Study (author, year)
Subjects
Medication
Method
Main findings
al-Mousawi et al. (1996)
15 BD-I (15 M)
+
11FDG-PET resting state
Decreased left dorsolateral prefrontal cortex and left amygdala in the manic BD patients compared to HC
14 SZ
10 MDD
10 HC
Bauer et al. (2005)
9 BD-I (9 E)
+
11FDG-PET treatment with levothyroxine CPT
Before levothyroxine treatment, BD patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis and had lower relative activity in the middle frontal gyri bilaterally. Levothyroxine decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis
1 BD-II (1 E)
Baxter et al. (1985)
5 BD (5 M, 2 Mi, 5 D)
+
11FDG-PET resting state
The whole brain CMR for patients with bipolar depression increased going from depression or a mixed episode to a euthymic state or manic episode
11 MDD
HC
Baxter et al. (1989)
15 BD (10 D, 5 M)
+
11FDG-PET resting state
The results in CMR of the dorsal anterolateral PFC for MDD and BD D were the same, but lower than in controls
10 MDD
10 OCD w/o D
14 OCD w/ D
12 HC
Benabarre et al. (2005)
43 BD (12 D, 3 E, 8 HM, 7 M)
+/−
99mTc-HMPAO SPECT resting state
Several corrected correlations between neuropsychological function and CBF were identified
6 HC
Blumberg et al. (1999)
11 BD-I (6 E, 5 M)
+
H2 15O PET word generation, letter repetition, resting state
Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania
5 HC
Blumberg et al. (2000)
11 BD-I (6 E, 5 M)
+
H2 15O PET resting state
The principal findings were an increased activity in left dorsal anterior cingulate and left head of caudate during manic episodes
5 HC
Bonne et al. (1996)
9 BD (9 D)
+
99mTc-HMPAO SPECT resting state
Examining individual regions of interest significantly lower perfusion in the left superior temporal, right parietal, and bilateral occipital regions in the patient group was found
11 MDD
21 HC
Brooks et al. (2006)
8 BD (8 D)
−
11FDG-PET CPT
No statistically significant differences in performance in CMR between the two groups were found
27 HC
Buchsbaum et al. (1986)
16 BD (16 D)
−
11FDG-PET electrical stimulation to the forearm
Global cerebral metabolism was found to be significantly higher in subjects with affectiveness (both unipolar and bipolar depressed) compared to normal controls
4 MDD
24 HC
Culha et al. (2008)
16 BD (16 E)
+
99mTc-HMPAO SPECT resting state
The mean regional cerebral blood flow values of the euthymic BD patients were significantly lower than those of the controls in the bilateral medial-basal temporal, occipital, medial frontal, parietal regions, and in the cingulate gyrus
10 HC
Drevets et al. (1997)
21 BD (9 D, 8 E, 4 M)
+
11FDG and H2 15O PET resting state
An area of abnormally increased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depressives and familial unipolar depressives has been found after correction for grey matter volume
17 MDD
51 HC
Drevets et al. (2002)
15 BD (7 D, 9 E)
−
11FDG-PET resting state
Amygdala activity, which was correlated with stress plasma cortisol levels, was increased in depressed BD patients. Mood stabilizers normalize the amygdala activity in remitted BD
21 MDD
12 HC
Dunn et al. (2002)
27 BD (27 D)
−
11FDG-PET auditory CPT
In both MDD and BD, the psychomotor-anhedonia symptom cluster correlated with lower absolute metabolism in right insula, claustrum, anteroventral caudate/putamen, and temporal cortex and with higher normalized CMR in anterior cingulate
31 MDD
Goodwin et al. (1997)
14 BD (14 E)
+
99mTc-EMZ SPECT lithium withdrawal
Lithium withdrawal was associated with an important redistribution of brain perfusion, with increases in inferior posterior regions and decreases in limbic areas, particularly ACC
Gyulai (1997)
13 BD (7 HM, 2 M)
+
123I-IMP SPECT resting state
The CBF distribution in the anterior part of the temporal lobes was asymmetric in both depressive and manic but not in euthymic state. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathologic mood states that diminished or disappeared in the euthymic state
Ito et al. (1996)
6 BD (6 D)
+
99mTc-HMPAO SPECT resting state
Significant decreases in CBF in the prefrontal cortices, limbic systems, and paralimbic areas were observed in both depression groups compared with the healthy control group
11 MDD
9 HC
Ketter (2001)
14 BD-I (11 D, 4 E)
−
11FDG-PET CPT
In bipolar depression, a pattern of prefrontal hypometabolism was observed. Additionally a cerebello-posterior cortical normalized hypermetabolism was seen in all bipolar subgroups
29 BD-II (22 D, 7 E)
43 HC
Krüger et al. (2006)
9 BD-I (9 E)
+
H2 15O PET transient sadness induction
Common to all three groups with induced sadness were CBF increases in the dorsal/rostral anterior cingulate and anterior insula and decreases in the orbitofrontal and inferior temporal cortices. Distinguishing the groups were decreases in the medial frontal cortex in the patients but an increase in this region in the siblings
9 HS
Mah et al. (2007)
13 BD-II (13 D)
+
11FDG-PET resting state
CMR was increased in the bilateral amygdala, accumbens area, and anteroventral putamen, left orbitofrontal cortex and right pregenual ACC in depressive patients versus healthy control subjects. Post hoc exploratory analysis additionally revealed increased metabolism in left parahippocampal, posterior cingulate, and right anterior insular cortices in depressive patients versus healthy control subjects
18 HC
Rubin et al. (1995)
11 BD-I (11 M)
+
133Xe SPECT resting state
The three groups were equivalent in global CBF. Both patient groups showed significant reductions of CBF in anterior cortical areas and reduction of the normal anteroposterior gradient
11 MDD
11 HC
Rubinsztein (2001)
6 BD (6 M)
+
H2 15O PET probability-based decision-making task
Task-related activation was increased in the manic patients compared with the control patients in the left dorsal ACC but decreased in the right frontal polar region
6 MDD
10 HC
Rush et al. (1982)
12 BD
133Xe SPECT resting state
During manic episode, global CBF was increased compared to HC
16 HC
Silfverskiöld and Risberg(1989)
40 BD (10 D, 30 M)
+/−
133Xe SPECT resting state
Both patient groups showed a normal cerebral blood flow level and regional distribution compared with age- and sex-matched normal controls
22 MDD
61 HC
Tutus et al. (1998)
7 BD (7 D)
+/−
133Xe SPECT between groups and before/after medication resting state
No significant differences in CBF emerged between the BD patients and the healthy control subjects
10 MDD
9 HC
9.2.2.1 Prefrontal Cortex
The prefrontal cortex (PFC) is the area of the frontal lobes of the cerebral cortex that is located before the motor and premotor areas. It plays an important role in executive functioning such as planning complex behavior, personality expression, decision making, and moderating social behavior (Miller et al. 2002). Regions of the brain are defined as Brodmann areas (BA) based on their cytoarchitectonic structure.
In general, BD patients in a depressive or manic episode have a decreased prefrontal cortex CMR and CBF, compared to euthymic patients or healthy controls. Blumberg et al. found a reduced CBF in the right orbital PFC (BA 11) and medial frontal gyrus (BA 10) in manic patients when compared to euthymic patients (Blumberg et al. 1999). CMR activation related to a decision-making task was also decreased in manic patients in this region (Rubinsztein et al. 2001).
Euthymic patients demonstrated an orbitofrontal CBF decrease (Culha et al. 2008). The healthy siblings of BD patients demonstrated a comparable CBF decrease in the orbitofrontal PFC during induced sadness (Krüger et al. 2006).
In manic patients, a decrease in dorsolateral PFC (BA 8, 9, 46) CBF has been demonstrated (Rubin et al. 1995; al-Mousawi et al. 1996). Manic patients also showed a decrease of CMR during a decision-making task in the ventrolateral PFC (BA 47) when compared to controls (Rubinsztein et al. 2001). Furthermore, euthymic older BD patients (50–65 years) had a lower CMR in this region than controls of the same age (Brooks et al. 2006).
9.2.2.2 Limbic System and Subcortical Structures
The limbic system is a combination of, in origin, different brain structures that are involved in visceral behavioral patterns (related to survival: eating, drinking, sexual activity), emotions, and memory. Some structures, such as the hippocampus, amygdala, and anterior thalamic nuclei, are phylogenetically rather old structures (hence the other name paleomammalian brain), while the septum, fornix, and limbic cortex are more recently developed structures.
The limbic cortex consists of the parahippocampal gyrus (BA 34–36), the cingulate gyrus (BA 23–26; 29–33), and the dentate gyrus, which are parts of the frontal, parietal, and temporal cortical lobes on the medial surfaces of both hemispheres, surrounding the corpus callosum. The anterior part of the cingulate gyrus, the anterior cingulate cortex (ACC, BA 24, 25, 32, 33), plays a role in autonomic functions (regulating blood pressure, heart rate), rational cognitive functions (reward anticipation, decision making, empathy), pain perception, and emotion (Luu and Posner 2003).
In BD patients with depressive or manic episodes, an increased CMR and CBF were demonstrated in various parts of the limbic system. In depressed BD patients, Drevets et al. found an increased CMR in the subgenual portion of the ACC (BA 25) when compared to controls, after correction for grey matter volume (Drevets et al. 1997). This finding was repeated both in treated (Bauer et al. 2005) and in untreated depressed patients (Dunn et al. 2002). Dunn reported an association between this CMR increase and the presence of psychomotor and anhedonia symptoms. A similar increase in CMR was demonstrated in the pregenual and ventral area (BA 33, 24) of the ACC (Mah et al. 2007).
In manic patients, an increase in CBF in the subgenual portion of the ACC (BA 25) was described compared to controls (Drevets et al. 1997). This increase was also found in the left dorsal ACC (BA 32) when compared to euthymic patients (Blumberg et al. 2000). In the manic patients, CMR during a decision-making task was increased in the left dorsal ACC, when compared with controls (Rubinsztein et al. 2001). In untreated manic patients, a SPECT study showed that increased cingulate cortex CBF is associated with poor executive functioning (Benabarre et al. 2005).
Goodwin et al. (Goodwin et al. 1997) examined 14 euthymic patients on lithium with SPECT before and after acute double-blind withdrawal of lithium. As often seen clinically, rapid withdrawal was associated with an increase of manic symptoms. The increase of manic symptoms correlated with a CBF decrease in the limbic areas, particularly the ACC.
Euthymic patients also demonstrated ACC CBF aberrations (Culha et al. 2008). The healthy siblings of BD patients demonstrated a comparable CBF increase in the ACC during induced sadness (Krüger et al. 2006).
The amygdala, part of the limbic system, is one of the subcortical areas that is known to be involved in BD. Others are the nucleus accumbens, globus pallidus, striatum (including nucleus caudatus), and all parts of the basal ganglia of the brain that play a role in higher-order motor control. Individually they are involved in different functions, the nucleus accumbens in the reward circuitry; nucleus caudatus in learning and memory, particularly regarding feedback processing; and the globus pallidus in visceral regulation such as fever induction and emotion-induced tachycardia (Packard and Knowlton 2002).
Initially, studies of depressed BD patients versus controls described a reduced CMR in the amygdala (al-Mousawi et al. 1996) as well as the striatum (Baxter et al. 1985; Bonne et al. 1996; Ito et al. 1996). However, thereafter, various PET studies in depressed patients showed increased activity in the striatum, together with increased activity in limbic structures including the amygdala, hippocampus, and parahippocampal regions (Bauer et al. 2005; Brooks et al. 2009; Drevets et al. 2002; Ketter et al. 2001; Mah et al. 2007). Additionally, amygdala and ventral striatal CMR correlated positively with depression severity and with cortisol levels (Drevets et al. 2002; Ketter et al. 2001). The difference between these initial and later studies is most probably explained by a higher signal quality and more careful patient selection in the later studies (Gonul et al. 2009).
9.2.2.3 Other Cortical Regions
An asymmetric CBF was found in the anterior temporal cortex in manic and depressed patients but not when the patients were euthymic (Gyulai et al. 1997). In a more recent study, it was demonstrated that euthymic older BD patients (50–65 years) have a higher CMR in this region than controls of the same age (Brooks et al. 2009). Furthermore, CBF in the temporal cortex of BD patients was positively associated with executive functions but negatively with attention and memory (Benabarre et al. 2005).
9.2.2.4 Corticolimbic Theory of Mood Disorders
Partly based on the abovementioned molecular imaging results, complemented with functional MRI (fMRI) research, a recent meta-analysis displays an overall hyperactivation of limbic brain regions in BD patients relative to controls, along with an overall hypoactivation of frontal regions (Kupferschmidt and Zakzanis 2011). This corresponds to findings in other mood disorders, especially MDD, which is known as the corticolimbic theory of depression (Mayberg 1997). Hypo- and hyperactivity in frontal and limbic regions, respectively, was most pronounced in manic patients, although also present in depressed and euthymic ones. Depressed patients exhibit more pronounced hypoactivation of frontal regions than euthymic patients, whereas euthymic patients display, surprisingly, more hyperactivity in limbic regions than their depressed counterparts.
The corticolimbic theory has some overlap with several neurological networks that have been described and are thought to lay on the basis of physiological emotional processing. These networks can be divided into circuits that lay within the cerebral cortex and those that exceed to other parts of the brain (Price and Drevets 2010).
The limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit connects the PFC to the limbic and subcortical areas of the brain (al-Mousawi et al. 1996). This LCSPT circuit is thought to be particularly important to mediate emotional expression, because of its relation to visceral control structures (Drevets et al. 2008).
The mood-related cortico-cortical networks interact with and extend to the LCSPT (Ongür et al. 2003) via top-down inhibitory control (Savitz and Drevets 2009). The orbital prefrontal network consists of the central and caudal part of the orbital cortex and the ventrolateral PFC, and it includes sensory association areas such as the visual-associated areas in the inferior temporal cortex and somatic sensory-associated areas in the insula and frontal operculum, as well as olfactory and taste cortex. In addition to sensory integration, this system codes for affective characteristics of stimuli such as reward, aversion, and relative value (salience) (Drevets et al. 2008).
The medial prefrontal network of cortical areas includes the ventromedial PFC, the dorsolateral PFC, the anterior and posterior cingulate cortex, the anterior temporal cortex, and the entorhinal and posterior parahippocampal cortex. This system does not have substantial sensory connections, but is a visceromotor system that is particularly involved in introspective functions, such as mood and emotion, and in visceral reactions to emotional stimuli (Price and Drevets 2010). It is widely known as the “default system,” because it appeared activated as a network of areas that become inactive in most tasks that involve external attention in fMRI (Gusnard et al. 2001).
It has been proposed that the “ventral” orbital prefrontal network and the “dorsal” medial prefrontal network are reciprocally connected and that the orbital PFC may mediate connections between higher-order dorsolateral prefrontal regions and subcortical limbic regions such as the amygdala during emotion regulation (Phillips et al. 2008).
9.2.3 Neurotransmitter Studies
Departing from the neurotransmitter theory of affective disorders (Schildkraut 1965), PET/SPECT radioligand studies have focused on the serotonergic, dopaminergic, and cholinergic systems (Table 9.2).
Table 9.2
Overview of PET/SPECT studies on neurotransmitter systems in BD patients
Neurotransmitter | Study (author, year) | Subjects | Medication | Target | Method | Main findings |
|---|---|---|---|---|---|---|
Serotonin | Yahtam et al. (2005b) | 7 BD (7 M) | + | 5-HT2 | 18F-setoperone PET valproate treatment | Treatment with valproate had no significant effect on brain 5-HT2A receptor binding in manic patients |
Ichimiya et al. (2002) | 6 BD (1 D, 5 E) | − | SERT | 11C(+)-McNeil 5652 PET | Binding potential in the thalamus was significantly increased in patients with mood disorders as compared to control subjects, whereas binding potential in the midbrain did not differ between the groups | |
7 MDD | ||||||
21 HC | ||||||
Oquendo et al. (2007) | 18 BD (18 D) | − | SERT | 11C(+)-McNeil 5652 PET | BD patients had 16–26 % lower SERT density in the midbrain, amygdala, hippocampus, thalamus, putamen, and ACC | |
41 HC | ||||||
Chou et al. (2010) | 10 BD-I | − | SERT | 123I-ADAM SPECT | A lower SERT density was found in the midbrain of euthymic BD-I patients when compared to euthymic BD-II patients and healthy controls | |
14 BD-II | ||||||
28 HC | ||||||
Cannon et al. (2006b) | 18 BD (18 D) | − | SERT | 11C-DASB PET | In BD, the mean SERT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex, and insula and decreased in the brainstem at the level of the pontine raphe nuclei when compared to controls | |
37 HC | ||||||
Cannon et al. (2007) | 18 BD (18 D) | − | SERT | 11C-DASB PET | Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24 %, 14 %, respectively), insula (15 %), and striatum (12 %). The bipolar depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei | |
18 MDD | ||||||
34 HC | ||||||
Dopamine | Pearlson et al. (1995) | 14 BD (3 D, 11 M) | − | D2 | 11C-3-N-methylspiperone PET | No statistical difference in D2 binding was found between nonpsychotic BD patients and controls. Post hoc tests showed higher binding for psychotic patients with BD and SZ compared with controls and for SZ and psychotic BD patients compared to nonpsychotic BD patients |
10 SZ | ||||||
12 HC | ||||||
Anand et al. (2000) | 13 BD (13 E) | + | D2 | 123I-IZBM SPECT baseline, after amphetamine induction | BD patients and healthy subjects did not differ in terms of mood state or striatal D2-receptor binding at baseline. Amphetamine challenge led to a significantly greater behavioral response in BD patients than in healthy subjects. However, there was no significant difference between the two groups in the amphetamine-induced decrease in striatal binding | |
13 HC | ||||||
Yatham et al. (2002a) | 13 BD-I (13 M) | − | DOPA uptake | 18F-DOPA PET baseline, after valproate treatment | No significant differences in 18F-DOPA uptake rate constants in the striatum were found between the manic patients and the comparison subjects. After treatment with valproate, 18F-DOPA rate constants were significantly reduced in the patients and were lower in the patients than in the comparison subjects | |
14 HC | ||||||
Suhura et al. (1992) | 10 BD (3 D, 6 E, 1 M) | + | D1 | 11C-SCH23390 | The binding potentials for the frontal cortex for the patients were significantly lower than those for normal controls, whereas those for striatum were not significantly different | |
21 HC | ||||||
Yatham et al. (2002) | 13 BD-I (13 M) | − | D2 | 11C-raclopide PET baseline, after valproate treatment | The D2 binding potential was not significantly different in manic patients than in the comparison subjects in the striatum. Treatment with valproate had no significant effect on the D2 binding potential in manic patients | |
14 HC | ||||||
Amsterdam et al. (2007) | 5 BD-II (5 D) | − | DAT | 99mTc-TRODAT-1 SPECT | BD patients had greater binding compared to controls in the right posterior putamen and in the left caudate region. BD patients had modestly lower binding in all brain regions examined and a significantly lower binding in the right caudate region compared to MDD patients | |
10 MD | ||||||
46 HC | ||||||
Chang et al. (2010) | 17 BD (17 E) | − | DAT | 99mTc-TRODAT-1 SPECT | Compared to the controls, the euthymic BD patients had significantly higher availability of striatal DAT | |
17 HC | ||||||
Anand et al. (2011) | 11 BD-I (6 D; 5 E) | − | DAT | 11C-CFT PET | BPD subjects had significantly lower DAT availability relative to controls in bilateral dorsal caudate | |
13 HC | ||||||
Zubieta et al. (2001) | 15 BD-I (15 E) | + | VMAT | 11C-DTBZ PET | Binding of VMAT2 in the thalamus was higher in BD patients than in control subjects and SZ patients. Conversely, ventral brainstem binding was nearly identical between BD and SZ patients and were higher than in the control group | |
12 SZ | ||||||
15 HC | ||||||
Choline | Cannon et al. (2006a) | 16 BD (16 D) | − | M2 | 18F-FP-TZTP PET | Receptor binding was found to be decreased in the ACC of BD patients when compared to MDD patients and controls |
17 MDD | ||||||
23 HC | ||||||
Cannon et al. (2011) | 16 BD (16 D) | − | M2 | 18F-FP-TZTP PET | Decreased receptor binding in BD is associated with genetic variation within CHRM2 | |
24 MDD | ||||||
25 HC |
9.2.3.1 Serotonin
Serotonin (5-hydroxytryptamine) is a monoamine neurotransmitter that is formed out of the amino acid tryptophan. It is mainly found in the gastrointestinal tract, where its secreting cells regulate intestinal movement; in platelets, where it is released during aggregation; and in the central nervous system. Serotonin has a regulatory effect with regard to mood, sleep, sexual activity, and appetite.
The neurons located in the raphe nuclei, a cluster of nuclei in the brain stem, are the main source of serotonin in the brain. The axons from the raphe nuclei neurons project to nearly every part of the central nervous system. After serotonin is released in the synaptic cleft, it can bind to one of the various receptors or it can be removed by the presynaptic neuron for reuse via the serotonin transporter.
As the primary site of serotonergic antidepressant activity, the serotonin transporter (SERT) is the part of the serotonin neurotransmitter system that has received the most attention in molecular imaging. Among the various ligands that are available, the PET ligands trans- 1,2,3,5,6,10- -hexahydro-6-[4-(methylthio) phenyl] pyrrolo-[2,1-a] isoquinoline (11C(+)-McNeil 5652), 3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB) and the SPECT ligand 2-([2-([dimethylamino]methyl)phenyl]thio)-5-123I-iodophenylamine (123I-ADAM) are used in BD research. An increase of SERT density was found in the thalamus using 11C(+)-McNeil 5652 in a combined group of euthymic or mildly depressed patients (Ichimiya et al. 2002) and a reduction in the midbrain, hippocampus, thalamus, putamen, and ACC in a group of untreated depressed patients (Oquendo et al. 2007). With the use of 123I-ADAM SPECT, a lower SERT density was found in the midbrain of euthymic BD-I patients when compared to euthymic BD-II patients and healthy controls (Chou et al. 2010). Using the more stable and selective 11C-DASB ligand, an increased SERT density was found in the thalamus, dorsal cingulate cortex, medial prefrontal cortex, and insula of depressed untreated BD patients, which was comparable to MDD (Cannon et al. 2006b, 2007).
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