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Neuroanatomical studies on bipolar disorder Neuroanatomical ... Neuroanatomical studies on bipolar disorder Neuroanatomical ... Document Transcript

  • B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 1 ) , 1 7 8 ( s u p p l . 4 1 ) , s 1 4 2 ^ s 1 4 7Neuroanatomical studies on bipolar disorder a temporo-occipital cortical dysplasia asso- ciated with rapid-cycling bipolar disorder and learning disability (Raghavan et al, 1995). al,BRUNO BAUMANN and BERNHARD BOGERTS These studies suggest that both bipolar and major depressive mood disorder might be associated with circumscribed neurodevelop- mental disturbances in temporal regions. Another alteration in the temporal lobe was reported by Benes and co-workers who showed a selective reduction of non- pyramidal neurons in the CA2 region on the hippocampus of patients with bipolarBackground Neuroimaging data In contrast to schizophrenia, little work has disorder and schizophrenia (Benes et al, al,showing structural and functional brain been done on the neurohistology of mood 1998). These studies confirm and extend disorders, indicating that this kind of research recent MRI findings suggesting a temporalabnormalities in mood disorders strategy is still in its infancy, and the results pathology not only in schizophrenia but alsosuggestthat brain alterations atthe obtained from these studies provide only a in bipolar disorder (Altshuler et al, 1998; al,neurohistologicallevel may underlie the fragmentary pattern. Most of the studies Roy et al, 1998; Strakowski et al, 1999). al, al,macropathology seen by imaging in vivo. vivo. include subjects who had committed suicide, The prefrontal lobe is another focus of and a retrospective diagnosis of a mood disor- interest in mood disorders (Goodwin, 1997).Aims To summarise recent post- der was not established in all cases. Some Decreased cortical and laminar thicknessmortem studies on affective disorders, investigations did not focus on affective disor- but unchanged overall neuronal density ders, but used subjects with mood disorders and laminar density were demonstrated inwith a focus on bipolar disorder. as a control group. Since this article empha- the dorsolateral prefrontal cortex in bothMethod Literature review and sises regional neurohistology, biochemical bipolar disorder and major depressive dis- studies performed on homogenate of brain tis- order. In contrast to patients with schizo-discussion of results from volumetric, sue are not considered in the following survey. phrenia, who also showed smaller corticalcyto-architectural and thickness but an increased neuronal densityimmunohistochemical analyses. in this area, patients with mood disorders POST-MORTEM STUDIES appear to have unchanged neuronal densi-Results Basal ganglia are smaller ties in this part of the prefrontal cortexin patients with depression irrespective Studies on brain structure (Rajkowska, 1997). Also relevant to moodof diagnostic polarity.In addition, higher One early post-mortem study found a disorders, theoretically speaking, are the greater brain weight, a thicker parahippo- medial prefrontal cortex and the anteriorneuron numbers have been reported in campal cortex and smaller temporal horns cingulate cortex. Drevets and colleaguesthe locus caeruleus of patients with bipolarthelocus in patients with affective disorder compared found a volume reduction and fewer glialdisorder compared with those with with those with schizophrenia (Brown et al, al, (but no neuronal) cells in the subgenualunipolar depression.Patients with bipolar 1986), suggesting that temporal lobe struc- prefrontal cortex ± which is part of theas well as unipolar illness show subtle ture differs in these disorders. Unfortunately, anterior cingulate cortex ± in familial no control group without neuropsychiatric mood disorders (Drevets et al, 1998). No al,structural deficits in the dorsal raphe. disorder was included in this study. There- differences were described between bipolarHistological data are consistent with a fore, it is difficult to compare these data with disorder and unipolar depression. In anotherregional reduction in the synthesis of magnetic resonance imaging (MRI) studies post-mortem study a layer-specific reduc-noradrenalin and serotonin, which that report smaller entorhinal cortex sizes tion of interneurons in the anterior cingu-appears to be compensated by in schizophrenia, but not in bipolar disor- late cortex was observed in subjects with der (Pearlson et al, 1997). It is conceivable, al, bipolar disorder (Vincent et al, 1997). This al,antidepressants. however, that a structural disturbance of is consistent with the finding of a deficit in the parahippocampal cortex is present in a neuronal subpopulation detected byConclusion Preliminary results mood disorders, since one post-mortem immunoreactivity for the calcium-bindingsuggestthat, aside from functional study showed a reduction in size of this protein calretinin (Diekmann et al, 1998). al,dysregulation, subtle structural cortex in suicide victims compared with These results confirm and extend previousabnormalities in the brain may contribute non-psychiatric controls (Altshuler et al, al, neuroimaging work revealing structuralto the pathogenesis of mood disorders. 1990). Further evidence for a disturbed and functional abnormalities of certain parts morphological integrity of this region comes of the prefrontal cortex in mood disordersDeclaration of interest This paper from cyto-architectural studies reporting (Goodwin, 1997).was supported by the Deutsch that malformations in the entorhinal lamination were observed in patients withForschungsgemeinschaft (79916 -1) (79916-1) Studies on monaminergic systems bipolar disorder or with major depressionand theTheodore and Vada Stanley (Beckmann & Jakob, 1991; Bernstein et al, al, Some neurohistological studies investigatedFoundation. 1998). In addition, one case report described the role of monaminergic systems in moods14 2
  • N E U R OA N ATO M I C A L S T U D I E S ON B I P OL A R D I S O R D E R ROA UDdisorders. The serotonergic system was Despite indirect evidence that dopami- circuits in mood disorders using materialanalysed in one study reporting increased nergic systems are involved in the pathogen- from our new Magdeburg brain collection.binding of 5-HT1A autoreceptors in the esis of mood disorders, only one study of this Possible post-mortem artefacts arising frommidbrain of subjects with major depression transmitter system has been performed, autolysis or tissue processing as well as ef-who had committed suicide, suggesting re- reporting increased binding of the D1 recep- fects of age and gender were excluded byduced activity of dorsal raphe neurons tor in the nucleus accumbens of suicide careful matching of the case. Effects of(Stockmeier et al, 1998). Another investiga- al, victims with major depression (Bowden et medication were also controlled for.tion on presynaptic markers showed al, 1997). The nucleus accumbens shows al, The brains of eight patients sufferingunchanged serotonin transporter binding intense connectivity with the prefrontal from major depression or bipolar disorderand mRNA levels in the midbrain, hippo- cortex, mainly with its medial part. Since showed reduced volumes of the left nucleuscampus or frontal cortex in cases of suicide structural changes in telencephalic basal accumbens, the right putamen and the rightfollowing major depression (Little et al, al, ganglia as well as in the prefrontal cortex and left pallidum externum (Figs 1 & 2).1997). Stockmeier et al (1997) found that have been shown in patients suffering from No differences were seen between bipolarthe 5-HT1A and the 5-HT2A receptors were major depression, the chemo-architecture chemo-architecture or unipolar depression. The nucleus accum-unchanged in the right frontopolar cortex. of these closely interconnected brain regions bens was most affected. These data suggestThus some, but not all, post-mortem stu- would be of interest in mood disorders. that predominantly limbic-affiliated basaldies support the indolaminergic hypothesis ganglia are involved in the pathology ofof depression. This is in line with an ima- mood disorders, irrespective of diagnostic Neuroendocrinological studiesging study indicating decreased density of polarity (Baumann et al, 1999a). al, 1999aserotonin transporter binding sites in the Some histological investigations have ad- The brains of patients with majormidbrain of patients with major depression dressed the central endocrine cell groups depressive illness showed a trend towards(Malison et al, 1998). These data on living al, in the hypothalamus of patients with mood volume reduction for the left amygdala thatpatients contrast with the negative post- disorders. Expression and messenger mRNA was not seen in the bipolar disordermortem findings in suicide victims with transcripts of corticotrophin-releasing hor- patients. Taking into account MRI findingsmajor depression (Little et al, 1997). Taken al, mone have been shown to be upregulated of enlargement of the amygdala in bipolartogether, some post-mortem and neuro- in neurons of the hypothalamic paraventri- disorder (Altshuler et al, 1998) and reduced al,imaging studies reveal alterations in sero- cular nucleus (Raadsheer et al, 1995). al, volumes of amygdala core nuclei (Shelinetonergic neurons in major depression. It Moreover, data from the same laboratory et al, 1998), these data suggest structural al,remains unclear whether these results, if found an upregulation of vasopressin- and differences in the amygdala between majorreplicable, can be generalised for bipolar oxytocin-expressing neurons in the same depression and bipolar disorder. Thedisorder. nucleus (Purba et al, 1996). These findings al, volumes of other limbic regions such as As yet, no investigation has focused on are consistent with clinical data showing the hippocampus, the temporal horn, thethe cyto-architecture of monaminergic neu- a central overactivation of the hypo- stria terminalis and the basic limbic fore-ron systems, such as the raphe nuclei or the thalamic±pituitary±adrenal axis in depres- brain were unchanged in our sample.locus caeruleus, in mood disorders. An inci- sive disorders (Arborelius et al, 1999). No al, Volumes of the thalamus and thedental note on a geriatric case of depression differences were seen between major de- hypothalamus also showed no differencesmentioned a considerable lack of locus pression and bipolar disorder in these between the whole patient sample groupcaeruleus neurons (Chan-Palay & Asan, post-mortem studies. The investigated sam- compared with controls. In major depres-1989), which is in agreement with a study ples, however, were too small to allow sion, however, the right hypothalamusshowing fewer neurons in this crucial general conclusions. was smaller than in controls (Pˆ0.02) (P 0.02)noradrenergic nucleus in suicide victims and the left hypothalamus showed a non-(Arango et al, 1996). This needs further al, VOLUME MEASURES IN significant trend with 13% smaller volumesconfirmation by studies on larger patient MOOD DISORDERS (Pˆ0.07). 0.07).samples including unipolar and bipolar These post-mortem volume studies con-affective disorder. A notable study on the In addition to neurohistological studies, firm and extend previous neuroanatomicalnoradrenergic system was performed by structural imaging data provide evidence models of mood regulation, suggesting aKlimek and co-workers who demonstrated for the assumption that mood disorders crucial role for ventral parts of telencephalic-decreased levels of the noradrenalin trans- are not exclusively functional illnesses but basal ganglia and the involvement of theporter in patients with major depressive ill- also show a diversity of morphological amygdala and hypothalamus in these cir-ness (Klimek et al, 1997). Another post- al, changes (Soares & Mann, 1997; Drevets cuits (for review, see Soares & Mann,mortem analysis showed increased density et al, 1998; Parashos et al, 1998). Despite al, al, 1997). The preliminary results also showof the a2A-adrenoreceptor in the frontal cor- modern computed tomography and MRI structural differences between majortex of suicide victims who had depression techniques, resolution is still too poor to depressive and bipolar disorder for the(Callado et al, 1998). These two results al, detect subtle structural alterations of small amygdala.point to a presynaptic noradrenergic deficit brain nuclei such as the hypothalamus orin this disorder consistent with the noradre- some parts of the basal ganglia. A post- BR AIN-STEM STUDIES ONnergic hypothesis of depression (Schidkraut mortem study was therefore begun to inves- MOOD DISORDERSet al, 1965). Neurohistological studies on al, tigate volumes of all telencephalic basalthe noradrenergic system in bipolar disorder ganglia, of the diencephalon, and of limbic Monaminergic (in particular serotonergicare still required. regions, to obtain data on relevant brain and noradrenergic) systems are assumed s14 3
  • B AU M A NN & B O G E R T Sto be essentially involved in the pathologyof mood disorders. However, to date thereis no information on the possible patho-morphology of the brain-stem nuclei thatproduce these transmitters. A neurohisto-logical investigation of the dorsal rapheand the locus caeruleus ± the main sourcesof serotonergic and noradrenergic forebraininnervation ± was therefore performed.Locus caeruleusTwelve post-mortem brains of patients withmood disorders as well as 12 brains of non-psychiatric control subjects were includedin the study. Six patients had major depres- Fig. 1 Brain structure volumes of patients with affective disorder (nˆ8, shaded bars) and controls (n 8,sive disorder, the other six bipolar disorder. (nˆ8, black bars) ^ caudate nucleus and putamen.The volume of the right putamen is reduced in patients. 8,Based on the topographic organisation of *P40.05. Reproduced with permission from Baumann et al (1999a ). (1999aprojections from the locus caeruleus (LC),we performed neuron counts separated forthe dorsal, medial and ventral portions, aswell as the rostral, medial and caudal por-tions of this nucleus (Baumann et al, al,1999b). Surprisingly, total neuron numbers1999bin the whole nucleus were higher in bipolarthan unipolar disorder, with this phenom-enon being observed on both sides of theLC (Fig. 3). The finding of an enlargedLC in bipolar disorder is consistent with a`hypernormal pattern of bipolar disordermorphology comprising larger thalamic Fig. 2 Brain structure volumes of patients with affective disorder (nˆ8, shaded bars) and controls (n 8,volumes (Dupont et al, 1995), greater al, (nˆ8, black bars) ^ nucleus accumbens (NAc), pallidum externum (PE) and pallidum internum (PI). Reduced 8,grey/white ratios (Strakowski et al, 1993), al, volumes of the left NAc and both pallida external are seen in patients. *P40.05. Reproduced with permission *Pincreased gyral complexity (Bullmore et al, al, from Baumann et al (1999a ). (1999a1994) and enlarged amygdala (Altshuler etal, 1998; Strakowski et al, 1999).al, al, Topographical analysis revealed that 1994), this wide range of transmissionthe structural difference is restricted to the could provide a predisposition for bipolarrostral two-thirds and the dorsal part of psychomotor symptoms.the LC, in which patients with bipolar dis- In order to prove noradrenergicorder showed at least a trend to higher function of the LC we performed immuno-neuron numbers compared with patients histochemical analysis of tyrosine hydroxy-with major depression or controls. With lase, the key enzyme in noradrenalinregard to the topography of LC projections synthesis (Baumann et al, 1999c). The al, 1999c(Mason & Fibiger, 1979; Loughlin et al, al, number of tyrosine hydroxylase-immuno-1982, 1986), it is conceivable that cortical, reactive (TH-ir) neurons did not differhippocampal and hypothalamic projections between patients with bipolar and unipolarfrom the LC are part of a morphological disorder, nor between patients and con-substrate for the unipolar±bipolar dicho- trols. Further data analysis indicated thattomy of mood disorders. Together with suicide might be associated with caerulean Fig. 3 Pigmented neurons in the locus caeruleusmeasurements of noradrenalin or its noradrenergic function. The number of of patients with bipolar disorder (nˆ6, white bars), (n 6,metabolites in mood disorders (Roy et al, al, TH-ir neurons in patients with unipolar or major depressive disorder (nˆ6, shaded bars) and (n 6,1985; Azorin et al, 1990), our data indicate al, bipolar disorder who died from natural controls (black bars). Reduced neuron numbers arethat the span between minimum and maxi- causes was lower than in suicide victims seen in patients. *P40.05. Reproduced with permis- *Pmum caerulean noradrenergic transmission and controls (Fig. 4). This difference re- sion from Baumann et al (1999b). (1999bin certain brain areas is greater in bipolar mained significant after covarian analysisdisorder than in major depressive disorder. for mean doses of recent medication with group. Numbers of TH-ir neurons corre-Since noradrenergic tone correlates primarily tricyclic or tetracyclic antidepressants. lated positively with mean doses of tricyclicwith clinical symptoms of drive (Carr et al,al, Unipolar and bipolar diagnoses were equally or tetracyclic antidepressants. These results1988; Katz et al, 1994; Swann et al, al, al, disturbed in the suicide and non-suicide suggest a presynaptic noradrenergic deficits14 4
  • N E U R OA N ATO M I C A L S T U D I E S ON B I P OL A R D I S O R D E R ROA UDof the LC in non-suicidal patients with de-pression irrespective of unipolar or bipolardiagnosis; they also provide indirectevidence that suicidal behaviour may berelated to normalised noradrenergic func-tion, and that traditional antidepressantsmay enhance noradrenergic activity of theLC in patients with depression.Dorsal rapheThe dorsal raphe (DR) exhibits a topo-graphic organisation similar to that of theLC. For example, neuronal projections tothe prefrontal cortex and combined pro-jections to the nucleus accumbens and the Fig. 4 Tyrosine hydroxylase-immunoreactive Fig. 5 Neuron numbers in ventral subnuclei of theprefrontal cortex arise from more ventral neurons in the locus caeruleus.There are fewer dorsal raphe. Reduced numbers are seen in patientsand rostral subnuclei of the DR (OHearn immunoreactive neurons in the depressed non- with major depressive disorder (unipolar) and bipolar& Molliver, 1984; Wilson & Molliver, suicide group compared with the depressed suicide disorder.The line indicates the mean value for each1991; Kazakov et al, 1993; Van Bockstaele al, group and controls; a, significant group effect group.et al, 1993). Both these projection targets al, (Fˆ4.63, d.f.ˆ2, 21, Pˆ0.02); b, significant post-hoc 4.63, d.f. 2, 0.02);have been implicated in the pathology ofdepression. Together with the median test; c, significant post-hoc test. Reproduced with the DRvp in patients with mood disordersraphe, the DR provides the ascending permission from Baumann et al (1999c ). (1999c treated by antidepressants is partly com-serotonergic raphe projections to the fore- pensated for by upregulation of serotoninbrain. From these topographic aspects of synthesis as an effect of antidepressantthe raphe system it has been assumed that of depressive illness subtype. This structural medication. Moreover, our data suggestthe DR has a major role in mood regulation change may contribute to impaired sero- that in mood disorders, irrespective of(Molliver, 1987). The cyto-architecture of tonergic innervation of brain regions that diagnostic polarity and apart from medi-this complex nucleus was investigated in are involved in the pathology of mood dis- cation, synthesis of serotonin may be state-post-mortem brains of 12 patients with order. Increased nucleolar size indicating dependently reduced in distinct regions ofmood disorders and 12 subjects without neuronal activation in the DR may reflect the DR.any neuropsychiatric disorder. The ventral an adaptive process partly induced by anti-parts of the mesencephalic DR (DRvp), depressant medication.i.e. the interfascicular, ventral and ventro- In order to gain a closer insight CONCLUSIONlateral subnuclei, showed fewer neurons in into serotonergic function of the DR,patients with a mood disorder (Fig. 5). tryptophan hydroxylase was investigated There are few post-mortem studies on bi-No differences were seen between major by immunodetection in the same sample. polar disorder, and definite conclusionsdepression and bipolar disorder in this Numbers of tryptophan hydroxylase- can hardly be drawn owing to the smallrespect. Morphological analysis revealed immunoreactive (TPH-ir) neurons did not and selective nature of the samples, whichthat the reduction in the number of neurons differ between patients and controls, either in particular might produce false-negativein patients with a mood disorder was in the DRvp or in the dorsal or caudal parts results. Moreover, problems sometimesrestricted to the ovoid and round neurons. of the DR. In the group of patients, arise from effects of medication or agonal Since approximately 70% of the human however, there was a significant correlation and post-mortem changes. Data obtainedDR neurons are serotonergic, the lack of of TPH-ir neurons in the DRvp with mean from neuroimaging in mood disordersneurons in the DRvp is mostly consistent dosage of antidepressants given in the last showing structural abnormalities in thewith a regional deficit of serotonergic neu- 7 days before death (rˆ0.69, nˆ12, (r 0.69, 12, frontal and temporal cortices as well as inrons in mood disorders. Neuronal nucleoli Pˆ0.01). On the level of single subnuclei, 0.01). subcortical regions are widely confirmed,appeared enlarged in the DRvp of patients this association was most prominent in and also extended and specified, by resultswith mood disorders, suggesting neuronal the right ventrolateral nucleus. Using from neurohistological investigations. Basalactivation in this area. While antidepressant antidepressant medication as covariate ganglia, preferentially those closely asso-medication showed no correlation with (ANCOVA), a nearly significant reduction ciated with the limbic system, have smallerneuron numbers in any part of the DR, a was found for TPH-ir neurons in the DRvp, volumes in patients with depressive illnesspositive correlation of mean dosage of anti- but not in the dorsal or caudal DR of irrespective of diagnostic polarity. Higherdepressant agents with nucleolar size was patients. No difference was observed neuron numbers in the locus caeruleus offound for the right ventrolateral sub- between major depressive and bipolar dis- patients with bipolar disorder than in thatnucleus, which is part of the DRvp. order samples. of patients with major depressive disorder These results show that patients with a Unchanged serotonin immunohisto- are in agreement with neuroimaging dataprimary mood disorder have a numeric chemistry and a reduction in Nissl-stained indicating a `hypernormal structural pat-neuronal deficit in the DRvp, irrespective neurons indicate that a neuronal deficit in tern in bipolar disorder that does not s14 5
  • B AU M A NN & B O G E R T Sappear to exist in major depression. Post-mortem studies showed no differences CLINICAL IMPLICATIONSbetween the two types of disorder fornoradrenalin and serotonin synthesis in & Morphological changes in basal ganglia and monaminergic transmitter systems maythe locus caeruleus and the dorsal raphe. be vulnerability markers for unipolar disorder.Our data suggest a regionally reducedsynthesis of these neurotransmitters, which & Brain biology differs between bipolar and unipolar disorders, suggesting the needhave a major role in the pathogenesis of for different treatment strategies.mood disorders. Antidepressant medication & Effects of antidepressants may be mediated by changes in monaminergic brain-seems to increase serotonin and noradrena-lin production in depressive states and may stem neurons.thereby contribute to normalisation of LIMITATIONSmonaminergic functions. & Neurohistological research in bipolar disorder is in its infancy and as yet providesREFERENCES only a preliminary assessment of morphological changes involved with this disease.Altshuler, L. L., Casanova, M. F., Goldberg,T. E., et al & Relatively small sample sizes and the high proportion of suicide cases in post-(1990) The hippocampus and parahippocampus inschizophrenia, suicide, and control brains. Archives of mortem studies on mood disorders make it difficult to generalise findings.General Psychiatry, 47, 1029^1034. 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