Biologic Alterations in the Brainstem of Suicides

SUICIDE 0193-953X/97 $0.00 + .20

BIOLOGIC ALTERATIONS IN THE BRAINSTEM OF SUICIDES

Victoria Arango, PhD, MD, Mark D. Underwood, PhD, and J. John Mann, MD

Biologic abnormalities in the brain of persons, who attempt or complete suicide, are increasingly recognized as an essential element in the cause of suicide, which claims the lives of more than 30,000 in the United States each year. Direct evidence for this arises in large part from careful quantitative studies of postmortem brain tissue. This article reviews the data supporting the notion that there are alterations in neurotransmitters long associated with regulation of cognition and mood in the brains of suicide victims. Neurotransmitter abnormalities have been found in the ventral prefrontal cortex of suicide victims, a brain region that plays a role in behavioral inhibition. A failure of behavioral restraint mechanisms may result in a predisposition to suicidal behavior.

The potential involvement of abnormalities in nuclei located in the brainstem in suicide was first suggested about 30 years ago.R0 After a series of brainstem studies, subsequent research has mainly focused on monoamine receptors in the prefrontal cortex, a major target of monoaminergic neuronal projections from neurons whose cell bodies reside in the brainstem. Most recently, the morphology and neurochemical function of key brainstem nuclei has again been the object of study. This article emphasizes findings from the brainstem. How is it that an abnormality in the phylogenetically oldest part of the brain could contribute to suicide, a uniquely human behavior?

This work was supported by MH40210, AA09004, and MH46745.

From the Departments of Anatomy and Cell Biology (VA), Neuroscience (VA, JJM), and Psychiatry (MDU), New York State Psychiatric Institute; and Department of Psychia- try, Columbia University (JJM), New York, New York

THE PSYCHIATRIC CLINICS OF NORTH AMERICA

VOLUME 20 * NUMBER 3 - SEPTEMBER 1997 581

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THE SEROTONERGIC SYSTEM

A preponderance of evidence suggests that suicidal behavior is associated with a deficit in brain serotonin (5-HT) neurotransmission as shown in Figure 1. In suicide attempters, findings of reduced 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the cerebrospinal fluid (CSF) and a blunted prolactin release to fenfluramine are consistent with reduced 5-HT function being associated with suicidal behavior.

A reduction in the concentration of the 5-HT metabolite 5-HIAA in the CSF of suicide attempters was first reported by Asberg in 1976.18 Subsequently, several ~tudies,'~, 16, 22* 27, 55, 64, 73, 86, 88, 89 though not all,74, 75

have confirmed the original observation. Furthermore, the altered 5- HIAA concentrations appear to be more strongly associated with the suicidal behavior than with depre~sion.~~ This reduction in 5-HIAA occurs in patients who make a lethal suicide attempt, independent of the psychiatric diagnosis. For example, 5-HIAA is reported to be lower in suicide attempters with major depres~ion,'~, 17, 22, 23, 55, 57* 86 personality disorder~,2~, 28 alcoholism,22 and schizophrenia.22, 27, 28, 86 The degree of metabolite reduction is correlated with the lethality of the attempt.55 The most lethal attempts are associated with the lowest concentrations of CSF 5-HIAA. The possible causes of the reduction are many: reduced release of transmitter, fewer 5-HT neurons or atrophied innervation of target regions, impaired 5-HT synthesis, or even augmented autoinhibi- tory actions of 5-HT itself. Whereas most studies have found the associa- tion between CSF 5-HT or 5-HIAA and suicide attempt, little is known regarding the cause of low CSF 5-HIAA. Nonhuman primate studies indicate several factors that can influence the concentration of 5-HT and 5-HIAA in the CSF including genetics, rearing, cholesterol, and stress.

Neuroendocrine challenge tests, designed to test the integrity of the serotonergic system by stimulating prolactin release in response to fenfluramine, have shown a blunted response in suicide at tempter^.^^, 52, Brain imaging using positron emission tomography (PET) has recently been employed as a means of examining serotonergic function in vivo. Using fenfluramine, Mann and colleagues found blunted cerebral metabolic responses in depressed patients compared with normal control

The most pronounced changes and differences between patients and controls were anatomically localized to the prefrontal and temporoparietal cortices, suggesting reduced serotonergic neurotransmission associated with major depression. Further studies comparing depressed patients, with and without a history of suicide attempt, are needed to determine what are specific correlates of suicidal behavior.

Postmortem findings in suicide completers provide further supporting evidence for abnormalities in the serotonergic system. Two im- portant aspects of this research need to be considered. First, studies of postmortem tissue allow direct examination of the brain with high anatomical resolution possible and the ability to perform quantitative measures. Second, because the studies are performed postmortem, there are several clinical and experimental limitations. The clinical limitations

BIOLOGIC ALTERATIONS IN THE BRAINSTEM OF SUICIDES 583

SEROTONIN

Serotonin ' Transporter

Sites

CONTROL Postsynaptic 5-HT,,, SHT, Receptois 00

Dorsal Raphe Nucleus Serotonin neurons

SUICIDE

Reduced c-mtnnin v Sites 5-HT,;, 51HT,

Receptors

-7-1 --I- More but less functional neurons.

A Smaller 5-HT neurons. B

NOREPINEPHRINE

CONTROL

Locus Coeruleus Pigmented NE neurons

SUICIDE

Fewer

Receptors lncreas NE

--I- t - t - -

0'0 FewerAower density LC neurons. No morphologic alterations. Decreased NE transporter. Increased tyrosine hydroxylase. Increased a,-adrenergic receptors.

Figure 1. Models of serotonergic (A) and noradrenergic (B) pathology in suicide (lower panels) compared to controls (upper panels). Serotonergic innervation of the cerebral cortex arises from .the dorsal raphe nucleus. Noradrenergic innervation of the cerebral cortex arises from pigmented neurons in the locus coeruleus. Note that suicide is character- ized by more serotonergic neurons and fewer noradrenergic neurons.

584 ARANGO et a1

include difficulties in obtaining accurate information as to the person’s psychiatric history and medication history, particularly regarding indi- viduals who are socially isolated. The difficulties for bench research involve postmortem delay artifacts, the potential confounding effects of drugs and medication, and the limited availability of the tissue.

Presynaptic and postsynaptic serotonin receptor alterations have been observed in prefrontal cortex of people who commit suicide that are consistent with reduced serotonergic function. Binding to the serotonin transporter is found to be reduced by some? 8, 9, 32, 45, 46, 48, 54, 82 though not alF 10, 12, 38, 42, 48, 49, 67 investigators, particularly in ventral and lateral prefrontal cortical regions. Increased binding to postsynaptic 5-HTIA6* 59

and 5-HTzA3. 11, 42, 587 81 receptors in prefrontal cortex has been reported in most studies.

A separate potential focus of impaired transmission is at the level of second messenger systems for transducing the 5-HT and other neurotransmitters’ action on receptors is impaired in depressed suicide victims.31, 68

Taken together, the data suggest that reduced serotonergic function in the ventral prefrontal cortex constitutes a critical element in the vulnerability to suicidal behavior. The importance of the prefrontal cortex in suicide is thought to involve its role in mediating behavioral inhibition. Impaired PFC function may underlie reduced capacity to resist the impulse to act on suicidal thoughts. Further discussion of the possible consequences of an involvement of the prefrontal cortex in suicide behavior can be found el~ewhere.~,

THEDORSALRAPHENUCLEUS

Serotonin synthesizing neurons innervating the forebrain in ani- mals, and presumably humans, are located primarily in the dorsal and median raphe nuclei in the brainstem (i.e. references 25, 30, 71, and 78). In the human, the DRN is a large group of approximately 100,000 neurons embedded in the ventral part of the central gray matter of caudal mesencephalon and rostral pons. Based on topographic and cytoarchitectonic characteristics in Nissl-stained material, the DRN has been subdivided into distinct subnuclei.21 These subdivisions correspond to those observed in tissue immunoreacted with an antitryptophan hydroxylase 85 which also reveals an additional component (the ventral subnucleus), not recognized in Nissl material. The subnuclei are median (or interfascicular), ventrolateral, dorsal, lateral, and caudal. The median subnucleus is long and dense; its cells are oriented parallel to the midline and the processes extend within the medial .longitudinal fasciculi. Its anteroposterior extent goes from the anterior pole of the DRN to the rostral appearance of the median sulcus of the fourth ventricle. Caudal to this point, all DRN neurons are on either side of the floor of the fourth ventricle and none are on the midline. The ventrolat- era1 subnucleus is made up of small, multipolar neurons extending caudally from the central gray to a position just dorsal to the trochlear


nuclei and the medial longitudinal fasciculus. This subdivision has the highest density of PHS-immunoreactive neurons, has no midline component and extends further caudally than the median subnucleus in the rostral pons. The dorsal subnucleus has loosely arranged medium-sized neurons dorsomedially flanking the dense ventrolateral subgroup. The two wings of this subnucleus are joined in the midline. The caudal subnucleus is made of two dense strips of PH8-immunoreactive neurons lateral to the midline and dorsal to the medial longitudinal fasciculus. Its cells are small- to medium-sized and processes are oriented parallel to the floor of the fourth ventricle. The lateral subdivision cannot be recognized in Nissl-stained material. It is very loosely organized and has the largest multipolar neurons of any of the DRN subdivisions. Neuronal processes extend across large fields in the central gray and axons are characteristically coiled close to the soma. The ventral subdivision is made up of round neurons located between the dorsal and ventrolateral subnucleus.

Presently, it is not possible to verify the cortical targets of the various DRN nuclear subdivisions in the human. The projection from the DRN to cortical targets in the monkey exhibits a coarse rostrocaudal topographic relationship, as opposed to the median raphe nucleus projections that are not separated rostr~caudally.~~ The serotonergic projection to the prefrontal cortex has a very heavy component arising from cells in the rostral part of the DRN. Regarding cortical innervation in the primate, the density is highest in layer 1, except in sensory areas where the highest density is in layer IV. The serotonergic target cells in the cortex are GAD-IR indicating that they are GABAergic, inhibitory neurons.

The ascending dual serotonergic projection system described in the rat53 has also been demonstrated in nonhuman primates?l< 92 as arising from both the dorsal and median raphe nuclei. The fine varicose axon system originates in the DRN and has fibers that branch profusely in the target area. It has been difficult and controversial to estimate the incidence of synaptic contacts from this system. The second system has large round varicosities, more divergent innervation and originates in the median raphe nucleus. The fine, DR nucleus system is more suscepti- ble to degeneration by amphetamine-derivatives, while the median raphe fiber system appears spared by the use of psycho tropic^.^^

The finding of reduced serotonin transporter binding in the prefrontal cortex of completed suicides (see above), in particular, raises the possibility that there is reduced serotonergic innervation. Alternatively, a normal or increased number of serotonergic neurons may be deficient in the extent of innervation and the number of serotonin transporter sites synthesized.

The early studies of brainstem serotonergic neurons found reduced concentrations of 5-HT69, or 5-HIAAZ6 in whole brainstems in suicide victims. The DRN was more specifically examined by Lloyd et al,51 who found reduced amounts of 5-HT but not 5-HIAA in dissected tissue. The amounts of 5-HT or 5-HIAA were not different between suicides and

586 ARANGO et a1

controls in other raphe nuclei, with the exception of the median raphe where 5-HT was also reduced. To our knowledge, no other study has replicated the finding or otherwise specifically examined the brainstem raphe nuclei in suicide victims.

Studies are currently being untaken by the authors using a morpho- metric analysis of serotonin neurons of the dorsal raphe nucleus. Whether the density and number of 5-HT synthesizing DRN neurons in suicide victims is altered compared to nonsuicide controls is being determined. The estimated total number and anatomical distribution of DRN serotonergic neurons in our normal controls is comparable with those reported el~ewhere.'~, 2o Another index of neuron function can be addressed by the neuron morphology, where the neuron appearance may suggest atrophy or other neurodegenerative processes. Neuron size and shape between groups are being compared. Both controls and suicides exhibit a loss of serotonin neurons with increasing age.

Careful study design can insure that any findings of alteration in number and density of DRN neurons is owing to the suicide status of the experimental group and not due to other factors, some of which were described above regarding the difficulties in studying human postmortem tissue. Alterations owing to age differences between the groups must be considered because of the observed decline in the number of DRN neurons with increasing age. The potential confounding influence of the presence of drugs can be avoided by limiting or eliminating the number of controls and suicides having a positive toxicology. The possibility of a counting bias is unlikely if unbiased stereologic methods are used. The findings will not be owing to group differences in sex, race, or postmortem interval if these variables are similar in distribution or does not differ between groups.

Serotonergic innervation of the cerebral cortex arises from neurons located predominantly in the dorsal and median raphe nuclei in ro- dent~, '~, 30, 43 nonhuman primates47* 63, 9o and presumably humans. The finding of reduced 5-HT in the dorsal (and median) raphe nuclei51 and receptor changes in prefrontal cortex in suicide victims6 led us to hypothesize that the reduced 5-HT indices may be due to fewer 5-HT synthesizing neurons in the DRN in suicide victims. Other studies have found fewer DRN neurons in diseases such as Alzheimer's' and alcoholism.4o

An alteration in the number of 5-HT neurons in suicide victims may reflect a neurodevelopmental effect and, perhaps, a genetic role in the neurobiology of suicide origin. The notion of a genetic component to suicide is not new. Studies in twins39 have demonstrated an increased suicide rate in the identical twin, regardless of like or different parent- age. Studies have similarly shown that suicide can run in families34 and people who have relatives who died by suicide are at greater risk for Furthermore, serotonergic indices have been shown in nonhuman primates to have a strong genetic contribution. The offspring of monkeys with either high or low amounts of CSF 5-HIAA tend to have similar concentrations to the parent^.^' An altered number of neu-


rons may, therefore, represent a form of biological and perhaps genetic predisposition to suicide risk. The evidence from receptor binding studies postmortem or CSF levels of 5-HT or 5-HIAA in suicide attempters, suggest that there is reduced serotonergic neuronal function associated with suicidal behavior.

THE NORADRENERGIC SYSTEM

Alterations in noradrenergic neurotransmission in suicide are also suggested based on a variety of findings, including changes in neurotransmitter indices in postmortem brain tissue and comparable findings in vivo. Noradrenergic innervation of the mammalian cerebral cortex is derived nearly exclusively from pigmented neurons of the LC.33, 35* 50, 72

Much like the serotonergic neurons of the DRN, these noradrenergic neurons provide widespread innervation throughout the neuraxis including the limbic system. The normal distribution and morphology of pigmented neurons in the human LC is described in detail e l ~ e w h e r e . ~ ~ , ~ ~ Pigmented LC neurons appear in the dorsomedial pons at the junction between the pons and the cerebral peduncles. The neurons are located bilaterally and symmetrically in the ventrolateral quadrants of the central gray. Proceeding in a caudal direction, the neurons relative location moves laterally and end at approximately the rostral-most appearance of the motor subdivision of the trigeminal nucleus. The neurons of the LC appear clustered throughout the rostrocaudal extent of the nucleus giving it a compact and tubular organization. The packing density of pigmented neurons reach their maximum 3 to 5 mm caudal to the decussation of the trochlear nerves.

Fewer noradrenergic locus coeruleus neurons in the brain of completed suicides were r ep~r t ed .~ Ordway and colleagues found increased binding to {alpha],-adrenergic receptors66 and increased tyrosine hydroxylase in the LC of suicide victims, but no difference between groups in the number of LC neurons65 or the concentration of NE in the LC.66 Evidence from neurotransmitter or metabolite concentrations in the cerebrospinal fluid (CSF) is less convincing with only a m i n ~ r i t y ' ~ , ~ ~ of studiesz7, 70* 75, 76, 79, 86 finding reduced concentrations of the norepinephrine metabolite 3-methoxyl, 4-hydroxyphenyl glycol (MHPG) in suicide attempters. Reduced urinary excretion of the metabolite MHPG in suicide attempters provides further indirect evidenceI4, 15; (beta]-adrenergic receptor binding is increased in the cerebral cortex of suicide victim^.^, 24, 58 Increased a,-adrenergic and a,-adrenergic receptor binding in suicide victims in cerebral cortex has also been rep~rted.~, 6o Taken together, these studies suggest reduced noradrenergic neurotransmission is associated with suicidal behavior.

Findings show that suicides have 23% fewer LC neurons and a 38% lower density of LC neurons than control^.^ The reduction in neuron number was localized to the rostra1 two thirds of the LC. Every suicide case studied had fewer neurons in the left LC than the right LC, whereas

588 ARANGO et al

no left-right difference was present in the control group. Neither the LC length nor the LC volume in suicide victims differs from controls.

LC neuron morphometry in suicides was examined for evidence of alterations or neuropathology compared to the normal controls. Mea- sures of size (area, perimeter) and shape (form factor) were made from three matched rostrocaudal levels of the LC from the same subjects. Rostrocaudal differences in the normal distribution of neuron size and shape were found within the LC for both groups. However, there were no significant differences in either the size or shape of neurons in suicides compared to control subjects in any region of the LC. Interest- ingly, females and males differed in neuron morphometry. Females had greater neuron area and perimeter on the left side of the LC compared to the right side of the LC, whereas there was no significant difference between the two sides in males. Similar sex differences were found in neuron shape.

CONCLUSION

Research into the biology of suicide has provided compelling evidence of alterations in the neurotransmitters serotonin and norepinephrine. Earlier research served to implicate these transmitters, but could not identify the source of the changes. For example, the evidence for an involvement of serotonin began with observations of reduced amounts of the 5-HT metabolite 5-HIAA in the cerebrospinal fluid of suicide attempters.ls The serotonin in CSF is thought to end up there after being released from serotonin nerve terminals in the central nervous system and then by diffusion through the parenchyma ultimately contribute to the CSF. The contributors of this serotonin are serotonin neurons that are located throughout the brainstem as groups of cells belonging to the raphe or B-cell

Since the CSF studies cannot identify which of the several raphe nuclei are affected in disease, subsequent research sought to identify the locus of change. Brain homogenates importantly demonstrated differences in multiple brain regions and suggested an involvement of serotonergic and monoaminergic receptors in the prefrontal cortex and the source neurotransmitter synthesizing neurons in the brainstem. Autora- diographic analyses brought a higher anatomical resolution than brain homogenates. Some studies reporting differences in suicide have raised the notion that the biochemical differences are anatomically discrete.

Central to the discussion are hypotheses as to the cause(s) of reported changes in the amounts of neurotransmitters, metabolites, receptors, or cell numbers. At this point, the discussion is speculative. There are no animal models of suicide. However, genetics, development, treat- ment, diet, season, sex, stress, and age all play a role. As the findings suggest, alterations in the brainstem in suicide victims, the data suggest that serotonergic DRN but not other serotonin neurons appear deficient in their capacity to synthesize ~ero tonin .~~ Normal amounts of serotonin


are found in terminal fields such as the dorsolateral prefrontal cortex,5s but serotonin responses are defective at least in the hypothalamus.s2 Suicide victims appear to have fewer noradrenergic LC neurons; containing more of the tyrosine hydroxylase enzyme needed for transmitter synthesis.65 This could reflect excessive noradrenergic activity perhaps owing to stress.

A major future challenge is to distinguish neurochemical changes associated with suicidal behavior from neurochemical changes associated with the psychopathology or psychiatric disorder that generated the suicidal ideation in the first place.

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Biologic Alterations in the Brainstem of Suicides