres. These areas are related to behavioral activities and language based on clinical and experimental information. These areas establish a structural/functional relationship and are projected automatically by computers on the Neurospect three-dimensional images, in an anterior, right and left lateral, posterior and both saggital or mesial images of the brain. The projection of this matrix is automatic and therefore the reproducibility of results is 100%.

The analysis of age and sex distribution of both groups of patients studied either under basal or frontal activation by means of Wisconsin test was performed with the Fisher test. The comparison of basal results with the Wisconsin results were performed by means of the Kruskal-Wallis test with the correction of Pocock for multiple comparisons in multiple dependent samples. We considered as an abnormal result, areas of Brodmann that show significant differences between the basal and Wisconsin activation test with a P value smaller than 0.05.

TABLE 3. Statistical Analysis of comparison of Basal Spect vs. NeuroSpect during the Wisconsin test.

Demonstrates maximum statistical significance in the anterior Cyngulate Gyrus (Area 24) in both hemispheres, followed by subgenual area (Area 25), area 40 and area 32 in the left hemisphere and area 28 in the right hemisphere. We observe abnormality in area 28 and area 36 in the left hemisphere, area M and area 44 in both hemispheres, and area 32, 9 and 46 Brodmann in the right hemisphere.

Demonstrates maximal statistical significance in Anterior Cyngulate Gyrus ( Area 24) in both hemispheres followed by subgenual area (Area 25), Area 40 and 32 in the left hemisphere and Area 28 in Right hemisphere. These are followed by area 28 and 36 in left hemisphere, area M* and Area 44 in both hemispheres and areas 32, 9 and 46 in right hemisphere.
*Area M corresponds to the rostral image of the dorso-lateral prefrontal cortex

ANALYSIS OF LOCALIZATION OF RESULTS OF HYPOPERFUSION INDUCED BY WISCOSIN TEST

Table 3 and Figure 4 depict the most significant Brodmann areas affected by hypoperfusion induced by the Wiscosin Card Sorting Test. The areas of maximal significant differences between activation and basal studies are listed in decreasing order: left anterior cyngulate gyrus P<0.00005 and right cyngulate gyrus P<0.0003. These areas are followed in importance by subgenual area, area 25 (P<0.006), area 40 (P<0.005), area 32 (P<0.006) in the right hemisphere and area 28 (P<0.05) in the right hemisphere. Furthermore, these are followed by area 28 (P<0.02) and area 36 (P<0.05) in the left hemisphere, area M (P<0.042) in the left hemisphere and P<0.033 in the right hemisphere. Area 44 in the left hemisphere has a (P<0.013) and in the right hemisphere, (P<0.016) and areas 32 (P>0.031), 9 (P<0.016) and 46 (P<0.046) in the right hemisphere.

Area M corresponds to the anterior projection of the prefrontal dorsolateral area, that is related to superior intelligence. Intelligence in accordance to Wechsler, is the total capacity, global and aggregated (because it corresponds to the products of different capabilities), in order to think rationally, to behave with a purpose and cope effectively with the environment.

Normally this area is stimulated by activation by means of the Wisconsin test and in this study, however it demonstrates a diminution of cerebral perfusion in the Spect gathered during activation compared with the basal state. (P<0.033 in the right hemisphere and P<0.042 in the left hemisphere).

One of the behavioral characteristics described in patients with borderline personality disorders is variability in situations of fear, social performance, occupational or personal relations performance. These disruptive conducts are associated with frustration of the patient with regards to personal events or external events, sometimes of insignificant importance that lead however to a pattern full of disadaptative situations. This fact is observed also in patients with high intellectual quotient that loses their bearings at moments of crisis. For O. Kernberg, the patient "derails" (8).

Another difficulty of borderline patients is the incapability to assign hierarchy in daily life: this implies a correct perception of emotional detail and a definition of importance within a global activity. In periods of stress in which affectivity is interfered, the responsiveness is less predictable. This difficulty to evaluate the significance of the emotional weight on adaptation is more severe and permanent in schizophrenia. In a similar manner to patients with borderline personality disorder and schizophrenia the dorso-lateral prefrontal area diminishes paradoxically its cerebral perfusion during the Wisconsin card sorting test (21).

It is stated in the DSM-IV that borderline patients improve their behavior on or about 40 years of age and before that time they present with a blockade to change, which is difficult to break (difficulty to make their behavior more flexible or keep stable patterns of behavior DSM-IV). One of the reasons for consultation to the psychiatrist is the appearance of a crisis, like it occurred in all patients studied in this group; at this time the circuit that is being studied is dysfunctional. One could therefore deduct that there is a weak remembrance of remote or recent information, particularly of situations that are harming the patient again, and for this reason we can state that these patients do not learn from experience. Ana Freud (22) would say that in this condition there are defense mechanisms in action like negation or intellectualization. However, Gazzaniga (11) would remind us that human beings have a 98% of our perceptions in an automatic way where the left hemisphere is ready to explain the facts from its limited angle of observation that is influenced by false registers in memory.

Another characteristic of the performance of these patients is related to the use of psychotropic drugs where the dysfunction of the dorso lateral prefrontal area has been described and there is a more evident conduct of utilization of information from the environment and imitation. Both types of conduct can be adaptable to normal subjects such as consumerism due to imitation or the following of the dictates of fashion, however, in borderline patients this is expressed in compulsive buying, excessive gambling, sexual promiscuity and consumption of psychotropic drugs.

For Gazzaniga, memory keeps records that are influenced by the emotional circumstances at the time of codification. Furthermore, in front of new events the brain processes them comparing with events that were recorded previously.

It is of note to consider the pioneering vision of Freud, that refers to this condition as perception recharging the mnesic prints that would acquire therefore significantly an individual characteristic. Both investigations coincide with the fact that these patients have a difficulty to change opinions or make their judgements more flexible with respect to the perceived stimuli. This condition is very evident in the borderline patients with a manifestation of characteristic of rigid and polarized attitude in their affective relationships,. with regards to the dependency of overvaluing or devaluing from one extreme to another (DSM-IV). This phenomenon has a tendency to diminish in significance after 45 years of age. At this age the right hemisphere begins to acquire a preponderance of importance that is reflected by more common sense (as we understand by this the capability to detect social clues and environmental clues and to respond adaptively to them) and also a major capacity to structure in a globality. It is necessary to emphasize that all that is described corresponds functionally to the dorso lateral prefrontal circuit.

The conducts of utilization of environment and imitation that are clearly noted in the item of DSM-IV refer to the "loss of control" in different areas that are potentially harmful such as gambling, drugs, careless driving, consumption of psychotropic drugs and abnormalities of appetite.

Finally in this circuit we localize capabilities to perform complex areas of attention, to guide conduct with a structured thought, all these tasks of complex attention and the guidance of a conduct like thinking, all of which that are frequently impaired in patients with borderline personality disorders.

It corresponds to the anterior cyngulate gyrus and demonstrates in the studies a diminution of cerebral blood flow (P<0.0003 in the right hemisphere and P<0.00005 in the left hemisphere). This circuit begins in area 24 of Brodmann and its dysfunction can be expressed with demotivation (24). Furthermore, its clinical manifestations are expressed with episodic mutism and marked apathy as a response to demands of changes (DSM-IV). Furthermore the feeling of psychic "vacuum" could precede more impulsive acts (25). The indifference to physical pain in self-damaging acts is a situation that is frequently observed in these patients. It is important to remember the richness of opiate receptors and immunoreactive encephaline in this area (26).

In the left hemisphere, there is a significant diminution of perfusion during activation with the Wisconsin test P<0.006 that becomes P<0.031 in the right hemisphere. This area belongs to the limbic system and precedes anatomically the anterior cyngulate gyrus. It is an efferent target of the orbito-frontal cortex, that is related to mood disorder (27, 28).

The limbic system has a significant importance in areas of learning and we are aware of the interrelation of cognition and emotion (29).

This area is located in the medial temporal cortex which corresponds to the entorhinal and perirhinal cortex (30).

This area shows a significant difference with diminution during activation P<0.02 at the left and P<0.05 at the right and is related to emotional and neurovegetative situations and is accompanied in borderline patients with anxiety, with symptoms in the abdominal, thoracic region or in areas of visceral content.

Furthermore, this area is rich in connections with the hippocampus structure that appears to be a site of temporal memory, this temporal memory later on transfers to other areas of the cortex for permanent recording (31). Probably this storage is performed in a holonomic modality (32), which allows the retrieval from any detail of the totality of information.

The mnesic details have clearly an effective component in areas 28 that is closely related to the orbito frontal subcortical circuit, which is related to mood and other characteristics of personality and it becomes an important input in this sense.

The left hemisphere which shows a clear diminution of blood flow during activation with P<0.05 it is less significant than the previously described areas and it has connections with area 28.

The statistical significance of the findings concerning this area have a P<0.005 at the left and P<0.04 in the right.

There is a close correlation of this area with the memory of speech. Its function is shared with areas 9, 44, 39, 46, 47, that show a significant change in this study.

There is significance only in the left hemisphere P<0.006. This area is located in the "Genus angularis", subgenus area of the Corpus Callosus. It has been studied by Damasio and others (33) because of its important relation with the capacity of enjoying with performance and with positive anticipation to future facts or optimism, both functions therefore related to the capacity of finding a meaning to existence.

This area has been defined as the critical locus in Major Depression. In this condition there is a diminution of cerebral blood flow and metabolism and also in MRI there is a diminution of the volume of gray matter of this structure.

It is probable that in borderline patients this same finding is accompanied by dysthymias.

Both appear significantly diminished during activation P<0.016 in the right hemisphere and P<0.013 in the left hemisphere. This area together with areas 9, 40, 39, 46 and 47 participate in verbal memory.

Together with area 8 of Brodmann corresponds to the dorso lateral prefrontal cortex in a lateral and medial image, for this reason the observations that we made for area M are equally applicable: in the right hemisphere P<0.016.

DISCUSSION

In a previous publication from our group ^*(http://www.alasbimnjournal.cl/revistas/3/pradoia.htm) we have described the complex, but well defined web of cortical-subcortical circuits that participate in human behavior. These lead to conclude that frontal lobes can be envisioned as structures of rich interconnectivity that integrates information between the external environment and the internal milieu of the subject.

These facts make us remember the significant refinements experienced by the dorso-lateral prefrontal cortex at the time of adolescence in all subjects. In the case of pathological conditions that begin their manifestations in that period of life, like schizophrenia and also borderline personality disorders these facts may have an influence in the clinical manifestation of the respective clinical conditions.

During adolescence normally, there is a diminution of connectivity of the pyramidal cells of the third layer of the cerebral cortex. The activity of this layer is modulated by local inhibitory GABA input circuitry and afferent fibers of dopamine (34). In schizophrenia this area has a diminution in the size of the pyramidal cells in comparison to normal subjects.

Furthermore, if we consider the high sensitivity and specificity parameters used in Scales of neurobehavioral performance such as Levin (35) for brain lesions, we find that these can be correlated with the semiology described by the DSM-IV for borderline personality disorders that are listed ahead (9 of 12 items abnormal and highlighted in bold). These facts allow us to state that there is a functional and anatomical correlation also in borderline patients.

• Diminution of initiative/motivation (lack of normal initiative in work or during the use of free time, difficulty to keep performing a task, resistance to accept new changes) (anterior cyngulate gyrus).

• Emotional lability. Sudden changes of mood that are disproportionate to the trigger (dorsolateral prefrontal area).

• Disinhibition. Inappropriate socialization, commentaries and actions, including sexual, aggressive comments, comments inappropriate to the situation and temperamental explosions (related to orbito frontal area).

• Hostility/Lack of cooperation. Animosity, irritability, belligerence, disregard for others, challenge of authority (dysfunction of orbito frontal and dorso lateral prefrontal cortex).

• Excitability. Emotional tone increased, increase of reactivity to environment (orbito frontal/dorso lateral prefrontal cortex).

• Poor planning/unrealistic targets, failure to take into account personal incapacity, poor definition of plans for future, etc. (dorso lateral prefrontal dysfunction).

• Difficulty for insight. Excessive autovaloration with exaggerated opinions with regards to oneself. Increased or subvaloration of the personal capabilities. Differences in the evaluation of personality between psychiatrist and family (dorso lateral prefrontal dysfunction).

• Lack of spontaneous interaction. Isolation, difficulties in relations with other people (dorso lateral area and prefrontal dorsal medial area and anterior cyngulate gyrus).

• Sadness, pessimism, disappointment (dysfunction of area 25 and anterior cyngulate gyrus).

• Motor impairment.

• Depressive mood.

• Incapacity to confront stressful conditions and to become aware of environmental aspects.

Finally, it is important to consider that this research opens an area of interest for the study of human behavior in the definition of conduct. The present findings although preliminary, shed some light into this matter. Furthermore, these results are concordant with diagnostic and semiologic instruments such are those suggested by Kandel (36) and Kaplan (37), among others.

Furthermore, this could also become a contribution to the approach (38) of understanding personality disorder as manifestations of changes of structure and functions in specific circuitry in the CNS, while in psychotic disorders we would observe exclusively structural changes in cerebral cortex such as in schizophrenia. In the genesis of these clinical conditions we must consider genetic factors as well as environmental issues such as parental relations (39, 40), social stressors, work-related stressors, familiar stressors (41) etc. It is important to consider that an improvement in these factors would have a structural and functional cerebral outcome. For this reason, a successful psychotherapeutic work or pharmacologic approach could temporally or permanently revert changes which are observed under clinical conditions of the Borderline Personality. These statements look forward to the pre and post treatment imagenologic study that we will entertain in the near future.