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  • 1. BackgroundBackground NeuroimagingdataNeuroimagingdata showing structural and functionalbrainshowing structural and functionalbrain abnormalitiesinmood disordersabnormalitiesinmood disorders suggestthat brain alterations atthesuggestthat brain alterations atthe neurohistologicallevelmayunderlietheneurohistologicallevelmayunderliethe macropathologyseen byimagingmacropathology seen byimagingin vivoin vivo.. AimsAims To summariserecentpost-To summariserecentpost- mortem studies on affective disorders,mortem studies on affective disorders, with a focus on bipolardisorder.with a focus on bipolardisorder. MethodMethod Literaturereview andLiteraturereview and discussion ofresults fromvolumetric,discussion of results fromvolumetric, cyto-architectural andcyto-architectural and immunohistochemical analyses.immunohistochemical analyses. ResultsResults Basalganglia are smallerBasalganglia are smaller inpatientswith depressionirrespectiveinpatientswith depressionirrespective of diagnostic polarity.In addition, higherofdiagnostic polarity.In addition, higher neuronnumbershave beenreportedinneuronnumbers have beenreportedin thelocuscaeruleusofpatientswithbipolarthelocuscaeruleusofpatientswithbipolar disordercomparedwiththose withdisordercomparedwiththose with unipolardepression.Patientswith bipolarunipolardepression.Patientswith bipolar aswell asunipolarillness show subtleaswell asunipolarillness show subtle structuraldeficitsinthe dorsalraphe.structural deficitsinthe dorsalraphe. Histologicaldata are consistent with aHistologicaldata are consistent with a regionalreductioninthe synthesis ofregionalreductioninthe synthesis of noradrenalin and serotonin, whichnoradrenalin and serotonin, which appears to be compensated byappears to be compensated by antidepressants.antidepressants. ConclusionConclusion PreliminaryresultsPreliminaryresults suggestthat, aside fromfunctionalsuggestthat, aside fromfunctional dysregulation, subtle structuraldysregulation, subtle structural abnormalitiesinthe brainmaycontributeabnormalitiesinthe brainmaycontribute tothe pathogenesis of mood disorders.tothe pathogenesis of mood disorders. Declaration of interestDeclaration of interest ThispaperThispaper was supported by the Deutschwas supported by the Deutsch Forschungsgemeinschaft (79916-1)Forschungsgemeinschaft (79916-1) andtheTheodore and Vada StanleyandtheTheodore and Vada Stanley Foundation.Foundation. In contrast to schizophrenia, little work hasIn contrast to schizophrenia, little work has been done on the neurohistology of moodbeen done on the neurohistology of mood disorders, indicating that this kind of researchdisorders, indicating that this kind of research strategy is still in its infancy, and the resultsstrategy is still in its infancy, and the results obtained from these studies provide only aobtained from these studies provide only a fragmentary pattern. Most of the studiesfragmentary pattern. Most of the studies include subjects who had committed suicide,include subjects who had committed suicide, and a retrospective diagnosis of a mood disor-and a retrospective diagnosis of a mood disor- der was not established in all cases. Someder was not established in all cases. Some investigations did not focus on affective disor-investigations did not focus on affective disor- ders, but used subjects with mood disordersders, but used subjects with mood disorders as a control group. Since this article empha-as a control group. Since this article empha- sises regional neurohistology, biochemicalsises regional neurohistology, biochemical studies performedon homogenateofbrain tis-studiesperformed onhomogenate ofbrain tis- sue arenotconsidered in the followingsurvey.sueare not consideredin the following survey. POST-MORTEM STUDIESPOST-MORTEM STUDIES Studies on brain structureStudies on brain structure One early post-mortem study found aOne early post-mortem study found a greater brain weight, a thicker parahippo-greater brain weight, a thicker parahippo- campal cortex and smaller temporal hornscampal cortex and smaller temporal horns in patients with affective disorder comparedin patients with affective disorder compared with those with schizophrenia (Brownwith those with schizophrenia (Brown et alet al,, 1986), suggesting that temporal lobe struc-1986), suggesting that temporal lobe struc- ture differs in these disorders. Unfortunately,ture differs in these disorders. Unfortunately, no control group without neuropsychiatricno control group without neuropsychiatric disorder was included in this study. There-disorder was included in this study. There- fore, it is difficult to compare these data withfore, it is difficult to compare these data with magnetic resonance imaging (MRI) studiesmagnetic resonance imaging (MRI) studies that report smaller entorhinal cortex sizesthat report smaller entorhinal cortex sizes in schizophrenia, but not in bipolar disor-in schizophrenia, but not in bipolar disor- der (Pearlsonder (Pearlson et alet al, 1997). It is conceivable,, 1997). It is conceivable, however, that a structural disturbance ofhowever, that a structural disturbance of the parahippocampal cortex is present inthe parahippocampal cortex is present in mood disorders, since one post-mortemmood disorders, since one post-mortem study showed a reduction in size of thisstudy showed a reduction in size of this cortex in suicide victims compared withcortex in suicide victims compared with non-psychiatric controls (Altshulernon-psychiatric controls (Altshuler et alet al,, 1990). Further evidence for a disturbed1990). Further evidence for a disturbed morphological integrity of this region comesmorphological integrity of this region comes from cyto-architectural studies reportingfrom cyto-architectural studies reporting that malformations in the entorhinalthat malformations in the entorhinal lamination were observed in patients withlamination were observed in patients with bipolar disorder or with major depressionbipolar disorder or with major depression (Beckmann & Jakob, 1991; Bernstein(Beckmann & Jakob, 1991; Bernstein et alet al,, 1998). In addition, one case report described1998). In addition, one case report described a temporo-occipital cortical dysplasia asso-a temporo-occipital cortical dysplasia asso- ciated with rapid-cycling bipolar disorder andciated with rapid-cycling bipolar disorder and learning disability (Raghavanlearning disability (Raghavan et alet al, 1995)., 1995). These studies suggest that both bipolar andThese studies suggest that both bipolar and major depressive mood disorder might bemajor depressive mood disorder might be associated with circumscribed neurodevelop-associated with circumscribed neurodevelop- mental disturbances in temporal regions.mental disturbances in temporal regions. Another alteration in the temporalAnother alteration in the temporal lobe was reported by Benes and co-workerslobe was reported by Benes and co-workers who showed a selective reduction of non-who showed a selective reduction of non- pyramidal neurons in the CA2 region onpyramidal neurons in the CA2 region on the hippocampus of patients with bipolarthe hippocampus of patients with bipolar disorder and schizophrenia (Benesdisorder and schizophrenia (Benes et alet al,, 1998). These studies confirm and extend1998). These studies confirm and extend recent MRI findings suggesting a temporalrecent MRI findings suggesting a temporal pathology not only in schizophrenia but alsopathology not only in schizophrenia but also in bipolar disorder (Altshulerin bipolar disorder (Altshuler et alet al, 1998;, 1998; RoyRoy et alet al, 1998; Strakowski, 1998; Strakowski et alet al, 1999)., 1999). The prefrontal lobe is another focus ofThe prefrontal lobe is another focus of interest in mood disorders (Goodwin, 1997).interest in mood disorders (Goodwin, 1997). Decreased cortical and laminar thicknessDecreased cortical and laminar thickness but unchanged overall neuronal densitybut unchanged overall neuronal density and laminar density were demonstrated inand laminar density were demonstrated in the dorsolateral prefrontal cortex in boththe dorsolateral prefrontal cortex in both bipolar disorder and major depressive dis-bipolar disorder and major depressive dis- order. In contrast to patients with schizo-order. In contrast to patients with schizo- phrenia, who also showed smaller corticalphrenia, who also showed smaller cortical thickness but an increased neuronal densitythickness but an increased neuronal density in this area, patients with mood disordersin this area, patients with mood disorders appear to have unchanged neuronal densi-appear to have unchanged neuronal densi- ties in this part of the prefrontal cortexties in this part of the prefrontal cortex (Rajkowska, 1997). Also relevant to mood(Rajkowska, 1997). Also relevant to mood disorders, theoretically speaking, are thedisorders, theoretically speaking, are the medial prefrontal cortex and the anteriormedial prefrontal cortex and the anterior cingulate cortex. Drevets and colleaguescingulate cortex. Drevets and colleagues found a volume reduction and fewer glialfound a volume reduction and fewer glial (but no neuronal) cells in the subgenual(but no neuronal) cells in the subgenual prefrontal cortex ± which is part of theprefrontal cortex ± which is part of the anterior cingulate cortex ± in familialanterior cingulate cortex ± in familial mood disorders (Drevetsmood disorders (Drevets et alet al, 1998). No, 1998). No differences were described between bipolardifferences were described between bipolar disorder and unipolar depression. In anotherdisorder and unipolar depression. In another post-mortem study a layer-specific reduc-post-mortem study a layer-specific reduc- tion of interneurons in the anterior cingu-tion of interneurons in the anterior cingu- late cortex was observed in subjects withlate cortex was observed in subjects with bipolar disorder (Vincentbipolar disorder (Vincent et alet al, 1997). This, 1997). This is consistent with the finding of a deficit inis consistent with the finding of a deficit in a neuronal subpopulation detected bya neuronal subpopulation detected by immunoreactivity for the calcium-bindingimmunoreactivity for the calcium-binding protein calretinin (Diekmannprotein calretinin (Diekmann et alet al, 1998)., 1998). These results confirm and extend previousThese results confirm and extend previous neuroimaging work revealing structuralneuroimaging work revealing structural and functional abnormalities of certain partsand functional abnormalities of certain parts of the prefrontal cortex in mood disordersof the prefrontal cortex in mood disorders (Goodwin, 1997).(Goodwin, 1997). Studies on monaminergic systemsStudies on monaminergic systems Some neurohistological studies investigatedSome neurohistological studies investigated the role of monaminergic systems in moodthe role of monaminergic systems in mood s14 2s14 2 B R I T IS H J O UR N AL O F P SYC HI AT RYBR I T IS H J O URNA L O F P SYC HIAT RY ( 2 0 0 1) , 17 8 ( s u p p l . 4 1) , s1 4 2 ^ s1 4 7( 2 0 0 1) , 17 8 ( s u p p l . 4 1) , s14 2 ^ s14 7 Neuroanatomical studies on bipolar disorderNeuroanatomical studies on bipolar disorder BRUNO BAUMANN and BERNHARD BOGERTSBRUNO BAUMANN and BERNHARD BOGERTS
  • 2. NEUROANATOMIC AL S TUDIE S ON B IP OL AR DIS OR D E RNEUROANATOMIC AL S TUDIE S ON B IP OL AR DIS OR D E R disorders. The serotonergic system wasdisorders. The serotonergic system was analysed in one study reporting increasedanalysed in one study reporting increased binding of 5-HTbinding of 5-HT1A1A autoreceptors in theautoreceptors in the midbrain of subjects with major depressionmidbrain of subjects with major depression who had committed suicide, suggesting re-who had committed suicide, suggesting re- duced activity of dorsal raphe neuronsduced activity of dorsal raphe neurons (Stockmeier(Stockmeier et alet al, 1998). Another investiga-, 1998). Another investiga- tion on presynaptic markers showedtion on presynaptic markers showed unchanged serotonin transporter bindingunchanged serotonin transporter binding and mRNA levels in the midbrain, hippo-and mRNA levels in the midbrain, hippo- campus or frontal cortex in cases of suicidecampus or frontal cortex in cases of suicide following major depression (Littlefollowing major depression (Little et alet al,, 1997). Stockmeier1997). Stockmeier et alet al (1997) found that(1997) found that the 5-HTthe 5-HT1A1A and the 5-HTand the 5-HT2A2A receptors werereceptors were unchanged in the right frontopolar cortex.unchanged in the right frontopolar cortex. Thus some, but not all, post-mortem stu-Thus some, but not all, post-mortem stu- dies support the indolaminergic hypothesisdies support the indolaminergic hypothesis of depression. This is in line with an ima-of depression. This is in line with an ima- ging study indicating decreased density ofging study indicating decreased density of serotonin transporter binding sites in theserotonin transporter binding sites in the midbrain of patients with major depressionmidbrain of patients with major depression (Malison(Malison et alet al, 1998). These data on living, 1998). These data on living patients contrast with the negative post-patients contrast with the negative post- mortem findings in suicide victims withmortem findings in suicide victims with major depression (Littlemajor depression (Little et alet al, 1997). Taken, 1997). Taken together, some post-mortem and neuro-together, some post-mortem and neuro- imaging studies reveal alterations in sero-imaging studies reveal alterations in sero- tonergic neurons in major depression. Ittonergic neurons in major depression. It remains unclear whether these results, ifremains unclear whether these results, if replicable, can be generalised for bipolarreplicable, can be generalised for bipolar disorder.disorder. As yet, no investigation has focused onAs yet, no investigation has focused on the cyto-architecture of monaminergic neu-the cyto-architecture of monaminergic neu- ron systems, such as the raphe nuclei or theron systems, such as the raphe nuclei or the locus caeruleus, in mood disorders. An inci-locus caeruleus, in mood disorders. An inci- dental note on a geriatric case of depressiondental note on a geriatric case of depression mentioned a considerable lack of locusmentioned a considerable lack of locus caeruleus neurons (Chan-Palay & Asan,caeruleus neurons (Chan-Palay & Asan, 1989), which is in agreement with a study1989), which is in agreement with a study showing fewer neurons in this crucialshowing fewer neurons in this crucial noradrenergic nucleus in suicide victimsnoradrenergic nucleus in suicide victims (Arango(Arango et alet al, 1996). This needs further, 1996). This needs further confirmation by studies on larger patientconfirmation by studies on larger patient samples including unipolar and bipolarsamples including unipolar and bipolar affective disorder. A notable study on theaffective disorder. A notable study on the noradrenergic system was performed bynoradrenergic system was performed by Klimek and co-workers who demonstratedKlimek and co-workers who demonstrated decreased levels of the noradrenalin trans-decreased levels of the noradrenalin trans- porter in patients with major depressive ill-porter in patients with major depressive ill- ness (Klimekness (Klimek et alet al, 1997). Another post-, 1997). Another post- mortem analysis showed increased densitymortem analysis showed increased density of theof the aa2A2A-adrenoreceptor in the frontal cor--adrenoreceptor in the frontal cor- tex of suicide victims who had depressiontex of suicide victims who had depression (Callado(Callado et alet al,, 1998). These two results1998). These two results point to a presynaptic noradrenergic deficitpoint to a presynaptic noradrenergic deficit in this disorder consistent with the noradre-in this disorder consistent with the noradre- nergic hypothesis of depression (Schidkrautnergic hypothesis of depression (Schidkraut et alet al, 1965). Neurohistological studies on, 1965). Neurohistological studies on the noradrenergic system in bipolar disorderthe noradrenergic system in bipolar disorder are still required.are still required. Despite indirect evidence that dopami-Despite indirect evidence that dopami- nergic systems are involved in the pathogen-nergic systems are involved in the pathogen- esis of mood disorders, only one study of thisesis of mood disorders, only one study of this transmitter system has been performed,transmitter system has been performed, reporting increased binding of the D1 recep-reporting increased binding of the D1 recep- tor in the nucleus accumbens of suicidetor in the nucleus accumbens of suicide victims with major depression (Bowdenvictims with major depression (Bowden etet alal, 1997). The nucleus accumbens, 1997). The nucleus accumbens showsshows intense connectivity with the prefrontalintense connectivity with the prefrontal cortex, mainly with its medial part. Sincecortex, mainly with its medial part. Since structural changes in telencephalic basalstructural changes in telencephalic basal ganglia as well as in the prefrontal cortexganglia as well as in the prefrontal cortex have been shown in patients sufferinghave been shown in patients suffering fromfrom major depression, the chemo-major depression, the chemo-architecturearchitecture of these closely interconnected brain regionsof these closely interconnected brain regions would be of interest in mood disorders.would be of interest in mood disorders. Neuroendocrinological studiesNeuroendocrinological studies Some histological investigations have ad-Some histological investigations have ad- dressed the central endocrine cell groupsdressed the central endocrine cell groups in the hypothalamus of patients with moodin the hypothalamus of patients with mood disorders. Expression and messenger mRNAdisorders. Expression and messenger mRNA transcripts of corticotrophin-releasing hor-transcripts of corticotrophin-releasing hor- mone have been shown to be upregulatedmone have been shown to be upregulated in neurons of the hypothalamic paraventri-in neurons of the hypothalamic paraventri- cular nucleus (Raadsheercular nucleus (Raadsheer et alet al, 1995)., 1995). Moreover, data from the same laboratoryMoreover, data from the same laboratory found an upregulation of vasopressin- andfound an upregulation of vasopressin- and oxytocin-expressing neurons in the sameoxytocin-expressing neurons in the same nucleus (Purbanucleus (Purba et alet al, 1996). These findings, 1996). These findings are consistent with clinical data showingare consistent with clinical data showing a central overactivation of the hypo-a central overactivation of the hypo- thalamic±pituitary±adrenal axis in depres-thalamic±pituitary±adrenal axis in depres- sive disorders (Arboreliussive disorders (Arborelius et alet al, 1999). No, 1999). No differences were seen between major de-differences were seen between major de- pression and bipolar disorder in thesepression and bipolar disorder in these post-mortem studies. The investigated sam-post-mortem studies. The investigated sam- ples, however, were too small to allowples, however, were too small to allow general conclusions.general conclusions. VOLUME MEASURES INVOLUME MEASURES IN MOOD DISORDERSMOOD DISORDERS In addition to neurohistological studies,In addition to neurohistological studies, structural imaging data provide evidencestructural imaging data provide evidence for the assumption that mood disordersfor the assumption that mood disorders are not exclusively functional illnesses butare not exclusively functional illnesses but also show a diversity of morphologicalalso show a diversity of morphological changes (Soares & Mann, 1997; Drevetschanges (Soares & Mann, 1997; Drevets et alet al, 1998; Parashos, 1998; Parashos et alet al, 1998). Despite, 1998). Despite modern computed tomography and MRImodern computed tomography and MRI techniques, resolution is still too poor totechniques, resolution is still too poor to detect subtle structural alterations of smalldetect subtle structural alterations of small brain nuclei such as the hypothalamus orbrain nuclei such as the hypothalamus or some parts of the basal ganglia. A post-some parts of the basal ganglia. A post- mortem study was therefore begun to inves-mortem study was therefore begun to inves- tigate volumes of all telencephalic basaltigate volumes of all telencephalic basal ganglia, of the diencephalon, and of limbicganglia, of the diencephalon, and of limbic regions, to obtain data on relevant brainregions, to obtain data on relevant brain circuits in mood disorders using materialcircuits in mood disorders using material from our new Magdeburg brain collection.from our new Magdeburg brain collection. Possible post-mortem artefacts arising fromPossible post-mortem artefacts arising from autolysis or tissue processing as well as ef-autolysis or tissue processing as well as ef- fects of age and gender were excluded byfects of age and gender were excluded by careful matching of the case. Effects ofcareful matching of the case. Effects of medication were also controlled for.medication were also controlled for. The brains of eight patients sufferingThe brains of eight patients suffering from major depression or bipolar disorderfrom major depression or bipolar disorder showed reduced volumes of the left nucleusshowed reduced volumes of the left nucleus accumbens, the right putamen and the rightaccumbens, the right putamen and the right and left pallidum externum (Figs 1 & 2).and left pallidum externum (Figs 1 & 2). No differences were seen between bipolarNo differences were seen between bipolar or unipolar depression. The nucleus accum-or unipolar depression. The nucleus accum- bens was most affected. These data suggestbens was most affected. These data suggest that predominantly limbic-affiliated basalthat predominantly limbic-affiliated basal ganglia are involved in the pathology ofganglia are involved in the pathology of mood disorders, irrespective of diagnosticmood disorders, irrespective of diagnostic polarity (Baumannpolarity (Baumann et alet al, 1999, 1999aa).). The brains of patients with majorThe brains of patients with major depressive illness showed a trend towardsdepressive illness showed a trend towards volume reduction for the left amygdala thatvolume reduction for the left amygdala that was not seen in the bipolar disorderwas not seen in the bipolar disorder patients. Taking into account MRI findingspatients. Taking into account MRI findings of enlargement of the amygdala in bipolarof enlargement of the amygdala in bipolar disorder (Altshulerdisorder (Altshuler et alet al, 1998) and reduced, 1998) and reduced volumes of amygdala core nuclei (Shelinevolumes of amygdala core nuclei (Sheline et alet al, 1998), these data suggest structural, 1998), these data suggest structural differences in the amygdala between majordifferences in the amygdala between major depression and bipolar disorder. Thedepression and bipolar disorder. The volumes of other limbic regions such asvolumes of other limbic regions such as the hippocampus, the temporal horn, thethe hippocampus, the temporal horn, the stria terminalis and the basic limbic fore-stria terminalis and the basic limbic fore- brainbrain were unchanged in our sample.were unchanged in our sample. Volumes of the thalamus and theVolumes of the thalamus and the hypothalamus also showed no differenceshypothalamus also showed no differences between the whole patient sample groupbetween the whole patient sample group compared with controls. In major depres-compared with controls. In major depres- sion, however, the right hypothalamussion, however, the right hypothalamus was smaller than in controls (was smaller than in controls (PPˆ0.02)0.02) and the left hypothalamus showed a non-and the left hypothalamus showed a non- significant trend with 13% smaller volumessignificant trend with 13% smaller volumes ((PPˆ0.07).0.07). These post-mortem volume studies con-These post-mortem volume studies con- firm and extend previous neuroanatomicalfirm and extend previous neuroanatomical models of mood regulation, suggesting amodels of mood regulation, suggesting a crucial role for ventral parts of telencephalic-crucial role for ventral parts of telencephalic- basal ganglia and the involvement ofbasal ganglia and the involvement of thethe amygdala and hypothalamus in these cir-amygdala and hypothalamus in these cir- cuits (for review, see Soares & Mann,cuits (for review, see Soares & Mann, 1997). The preliminary results also show1997). The preliminary results also show structural differences between majorstructural differences between major depressive and bipolar disorder for thedepressive and bipolar disorder for the amygdala.amygdala. BRAIN-STEM STUDIES ONBRAIN-STEM STUDIES ON MOOD DISORDERSMOOD DISORDERS Monaminergic (in particular serotonergicMonaminergic (in particular serotonergic and noradrenergic) systems are assumedand noradrenergic) systems are assumed s14 3s14 3
  • 3. B AUMANN & BOGE R T SB AUMANN & B OG E R T S to be essentially involved in the pathologyto be essentially involved in the pathology of mood disorders. However, to date thereof mood disorders. However, to date there is no information on the possible patho-is no information on the possible patho- morphology of the brain-stem nuclei thatmorphology of the brain-stem nuclei that produce these transmitters. A neurohisto-produce these transmitters. A neurohisto- logical investigation of the dorsal raphelogical investigation of the dorsal raphe and the locus caeruleus ± the main sourcesand the locus caeruleus ± the main sources of serotonergic and noradrenergic forebrainof serotonergic and noradrenergic forebrain innervation ± was therefore performed.innervation ± was therefore performed. Locus caeruleusLocus caeruleus Twelve post-mortem brains of patients withTwelve post-mortem brains of patients with mood disorders as well as 12 brains of non-mood disorders as well as 12 brains of non- psychiatric control subjects were includedpsychiatric control subjects were included in the study. Six patients had major depres-in the study. Six patients had major depres- sive disorder, the other six bipolar disorder.sive disorder, the other six bipolar disorder. Based on the topographic organisation ofBased on the topographic organisation of projections from the locus caeruleus (LC),projections from the locus caeruleus (LC), we performed neuron counts separated forwe performed neuron counts separated for the dorsal, medial and ventral portions, asthe dorsal, medial and ventral portions, as well as the rostral, medial and caudal por-well as the rostral, medial and caudal por- tions of this nucleus (Baumanntions of this nucleus (Baumann et alet al,, 19991999bb). Surprisingly, total neuron numbers). Surprisingly, total neuron numbers in the whole nucleus were higher in bipolarin the whole nucleus were higher in bipolar than unipolar disorder, with this phenom-than unipolar disorder, with this phenom- enon being observed on both sides of theenon being observed on both sides of the LC (Fig. 3). The finding of an enlargedLC (Fig. 3). The finding of an enlarged LC in bipolar disorder is consistent with aLC in bipolar disorder is consistent with a `hypernormal' pattern of bipolar disorder`hypernormal' pattern of bipolar disorder morphology comprising larger thalamicmorphology comprising larger thalamic volumes (Dupontvolumes (Dupont et alet al, 1995), greater, 1995), greater grey/white ratios (Strakowskigrey/white ratios (Strakowski et alet al, 1993),, 1993), increased gyral complexity (Bullmoreincreased gyral complexity (Bullmore et alet al,, 1994) and enlarged amygdala (Altshuler1994) and enlarged amygdala (Altshuler etet alal, 1998; Strakowski, 1998; Strakowski et alet al, 1999)., 1999). Topographical analysis revealed thatTopographical analysis revealed that the structural difference is restricted to thethe structural difference is restricted to the rostral two-thirds and the dorsal part ofrostral two-thirds and the dorsal part of the LC, in which patients with bipolar dis-the LC, in which patients with bipolar dis- order showed at least a trend to higherorder showed at least a trend to higher neuron numbers compared with patientsneuron numbers compared with patients with major depression or controls. Withwith major depression or controls. With regard to the topography of LC projectionsregard to the topography of LC projections (Mason & Fibiger, 1979; Loughlin(Mason & Fibiger, 1979; Loughlin et alet al,, 1982, 1986), it is conceivable that cortical,1982, 1986), it is conceivable that cortical, hippocampal and hypothalamic projectionshippocampal and hypothalamic projections from the LC are part of a morphologicalfrom the LC are part of a morphological substrate for the unipolar±bipolar dicho-substrate for the unipolar±bipolar dicho- tomy of mood disorders. Together withtomy of mood disorders. Together with measurements of noradrenalin or itsmeasurements of noradrenalin or its metabolites in mood disorders (Roymetabolites in mood disorders (Roy et alet al,, 1985; Azorin1985; Azorin et alet al, 1990), our data indicate, 1990), our data indicate that the span between minimum and maxi-that the span between minimum and maxi- mum caerulean noradrenergic transmissionmum caerulean noradrenergic transmission in certain brain areas is greater in bipolarin certain brain areas is greater in bipolar disorder than in major depressive disorder.disorder than in major depressive disorder. Since noradrenergic tone correlates primarilySince noradrenergic tone correlates primarily with clinical symptoms of drive (Carrwith clinical symptoms of drive (Carr et alet al,, 1988; Katz1988; Katz et alet al, 1994; Swann, 1994; Swann et alet al,, 1994), this wide range of transmission1994), this wide range of transmission could provide a predisposition for bipolarcould provide a predisposition for bipolar psychomotor symptoms.psychomotor symptoms. In order to prove noradrenergicIn order to prove noradrenergic function of the LC we performed immuno-function of the LC we performed immuno- histochemical analysis of tyrosine hydroxy-histochemical analysis of tyrosine hydroxy- lase, the key enzyme in noradrenalinlase, the key enzyme in noradrenalin synthesis (Baumannsynthesis (Baumann et alet al, 1999, 1999cc). The). The number of tyrosine hydroxylase-immuno-number of tyrosine hydroxylase-immuno- reactive (TH-ir) neurons did not differreactive (TH-ir) neurons did not differ between patients with bipolar and unipolarbetween patients with bipolar and unipolar disorder, nor between patients and con-disorder, nor between patients and con- trols. Further data analysis indicated thattrols. Further data analysis indicated that suicide might be associated with caeruleansuicide might be associated with caerulean noradrenergic function. The number ofnoradrenergic function. The number of TH-ir neurons in patients with unipolar orTH-ir neurons in patients with unipolar or bipolar disorder who died from naturalbipolar disorder who died from natural causes was lower than in suicide victimscauses was lower than in suicide victims and controls (Fig. 4). This difference re-and controls (Fig. 4). This difference re- mained significant after covarian analysismained significant after covarian analysis for mean doses of recent medication withfor mean doses of recent medication with tricyclic or tetracyclic antidepressants.tricyclic or tetracyclic antidepressants. Unipolar and bipolar diagnoses were equallyUnipolar and bipolar diagnoses were equally disturbed in the suicide and non-suicidedisturbed in the suicide and non-suicide group. Numbers of TH-ir neurons corre-group. Numbers of TH-ir neurons corre- lated positively with mean doses of tricycliclated positively with mean doses of tricyclic or tetracyclic antidepressants. These resultsor tetracyclic antidepressants. These results suggest a presynaptic noradrenergic deficitsuggest a presynaptic noradrenergic deficit s14 4s14 4 Fig. 1Fig. 1 Brain structure volumes of patients with affective disorder (Brain structure volumes of patients with affective disorder (nnˆ8, shaded bars) and controls8, shaded bars) and controls ((nnˆ8, black bars) ^ caudate nucleus and putamen.The volume of the right putamen is reduced in patients.8, black bars) ^ caudate nucleus and putamen.The volume of the right putamen is reduced in patients. **PP440.05.Reproduced with permission from Baumann0.05.Reproduced with permission from Baumann et alet al (1999(1999aa).). Fig. 2Fig. 2 Brain structure volumes of patients with affective disorder (Brain structure volumes of patients with affective disorder (nnˆ8, shaded bars) and controls8, shaded bars) and controls ((nnˆ8, black bars) ^ nucleus accumbens (NAc), pallidum externum (PE) and pallidum internum (PI).Reduced8, black bars) ^ nucleus accumbens (NAc), pallidum externum (PE) and pallidum internum (PI). Reduced volumes of the left NAc and both pallida external are seen in patients. *volumes of the left NAc and both pallida external are seen in patients. *PP440.05. Reproduced with permission0.05.Reproduced with permission from Baumannfrom Baumann et alet al (1999(1999aa).). Fig. 3Fig. 3 Pigmented neurons in the locus caeruleusPigmented neurons in the locus caeruleus of patients with bipolar disorder (of patients with bipolar disorder (nnˆ6, white bars),6, white bars), major depressive disorder (major depressive disorder (nnˆ6, shaded bars) and6, shaded bars) and controls (black bars). Reduced neuron numbers arecontrols (black bars).Reduced neuron numbers are seen in patients. *seen in patients. *PP440.05.Reproduced with permis-0.05.Reproduced with permis- sion from Baumannsion from Baumann et alet al (1999(1999bb).).
  • 4. NEUROANATOMIC AL S TUDIE S ON B IP OL AR DIS OR D E RNEUROANATOMIC AL S TUDIE S ON B IP OL AR DIS OR D E R of the LC in non-suicidal patients with de-of the LC in non-suicidal patients with de- pression irrespective of unipolar or bipolarpression irrespective of unipolar or bipolar diagnosis; they also provide indirectdiagnosis; they also provide indirect evidence that suicidal behaviour may beevidence that suicidal behaviour may be related to normalised noradrenergic func-related to normalised noradrenergic func- tion, and that traditional antidepressantstion, and that traditional antidepressants may enhance noradrenergic activity of themay enhance noradrenergic activity of the LC in patients with depression.LC in patients with depression. Dorsal rapheDorsal raphe The dorsal raphe (DR) exhibits a topo-The dorsal raphe (DR) exhibits a topo- graphic organisation similar to that of thegraphic organisation similar to that of the LC. For example, neuronal projections toLC. For example, neuronal projections to the prefrontal cortex and combined pro-the prefrontal cortex and combined pro- jections to the nucleus accumbens and thejections to the nucleus accumbens and the prefrontal cortex arise from more ventralprefrontal cortex arise from more ventral and rostral subnuclei of the DR (O'Hearnand rostral subnuclei of the DR (O'Hearn & Molliver, 1984; Wilson & Molliver,& Molliver, 1984; Wilson & Molliver, 1991; Kazakov1991; Kazakov et alet al, 1993; Van Bockstaele, 1993; Van Bockstaele et alet al, 1993). Both these projection targets, 1993). Both these projection targets have been implicated in the pathology ofhave been implicated in the pathology of depression. Together with the mediandepression. Together with the median raphe, the DR provides the ascendingraphe, the DR provides the ascending serotonergic raphe projections to the fore-serotonergic raphe projections to the fore- brain. From these topographic aspects ofbrain. From these topographic aspects of the raphe system it has been assumed thatthe raphe system it has been assumed that the DR has a major role in mood regulationthe DR has a major role in mood regulation (Molliver, 1987). The cyto-architecture of(Molliver, 1987). The cyto-architecture of this complex nucleus was investigated inthis complex nucleus was investigated in post-mortem brains of 12 patients withpost-mortem brains of 12 patients with mood disorders and 12 subjects withoutmood disorders and 12 subjects without any neuropsychiatric disorder. The ventralany neuropsychiatric disorder. The ventral parts of the mesencephalic DR (DRvp),parts of the mesencephalic DR (DRvp), i.e. the interfascicular, ventral and ventro-i.e. the interfascicular, ventral and ventro- lateral subnuclei, showed fewer neurons inlateral subnuclei, showed fewer neurons in patients with a mood disorder (Fig. 5).patients with a mood disorder (Fig. 5). No differences were seen between majorNo differences were seen between major depression and bipolar disorder in thisdepression and bipolar disorder in this respect. Morphological analysis revealedrespect. Morphological analysis revealed that the reduction in the number of neuronsthat the reduction in the number of neurons in patients with a mood disorder wasin patients with a mood disorder was restricted to the ovoid and round neurons.restricted to the ovoid and round neurons. Since approximately 70% of the humanSince approximately 70% of the human DR neurons are serotonergic, the lack ofDR neurons are serotonergic, the lack of neurons in the DRvp is mostly consistentneurons in the DRvp is mostly consistent with a regional deficit of serotonergic neu-with a regional deficit of serotonergic neu- rons in mood disorders. Neuronal nucleolirons in mood disorders. Neuronal nucleoli appeared enlarged in the DRvp of patientsappeared enlarged in the DRvp of patients with mood disorders, suggesting neuronalwith mood disorders, suggesting neuronal activation in this area. While antidepressantactivation in this area. While antidepressant medication showed no correlation withmedication showed no correlation with neuron numbers in any part of the DR, aneuron numbers in any part of the DR, a positive correlation of mean dosage of anti-positive correlation of mean dosage of anti- depressant agents with nucleolar size wasdepressant agents with nucleolar size was found for the right ventrolateral sub-found for the right ventrolateral sub- nucleus, which is part of the DRvp.nucleus, which is part of the DRvp. These results show that patients with aThese results show that patients with a primary mood disorder have a numericprimary mood disorder have a numeric neuronal deficit in the DRvp, irrespectiveneuronal deficit in the DRvp, irrespective of depressive illness subtype. This structuralof depressive illness subtype. This structural change may contribute to impaired sero-change may contribute to impaired sero- tonergic innervation of brain regions thattonergic innervation of brain regions that are involved in the pathology of mood dis-are involved in the pathology of mood dis- order. Increased nucleolar size indicatingorder. Increased nucleolar size indicating neuronal activation in the DR may reflectneuronal activation in the DR may reflect an adaptive process partly induced by anti-an adaptive process partly induced by anti- depressant medication.depressant medication. In order to gain a closer insightIn order to gain a closer insight into serotonergic function of the DR,into serotonergic function of the DR, tryptophan hydroxylase was investigatedtryptophan hydroxylase was investigated by immunodetection in the same sample.by immunodetection in the same sample. Numbers of tryptophan hydroxylase-Numbers of tryptophan hydroxylase- immunoreactive (TPH-ir) neurons did notimmunoreactive (TPH-ir) neurons did not differ between patients and controls, eitherdiffer between patients and controls, either in the DRvp or in the dorsal or caudal partsin the DRvp or in the dorsal or caudal parts of the DR. In the group of patients,of the DR. In the group of patients, however, there was a significant correlationhowever, there was a significant correlation of TPH-ir neurons in the DRvp with meanof TPH-ir neurons in the DRvp with mean dosage of antidepressants given in the lastdosage of antidepressants given in the last 7 days before death (7 days before death (rrˆ0.69,0.69, nnˆ12,12, PPˆ0.01). On the level of single subnuclei,0.01). On the level of single subnuclei, this association was most prominent inthis association was most prominent in the right ventrolateral nucleus. Usingthe right ventrolateral nucleus. Using antidepressant medication as covariateantidepressant medication as covariate (ANCOVA), a nearly significant reduction(ANCOVA), a nearly significant reduction was found for TPH-ir neurons in the DRvp,was found for TPH-ir neurons in the DRvp, but not in the dorsal or caudal DR ofbut not in the dorsal or caudal DR of patients. No difference was observedpatients. No difference was observed between major depressive and bipolar dis-between major depressive and bipolar dis- order samples.order samples. Unchanged serotonin immunohisto-Unchanged serotonin immunohisto- chemistry and a reduction in Nissl-stainedchemistry and a reduction in Nissl-stained neurons indicate that a neuronal deficit inneurons indicate that a neuronal deficit in the DRvp in patients with mood disordersthe DRvp in patients with mood disorders treated by antidepressants is partly com-treated by antidepressants is partly com- pensated for by upregulation of serotoninpensated for by upregulation of serotonin synthesis as an effect of antidepressantsynthesis as an effect of antidepressant medication. Moreover, our data suggestmedication. Moreover, our data suggest that in mood disorders, irrespective ofthat in mood disorders, irrespective of diagnostic polarity and apart from medi-diagnostic polarity and apart from medi- cation,cation, synthesis of serotonin may be state-synthesis of serotonin may be state- dependentlydependently reduced in distinct regions ofreduced in distinct regions of the DR.the DR. CONCLUSIONCONCLUSION There are few post-mortem studies on bi-There are few post-mortem studies on bi- polar disorder, and definite conclusionspolar disorder, and definite conclusions can hardly be drawn owing to the smallcan hardly be drawn owing to the small and selective nature of the samples, whichand selective nature of the samples, which in particular might produce false-negativein particular might produce false-negative results. Moreover, problems sometimesresults. Moreover, problems sometimes arise from effects of medication or agonalarise from effects of medication or agonal and post-mortem changes. Data obtainedand post-mortem changes. Data obtained from neuroimaging in mood disordersfrom neuroimaging in mood disorders showing structural abnormalities in theshowing structural abnormalities in the frontal and temporal cortices as well as infrontal and temporal cortices as well as in subcortical regions are widely confirmed,subcortical regions are widely confirmed, and also extended and specified, by resultsand also extended and specified, by results from neurohistological investigations. Basalfrom neurohistological investigations. Basal ganglia, preferentially those closely asso-ganglia, preferentially those closely asso- ciated with the limbic system, have smallerciated with the limbic system, have smaller volumes in patients with depressive illnessvolumes in patients with depressive illness irrespective of diagnostic polarity. Higherirrespective of diagnostic polarity. Higher neuron numbers in the locus caeruleus ofneuron numbers in the locus caeruleus of patients with bipolar disorder than in thatpatients with bipolar disorder than in that of patients with major depressive disorderof patients with major depressive disorder are in agreement with neuroimaging dataare in agreement with neuroimaging data indicating a `hypernormal' structural pat-indicating a `hypernormal' structural pat- tern in bipolar disorder that does nottern in bipolar disorder that does not s14 5s14 5 Fig. 4Fig. 4 Tyrosine hydroxylase-immunoreactiveTyrosine hydroxylase-immunoreactive neurons in the locus caeruleus.There are fewerneurons in the locus caeruleus.There are fewer immunoreactive neurons in the depressed non-immunoreactive neurons in the depressed non- suicide group compared with the depressed suicidesuicide group compared with the depressed suicide group and controls; a, significant group effectgroup and controls; a, significant group effect ((FFˆ4.63, d.f.4.63, d.f.ˆ2, 21,2, 21, PPˆ0.02); b, significant post-hoc0.02); b, significant post-hoc test; c, significant post-hoc test.Reproduced withtest; c, significant post-hoc test.Reproduced with permission from Baumannpermission from Baumann et alet al (1999(1999cc).). Fig. 5Fig. 5 Neuron numbers in ventral subnuclei of theNeuron numbers in ventral subnuclei of the dorsal raphe.Reduced numbers are seen in patientsdorsal raphe. Reduced numbers are seen in patients withmajordepressive disorder (unipolar) andbipolarwithmajor depressive disorder (unipolar) andbipolar disorder.The line indicates the mean value for eachdisorder.The line indicates the mean value for each group.group.
  • 5. B AUMANN & BOGE R T SB AUMANN & B OG E R T S appear to exist in major depression. Post-appear to exist in major depression. Post- mortem studies showed no differencesmortem studies showed no differences between the two types of disorder forbetween the two types of disorder for noradrenalin and serotonin synthesis innoradrenalin and serotonin synthesis in the locus caeruleus and the dorsal raphe.the locus caeruleus and the dorsal raphe. Our data suggest a regionally reducedOur data suggest a regionally reduced synthesis of these neurotransmitters, whichsynthesis of these neurotransmitters, which have a major role in the pathogenesis ofhave a major role in the pathogenesis of mood disorders. Antidepressant medicationmood disorders. Antidepressant medication seems to increase serotonin and noradrena-seems to increase serotonin and noradrena- lin production in depressive states and maylin production in depressive states and may thereby contribute to normalisation ofthereby contribute to normalisation of monaminergic functions.monaminergic functions. REFERENCESREFERENCES Altshuler, L. L.,Casanova, M. F.,Goldberg,T. E.,Altshuler, L. L.,Casanova, M. F.,Goldberg,T. E., et alet al (1990)(1990) The hippocampus and parahippocampus inThe hippocampus and parahippocampus in schizophrenia, suicide, and control brains.schizophrenia, suicide, and control brains. 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BiologicalBiological PsychiatryPsychiatry,, 4141,1156^1164.,1156^1164. Loughlin, S. E., Foote, S. L. & Fallon, J. H.Loughlin, S. E., Foote, S. L. & Fallon, J. H. (1982)(1982) Locus caeruleus projections to cortex: topography,Locus caeruleus projections to cortex: topography, s14 6s14 6 CLINICAL IMPLICATIONSCLINICAL IMPLICATIONS && Morphologicalchangesinbasalganglia andmonaminergic transmitter systemsmayMorphologicalchangesinbasalganglia andmonaminergic transmitter systemsmay be vulnerability markers for unipolar disorder.be vulnerability markers for unipolar disorder. && Brain biology differs between bipolar and unipolar disorders, suggesting the needBrain biology differs between bipolar and unipolar disorders, suggesting the need for different treatment strategies.for different treatment strategies. && Effects of antidepressants may be mediated by changes in monaminergic brain-Effects of antidepressants may be mediated by changes in monaminergic brain- stem neurons.stem neurons. LIMITATIONSLIMITATIONS && Neurohistological research in bipolar disorder is in its infancy and as yet providesNeurohistological research in bipolar disorder is in its infancy and as yet provides only a preliminary assessment of morphological changes involved with this disease.only a preliminary assessment of morphological changes involved with this disease. && Relatively small sample sizes and the high proportion of suicide cases in post-Relatively small sample sizes and the high proportion of suicide cases in post- mortem studies on mood disorders make it difficult to generalise findings.mortem studies on mood disorders make it difficult to generalise findings. && It is difficult to correlate morphological findings with acute symptoms.It is difficult to correlate morphological findings with acute symptoms. BRUNO BAUMANN, MD,BERNHARD BOGERTS, MD, Department of Psychiatry,University of Magdeburg,BRUNO BAUMANN, MD,BERNHARD BOGERTS, MD, Department of Psychiatry,University of Magdeburg, GermanyGermany Correspondence: Dr Bruno Baumann, Department of Psychiatry,University of Magdeburg, Leipziger StrasseCorrespondence: Dr Bruno Baumann, Department of Psychiatry,University of Magdeburg,Leipziger Strasse 44, Magdeburg D-39120,Germany.Tel: +49 391 67 15 029; fax: +49 391 67 15 223;44, Magdeburg D-39120,Germany.Tel: +49 391 67 15 029; fax: +49 391 67 15 223; e-mail: baumanne-mail: baumann@@medizin.uni-magdeburg.demedizin.uni-magdeburg.de
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