**4. Conclusions**

Since the introduction of CT, researchers focused their efforts in elucidating the connection between psychiatric diseases and the presence of structural cerebral alterations through neuroimaging. CT pioneered this research without providing, however, a complete answer. Actually, a growing body of evidence has been accumulated in literature as newer techniques such as MRI and functional imaging (i.e., SPECT, PET, fMRI) have been introduced revealing much about the biological underpinnings of neuropsychiatric disorders. Neuroimaging research in BD has already produced several data documenting the involvement of different cortical and subcortical regions in different phases of the

Neuroimaging Data in Bipolar Disorder: An Updated View 275

Bauer, M., London, E.D., Silverman, D.H., Rasgon, N., Kirchheiner, J., & Whybrow, P.C.

Bearden, C.E., Woogen, M., & Glahn, D.C. (2010). Neurocognitive and Neuroimaging

Beyer, J.L., & Krishnan, K.R. (2002). Volumetric brain imaging findings in mood disorders. *Bipolar Disorders*, Vol.4, No.2, (April 2002), pp. 89-104, ISSN 1398-5647 Botteron, K.N., & Figiel, G.S. (1997). The neuromorphometry of affective disorders, In: *Brain* 

Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., Charney, D.S. (2000).

Bruno, S., Cercignani, M., & Ron, M.A. (2008). White matter abnormalities in bipolar

Cannon, D.M., Ichise, M., Rollis, D., Klaver, J.M., Gandhi, S.K., Charney, D.S., Manji, H.K., &

Cassano G.B., Tundo A. (2006). *Psicopatologia e clinica psichiatrica*. Edizione UTET. ISBN

Cassidy, F. (2011). Risk factors of attempted suicide in bipolar disorder. *Suicide and Life-Threatening Behavior*, Vol.41, No.1, (February 2011), pp. 6-11, ISSN 0363-0234 Cavalcanti Filho, J.L., de Souza Leão Lima, R., de Souza Machado Neto, L., Kayat Bittencourt,

Chan, W.Y., Yang, G.L., Chia, M.Y., Woon, P.S., Lee, J., Keefe, R., Sitoh, Y.Y., Nowinski,

*Bipolar Disorders*, Vol.12, No.4, (June 2010), pp. 383-389, ISSN 1398-5647 Chaves, O.C., Lombardo, L.E., Bearden, C.E., Woolsey, M.D., Martinez, D.M., Barrett J., A.,

*Disorders*, Vol.13, No.1, (February 2011), pp. 118-23, ISSN 1398-5647

*Psychiatry,* Vol.157, No.1, (January 2000), pp. 115–118, ISSN 0002-953X Brooks, J.O., Bearden, C.E., Hoblyn, J.C., Woodard, S.A., & Ketter, T.A. (2010). Prefrontal

Suppl.3, (November 2003), pp. 215-21, ISSN 0176-3679

Dekker, ISBN 0824798597 , New York, USA.

No.4, (June 2008), pp. 460-8, ISSN 1398-5647

2007), pp. 870-877, ISSN 0006-3223

(2009), pp. 314-22, ISSN 0954-0261

8802071942. Torino, Italia.

Vol.12, No.6, (December 2010), pp. 499–504, ISSN 1523-3812

ISSN 0006-3223

ISSN 1398-5647

statistics analysis. *Biological Psychiatry,* Vol.66, No.3, (August 2009), pp. 238-44,

(2003). Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging. *Pharmacopsychiatry*, Vol.36,

Predictors of Clinical Outcome in bipolar disorder. *Current Psychiatry Reports*,

*Imaging in Clinical Psychiatry,* Krishnan, K.R., Doraiswamy, P.M.(Eds.), 145–184, M.

Hippocampal volume reduction in major depression. *The American Journal of* 

and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with BD. *Bipolar Disorders*, Vol.12, No.8, (December 2010), pp. 866-74,

disorder: a voxel-based diffusion tensor imaging study. *Bipolar Disorders*, Vol.10,

Drevets, W.C. (2007). Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. *Biological Psychiatry*, Vol.62, No.8, (October

L., Domingues, R.C., & da Fonseca, L.M. (2011). PET/CT and vascular disease: Current concepts. *European Journal of Radiology,* (March 2011), epub ahead of print. Cerullo, M.A., Adler, C.M., Delbello, M.P., & Strakowski, S.M. (2009). The functional

neuroanatomy of bipolar disorder. *International Review of Psychiatry*, Vol.21, No.4,

W.L., & Sim, K. (2010). Cortical and subcortical white matter abnormalities in adults with remitted first-episode mania revealed by Tract-Based Spatial Statistics.

Miller, A.L., Velligan, D.I., & Glahn, D.C. (2011). Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study. *Bipolar* 

illness. In particular, published studies explored structural and functional abnormalities present in BD and tried to establish specific correlations with outcome (Moore et al., 2001; Wingo et al., 2009, Bearden, 2010) as well as difficult-to-treat conditions such as treatment resistant forms (Regenold et al., 2008).

The possibility to study cognitive function in BD through fMRI represents another major acquisition of neuroimaging in psychiatric research. The attainment of this goal can be facilitated by identifying biomarkers reflecting pathophysiologic processes in BD, namely impaired emotion regulation, impaired attention, and distractibility, which persist during depression and remission and are not common to unipolar depression (Phillips & Vieta, 2007).

#### **5. References**


illness. In particular, published studies explored structural and functional abnormalities present in BD and tried to establish specific correlations with outcome (Moore et al., 2001; Wingo et al., 2009, Bearden, 2010) as well as difficult-to-treat conditions such as treatment

The possibility to study cognitive function in BD through fMRI represents another major acquisition of neuroimaging in psychiatric research. The attainment of this goal can be facilitated by identifying biomarkers reflecting pathophysiologic processes in BD, namely impaired emotion regulation, impaired attention, and distractibility, which persist during depression and remission and are not common to unipolar depression (Phillips & Vieta, 2007).

Abraham T., Feng J. (2011). Evolution of brain imaging instrumentation. *Seminars in nuclear* 

Adler, C.M., Holland, S.K., Schmithorst, V., Tuchfarber, M.J., Strakowsky, S.M. (2004).

Altamura, A.C., Serati, M., Albano, A., Paoli, R.A., Glick, I.D., & Dell'Osso, B. (2011). An

Altamura, A.C., Lietti, L., Dobrea, C., Benatti, B., Arici, C., & Dell'Osso, B. (2011). Mood

*Neurotherapeutics*, Vol.11, No.1, (January 2011), pp. 85-99, ISSN 1473-7175 (b) Altshuler, L., Bookheimer, S., Townsend, J., Proenza, M.A., Sabb, F., Mintz, J., & Cohen, M.S.

Altshuler, L., Bookheimer, S., Proenza, M.A., Townsend, J., Sabb, F., Firestine, A., Bartzokis,

Altshuler, L.L., Bartzokis, G., Grieder, T., Curran, J., & Mintz, J. (1998). Amygdala

Andreasen, N.C., Swayze, V., Flaum, M., Alliger, R., & Cohen, G. (1990). Ventricular

*Journal of Psychiatry*, Vol.147, No.7, (July 1990), pp. 893-900, ISSN 0002-953X Bandettini P.A. (2003). Functional MRI, In: *Handbook of Neuropsychology,* Vol. 9, J. Grafman

Barnea-Goraly, N., Chang, K.D., Karchemskiy, A., Howe, M.E., & Reiss, A.L. (2009). Limbic

*of Psychiatry*, Vol.162, No.6, (June 2005), pp. 1211–1213, ISSN 0002-953X Altshuler, L.L, Conrad, A., Hauser, P., Li, X.M., Guze, B.H., Denikoff, K., Tourtellotte, W.,

Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task. *Bipolar Disorders,* Vol.6, No.6, (December

epidemiologic and clinical overview of medical and psychopathological comorbidities in major psychoses. *European Archives of Psychiatry and Clinical* 

stabilizers for patients with bipolar disorder: the state of the art. *Expert Review of* 

(2008). Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study. *Bipolar Disorders,* Vol.10, No.6, (September 2008), pp. 708-

G., Mintz, J., Mazziotta, J., Cohen, M.S. (2005). Increased amygdala activation during mania: a functional magnetic resonance imaging study. *The American Journal* 

Post, R. (1991). Reduction of temporal lobe volume in bipolar disorder: A preliminary report of magnetic resonance imaging. *Archives of General Psychiatry*,

enlargement in bipolar disorder and hippocampal reduction in schizophrenia: An MRI study demonstrating neuroanatomic specificity. *Archives of General Psychiatry,*

abnormalities in affective disorder: clinical and demographic correlates. *The American* 

and corpus callosum aberrations in adolescents with BD: a tract-based spatial

*medicine*, Vol. 41, No.3, (May 2011), ISSN 0001-2998

*Neuroscience,* (February 2011), epub ahead of print (a)

Vol.48, No.5, (May 1991), pp. 482–483, ISSN 0003-990X

Vol.55, No.7, (July 1998), pp. 663–664, ISSN 0003-990X

and I.H. Robertson, ISBN 9780444503664, UK

2004), pp. 540–549, ISSN 1398-5647

17, ISSN 1398-5647

resistant forms (Regenold et al., 2008).

**5. References** 

statistics analysis. *Biological Psychiatry,* Vol.66, No.3, (August 2009), pp. 238-44, ISSN 0006-3223


Neuroimaging Data in Bipolar Disorder: An Updated View 277

Harvey, I., Persaud, R., Ron, M.A., Baker, G., & Murray, R.M. (1994). Volumetric MRI

Heng, S., Song, A.W., Sim, K. (2010). White matter abnormalities in bipolar disorder:

Iacono, W.G., Smith, G.N., Moreau, M., Beiser, M., Fleming, J.A.E., Lin, T., & Flak, B. (1988).

Jezzard P., Matthews P.M., Smith S.M. (2001) *Functional MRI: An Introduction to Methods.* Oxford University Press, pp. 6-8, ISBN 0 19 263071 7, New York, USA Johnstone, E.C., Owens, D.G., Crow, T.J., Frith, C.D., Alexandropolis, K., Bydder, G., &

Kato, T., Shioiri, T., Murashita, J., Hamakawa, H., Inubushi, T., Takahashi, S. (1995).

Konarski, J.Z., McIntyre, R.S., Soczynska, J.K., & Kennedy, S.H. (2007). Neuroimaging

*Psychiatry*, Vol.19, No.4, (October-December 2007), pp. 265-277, ISSN 1040-1237 Laje, G., Cannon, D.M., Allen, A.S., Klaver, J.M., Peck, S.A., Liu, X., Manji, H.K., Drevets,

Lewandowski, K.E., Cohen, B.M., & Ongur, D. (2011). Evolution of neuropsychological

Lin, F., Wenig, S., Xie, B., Wu, G., & Lei, H. (2011). Abnormal frontal cortex white matter

Lochhead, R.A., Parsey, R.V., Oquendo, M.A., & Mann, J.J. (2004). Regional brain gray

*Medicine*, Vol.41, No.2, (February 2011), pp. 225-241, ISSN 0033-2917 Lim, K.O., Rosenbloom, M.J., Faustman, W.O., Sullivan, E.V., & Pfefferbaum, A. (1999).

Vol.40, No.3, (December 1999), pp. 219–227, ISSN 0920-9964

*Disorders,* (January 2011), epub ahead of print.

*Psychiatry*, Vol.145, No.7, (July 1988), pp. 820–824, ISSN 0002-953X

Vol.117, No.5, (May 2010), pp. 639-54, ISSN 0300-9564

(January 2009), pp. 79-86, ISSN 0021-9630

2005), pp. 151-160, ISSN 0022-3956

1461-1457

916-927, ISSN 1398-5647

measurements in bipolars compared with schizophrenics and healthy controls. *Psychological Medicine,* Vol.24, No.3, (August 1994), pp. 689–699, ISSN 0033-2917 Hassel, S., Almeida, J.R., Kerr, N., Nau, S., Ladouceur, C.D., Fissell, K., Kupfer, D.J., &

Phillips, M.L. (2008). Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic BD: no associations with psychotropic medication load. *Bipolar disorders,* Vol.10, No.8, (December 2008), pp.

insights from diffusion tensor imaging studies. *Journal of Neural Transmission*,

Ventricular and sulcal size at the onset of psychosis. *The American Journal of* 

Colter, N. (1989). Temporal lobe structure as determined by nuclear magnetic resonance in schizophrenia and bipolar affective disorder. *Journal of Neurology, Neurosurgery & Psychiatry,* Vol.52, No.6, (June 1989), pp. 736-741, ISSN 0022-3050 Kafantaris, V., Kingsley, P., Ardekani, B., Saito, E., Lencz, T., Lim, K., & Szeszko, P. (2009).

Lower orbital frontal white matter integrity in adolescents with bipolar I disorder. *Journal of the American Academy of Child & Adolescent Psychiatry*, Vol.48, No.1,

Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia. *Psychiatry Research,* Vol.61, No.3, (September

approaches in mood disorders: technique and clinical implications. *Annals of Clinical* 

W.C., & McMahon, F.J. (2010). Genetic variation in HTR2A influences serotonin transporter binding potential as measured using PET and [11C]DASB. *International Journal of Neuropsychopharmacology*, Vol.13, No.6, (July 2010), pp. 715-724, ISSN

dysfunction during the course of schizophrenia and bipolar disorder. *Psychological* 

Cortical gray matter deficit in patients with bipolar disorder. *Schizophrenia Research*,

connections in bipolar disorder: A DTI tractography study. *Journal of Affective* 

matter volume differences in patients with bipolar disorder as assessed by


Coffman, J.A., Bornstein, R.A., Olson, S.C., Schwarzkopf, S.B., & Nasrallah, H.A. (1990).

*Clinical Neurophysiology,*Vo*l.* 56, No.1, (July 1983), pp.38-51, ISSN 0013-4694 Czobor, P., Jaeger, J., Berns, S.M., Gonzalez, C., & Loftus, S. (2007). Neuropsychological

Deckersbach, T., Dougherty, D.D., Savage, C., McMurrich, S., Fischman, A.J., Nierenberg,

DelBello, M.P., Strakowski, S.M., Zimmermann, M.E., Hawkins, J.M., & Sax, K.W. (1999).

*Psychiatrica Scandinavica*, Vol.77, No.6, (June 1988), pp. 670-682, ISSN 0001-690X Dougherty, D.D., Rauch, S.L., Rosenbaum, J.F. (2004)*. Essentials of Neuroimaging for Clinical* 

Elliott, R. (2004). Abnormal ventral frontal response during performance of an affective

Frodl, T., Meisenzahl, E., Zetzsche, T., Bottlelender, R., Born, C., Groll, C., Jäger, M.,

Glover G.H. (2011). Overview of functional magnetic resonance imaging. *Neurosurgery* 

Gonul, A.S., Coburn, K., & Kula, M. (2009). Cerebral blood flow, metabolic, receptor, and

Haller, S., Xekardaki, A., Delaloye, C., Canuto, A., Lövblad, K.O., Gold, G., &

*Clinics of North America,*Vol.22, No.2, (April 2011), ISSN 1042-3680

*Psychiatry*, Vol.59, No.2, (January 2006)), pp. 138–146, ISSN 0006-3223 Delaloye, C., Moy, G., de Bilbao, F., Weber, K., Baudois, S., Haller, S., Xekardaki, A., Canuto,

*Psychiatry*, Vol. 27, No.11, (June 1990), pp. 1188–1196, ISSN 0006-3223 Cohen D., Cuffin B.N. (1983). Demonstration of useful differences between

No.1-2, (February-March 2007), pp. 71-92, ISSN 1398-5647

epub ahead of print.

226, ISSN 1070-8022

ISSN 1180-4882

2004), pp. 1163–1170, ISSN 0006-3223

(May 2002), pp. 708–714, ISSN 0006-3223

Cognitive impairment and cerebral structure by MRI in bipolar disorder. *Biological* 

magnetoencephalogram and electroencephalogram. *Electroencephalography and* 

symptom dimensions in bipolar disorder and schizophrenia. *Bipolar disorders*, Vol.9,

A., Sachs, G., & Rauch, S.L. (2006). Impaired recruitment of the dorsolateral prefrontal cortex and hippocampus during encoding in bipolar disorder. *Biological* 

A., Giardini, U., Lövblad, K.O., Gold, G., & Giannakopoulos, P. (2011). Longitudinal analysis of cognitive performances and structural brain changes in late-life bipolar disorder. *International Journal of Geriatric Psychiatry*, (March 2011),

MRI analysis of the cerebellum in bipolar disorder: a pilot study. *Neuropsychopharmacology*, Vol.21, No.1, (July 1999), pp. 63–68, ISSN 0893-133X Dewan, M.J., Haldipur, C.V., Lane, E.E., Ispahani, A., Boucher, M.F., & Major, L.F. (1988). Bipolar

affective disorder: I. Comprehensive quantitative computed tomography. *Acta* 

*Practice.* American Psychiatric Publishing, ISBN 1-58562-079-3. Arlington, Virginia, USA

go/no go task in patients with mania. *Biological Psychiatry*, Vol.55, No.12, (June

Leinsinger, G., Hahn, K., Möller, H.J. (2002). Enlargement of the amygdala in patients with a first episode of major depression. *Biological Psychiatry,* Vol.51, No.9,

transporter changes in bipolar disorder: the role of PET and SPECT studies. *International Review of Psychiatry*, Vol.21, No.4, (2009), pp. 323-335, ISSN 0954-0261 Gujar, S.K., Maheshwari, S., Björkman-Burtscher, I., & Sundgren, P.C. (2005). Magnetic

resonance spectroscopy*. J Neuroophthalmol,* Vol.25, No.3, (September 2005), pp. 217-

Giannakopoulos, P. (2011). Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder. *Journal of Psychiatry Neuroscience*, Vol.36, No.1, (January 2011), pp 100140,


Neuroimaging Data in Bipolar Disorder: An Updated View 279

Pearlson, G.C., Garbacz, D.J., Tompkins, R.H., Ahn, H.S., Gutterman, D.F., Veroff, A.E., &

Pearlson, G.D., & Veroff, A.E. (1981). Computerized tomographic scan changes in manicdepressive illness. *The Lancet*, Vol.2, No.8244, (August 1981), pp. 470, ISSN 0140-6736 Pearlson, G.D., Barta, P.E., Powers, R.E., Menon, R.R., Richards, S.S., Aylward, E.H., et al.

*Biological Psychiatry*, Vol.41, No.1, (January 1997), pp. 1–14, ISSN 0006-3223 Person, C., Koessler, L., Louis-Dorr, V., Wolf, D., Maillard, L., & Marie, P.Y. (2010). Analysis

Phelps M.E., Hoffman E.J., Mullani N.A., Ter-Pogossian M.M. (1975). Application of

*of Nuclear Medicine,* Vol.16, No.3, (March 1975), pp.210-224, ISSN 0161-5505 Phillips M.L., Vieta E. (2007). Identifying functional neuroimaging biomarkers of bipolar

Quigley, H., Colloby, S.J., & O'Brien, J.T. (2010). PET imaging of brain amyloid in dementia: a

Regenold, W., Hisley, K., Phatak, P., Marano, C.M., Obuchowski, A., Lefkowitz, D.M.,

Roncali E., Cherry S.R. (2011). Application of silicon photomultipliers to positron emission

Salas-Gonzalez, D., Górriz, J.M., Ramírez, J., Illán, I.A., López, M., Segovia, F., Chaves, R.,

Savitz, J., & Drevets, W.C. (2009). Bipolar and major depressive disorder: neuroimaging the

Scherk, H., Kemmer, C., Usher, J., Reith, W., Falkai, P., & Gruber, O. (2008). No change to

No.11, (November 2010), pp. 6084-95, ISSN 1985-4811

No.5, (May 2009), pp. 699-771, ISSN 0149-7634

*Disorders*, Vol.10, No.7, (November 2008), pp. 753–764, ISSN 1398-5647 Rieder, R.O., Mann, L.S., Weinberger, D.R., van Kammen, D.P., Post, R.M. (1983). Computed

pp. 253-256, ISSN 0002-953X

Aires, August 31-September 4, 2010.

904, ISSN 0586-7614

739, ISSN 0003-990X

77, ISSN 0090-6964

ISSN 0940-1334 (a)

fiber tracts in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. *Biological Psychiatry*, Vol.65, No.7, (April 2009), pp. 586-93, ISSN 0006-3223

DePaulo, J.R. (1984). Clinical correlates of lateral ventricular enlargement in bipolar affective disorder. *The American Journal of Psychiatry,* Vol.141, No.2, (February 1984),

(1997). Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder.

of the relationship between interictal electrical source imaging and PET hypometabolism. *Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE,* pp. 3723-6, ISBN 978-1-4244-4123-5, Buenos

annihilation coincidence detection to transaxial reconstruction tomography. *Journal* 

disorder: toward DSM-V. Schizophrenia bulletin. Vol. 33, No. 4, (Jul 2007), pp. 893-

review. *International Journal of Geriatric Psychiatry*, (December 2010), epub ahead of print.

Sassan, A., Ohri, S., Phillips, T.L., Dosanjh, N., Conley, R.R., & Gullapalli, R. (2008). Relationship of cerebrospinal fluid glucose metabolites to MRI deep white matter hyperintensities and treatment resistance in bipolar disorder patients. *Bipolar* 

tomographic scans in patients with schizophrenia, schizoaffective, and bipolar affective disorder. *Archives of General Psychiatry*, Vol.40, No.7, (July 1983), pp. 735–

tomography. *Annals of Biomedical Engineering,* Vol.39, No.4, (April 2011), pp. 1358-

Padilla, P., & Puntonet, C.G. (2010). Feature selection using factor analysis for Alzheimer's diagnosis using 18F-FDG PET images. *Medical Physiology*, Vol.37,

developmental-degenerative divide. *Neuroscience & Biobehavioral Reviews*, Vol.33,

grey and white matter volumes in bipolar I disorder patients. *European Archives of Psychiatry and Clinical Neuroscience,* Vol.258, No.6, (September 2008), pp. 345–349,

optimized voxel-based morphometry. *Biological Psychiatry,* Vol.55, No.12, (June 2004), pp. 1154–1162, ISSN 0006-3223


Manji, H.K., Moore, G.J., & Chen, G. (2000). Lithium up-regulates the cytoprotective protein

Mazzuca, M., Jambaque, I., Hertz-Pannier, L., Bouilleret, V., Archambaud, F., Caviness, V.,

McDonald, C., Bullmore, E., Sham, P., Chitnis, X., Suckling, J., MacCabe, J., Walshe, M., &

Vol.40, No.4, (December 1991), pp. 211–220, ISSN 0022-3956

2004), pp. 1154–1162, ISSN 0006-3223

82–96, ISSN 0160-6689

pp. 172–176, ISSN 0007-1250

(March 2011), epub ahead print.

1997), pp. 1323– 1337, ISSN 0278-5846

(April 2008), pp. 485–497, ISSN 1053-8119

optimized voxel-based morphometry. *Biological Psychiatry,* Vol.55, No.12, (June

Bcl-2 in the CNS in vivo: A role for neurotrophic and neuroprotective effects in manic depressive illness. *Journal of Clinical Psychiatry,* Vol.61, Suppl.9, (2000), pp.

Rodrigo, S., Dulac, O., & Chiron, C. (2011). 18F-FDG PET reveals frontotemporal dysfunction in children with fever-induced refractory epileptic encephalopathy. *The Journal of Nuclear Medicine*, Vol.52, No.1, (January 2011), pp. 40-47, ISSN 0161-5505 McCrea, S.M. (2008). Bipolar Disorder and neurophysiologic mechanisms. *Neuropsychiatric Disease and Treatment*, Vol.4, No.6, (December 2008), pp. 1129-53, ISSN 1176-6328 McDonald, W.M., Krishnan, K.R., Doraiswamy, P.M., & Blazer, D.G. (1991). Occurrence of

subcortical hyperintensities in elderly subjects with mania. *Psychiatry Research*,

Murray, R.M. (2005). Regional volume deviations of brain structure in schizophrenia and psychotic bipolar disorder: computational morphometry study. *British Journal of Psychiatry*, Vol.186, (May 2005), pp. 369–377, ISSN 1472-1465 Mervaala, E., Fohr, J., Kononen, M., Valkonen-Korhonen, M., Vainio, P., Partanen, K.,

Partanen, J., Tiihonen, J., Viinamäki, H., Karjalainen, A.K., & Lehtonen, J. (2000). Quantitative MRI of the hippocampus and amygdala in severe depression. *Psychological Medicine,* Vol.30, No.1, (January 2000), pp. 117–125, ISSN 0033–2917 Monks, P.J., Thompson, J.M., Bullmore, E.T., Suckling, J., Brammer, M.J., Williams, S.C.,

Simmons, A., Giles, N., Lloyd, A.J., Harrison, C.L., Seal, M., Murray, R.M., Ferrier, I.N., Young, A.H., & Curtis, V.A. (2004). A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction.

Ferrier, I.N. (2001). Cerebral white matter lesions in bipolar affective disorder: relationship to outcome. *The British Journal of Psychiatry*, Vol.178, (February 2001),

Users Show Greater than Normal Age-Related Cortical Grey Matter Loss. *Addiction,* 

schizophrenia and mania: a comparative CT study. *The Journal of Clinical Psychiatry*,

patients with bipolar affective disorder by MRI: a review of the literature. *Progress in Neuro-Psychopharmacology and Biological Psychiatry*, Vol.21, No.8, (November

Pine, D.S., Price, J.L., & Drevets, W.C. (2006). Cortical abnormalities in BD investigated with MRI and voxel-based morphometry. *Neuroimage,* Vol.30, No.2,

Sweeney, J.A., & Zhou, X.J. (2009). Diffusion tensor imaging study of white matter

*Bipolar Disorders*, Vol.6, No.6, (December 2004), pp. 550–564, ISSN 1398-5647 Moore, P., Shepherd, D., Eccleston, D., Macmillan, I.C., Goswami, U., McAllister, V.L., &

Nakama H., Chang L., Fein G., Shimotsu R., Jiang C.S., Ernst T. (2011). Methamphetamine

Nasrallah, H.A., McCalley-Whitters, M., & Jacoby, C.G. (1982). Cortical atrophy in

Norris, S.D., Krishnan, K.R.R., & Ahearn, E. (1997). Structural changes in the brain of

Nugent, A.C., Milham, M.P., Bain, E.E., Mah, L., Cannon, D.M., Marrett, S., Zarate, C.A.,

Pavuluri, M.N., Yang, S., Kamineni, K., Passarotti, A.M., Srinivasan, G., Harral, E.M.,

Vol.43, No.11, (November 1982), pp. 439-441, ISSN 0160-6689

fiber tracts in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. *Biological Psychiatry*, Vol.65, No.7, (April 2009), pp. 586-93, ISSN 0006-3223


Neuroimaging Data in Bipolar Disorder: An Updated View 281

Swayze, V.W., Andreasen, N.C., Alliger, R.J., Yuh, W.T.C., & Ehrhard, J.C. (1992).

Takahashi, T., Malhi, G.S., Wood, S.J., Yücel, M., Walterfang, M., Tanino, R., Suzuki, M., &

Ter-Pogossian M.M., Phelps M.E., Hoffman E.J., Mullani N.A. (1975). A positron-emission

Townsend, J., Bookheimer, S.Y., Foland-Ross, L.C., Sugar, C.A., & Altshuler, L.L. (2010).

Usher, J., Leucht, S., Falkai, P., & Scherk, H. (2010). Correlation between amygdala volume

Van der Schot, A.C., Vonk, R., Brans, R.G., van Haren, N.E., Koolschijn, P.C., Nuboer, V.,

Van der Werf-Eldering, M.J., Burger, H., Holthausen, E.A., Aleman, A., & Nolen, W.A.

Versace, A., Almeida, J.R., Hassel, S., Walsh, N.D., Novelli, M., Klein, C.R., Kupfer, D.J., &

Versace, A., Thompson, W.K., Zhou, D., Almeida, J.R., Hassel, S., Klein, C.R., Kupfer, D.J., &

Videbech, P. (1997). MRI findings in patients with affective disorder: a meta-analysis. *Acta Psychiatrica Scandinavica*, Vol.96, No.3, (September 1997), pp. 157–168, ISSN 0001-690X Vyas N.S., Patel N.H., Nijran K.S., Al-Nahhas A., Puri B.K. (2011). The use of PET imaging in

Wang, F., Kalmar, J.H., He, Y., Jackowski, M., Chepenik, L.G., Edmiston, E.E., Tie, K., Gong,

(February 2009), pp. 11-18, ISSN 1398-5647

(January 1975), pp. 89-98, ISSN 0033-8419

No.1, (April 2010), pp. 22-29, ISSN 0022-3956

No.2, (February 2009), pp. 142-151, ISSN 0003-990X

1992), pp. 221–240, ISSN 0006-3223

190, ISSN 0022-3956

e13032, ISSN 1932-6203

1052, ISSN 0003-990X

37-51, ISSN 1473-7175

pp. 422-431, ISSN 0006-3223

diffusion tensor magnetic resonance imaging. *Bipolar Disorders*, Vol.11, No.1,

Subcortical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging study. *Biological Psychiatry,* Vol.31, No.3, (February

Pantelis, C. (2010). Insular cortex volume in established bipolar affective disorder: A preliminary MRI study. *Psychiatry Research*, Vol.182, No.2, (May 2010), pp. 187–

transaxial tomograph for nuclear imaging (PETT). *Radiology*, Vol.114, No.1,

fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects. *Psychiatry Research*, Vol.182,

and age in bipolar disorder— A systematic review and meta-analysis of structural MRI studies. *Psychiatry Research,* Vol.182, No.1, (April 2010),pp. 1–8, ISSN 0022-3956

Schnack, H.G., van Baal, G.C., Boomsma, D.I., Nolen, W.A., Hulshoff Pol, H.E., & Kahn, R.S. (2009). Influence of Genes and Environment on Brain Volumes in Twin Pairs Concordant and Discordant for BD. *Archives of General Psychiatry*, Vol.66,

(2010). Cognitive functioning in patients with bipolar disorder: association with depressive symptoms and alcohol use. *PLoS One*, Vol.5, No.9, (September 2010), pp.

Phillips, M.L. (2008). Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics. *Archives of General Psychiatry*, Vol.65, No.9, (September 2008), pp. 1041-

Phillips, M.L. (2010). Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces: state versus trait vulnerability markers of depression in bipolar disorder. *Biological Psychiatry,* Vol.67, No.5, (March 2010),

studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia. *Expert Review of Neurotherapeutics*, Vol.11, No.1, (January 2011), pp.

G., Shah, M.P., Jones, M., Uderman, J., Constable, R.T., & Blumberg, H.P. (2009). Functional and structural connectivity between the perigenual anterior cingulate


Scherk H., Backens M., Schneider-Axmann T., Kemmer C., Usher J., Reith W., Falkai P.,

Schlaepfer, T.E., Harris, G.J., Tien, A.Y., Peng, L.W., Lee, S., Federman, E.B., Chase, G.A.,

Schlegel, S., & Kretzschmar, K. (1987). Computed tomography in affective disorders, part I.

Schulte T., Mũller-Oehring E.M., Pfefferbaum A., Sullivan E.V. (2010). Neurocircuitry of

Soares, J.C., & Mann, J.J. (1997). The anatomy of mood disorders – review of structural

Steffens, D.C., & Krishnan, K.R.R. (1998). Structural Neuroimaging and Mood Disorders:

Stoll, A.L., Renshaw, P.F., Yurgelun-Todd, D.A., & Cohen, B.M. (2000). Neuroimaging in

Stork C., Renshae P.F. (2005). Mitochondrial dysfunction in bipolar disorder: evidence from

Strakowski, S.M., DelBello, M.P., Zimmerman, M.E., Getz, G.E., Mills, N.P., Ret, J., Shear, P.,

Strakowski, S.M., Wilson, D.R., Tohen, M., Woods, B.T., Douglass, A.W., & Stoll, A.L. (1993).

Suhara, T., Nakayama, K., Inoue, O., Fukuda, H., Shimizu, M., Mori, A., & Tateno, Y. (1992).

*Psychiatry*, Vol.43, No.10, (May 15), pp. 705-712, ISSN 0006-3223

Vol.159, No.11, (November 2002), pp. 1841–1847, ISSN 0002-953X

*Psychiatry*, Vol.66, No.3, (August 2009), pp. 223-230, ISSN 0006-3223 Supprian, T., Reiche, W., Schmitz, B., Grunwald, I., Backens, M., Hofmann, E., Georg, T.,

Vol.131, No.3., (September 2004), pp. 269– 276, ISSN 0022-3956

No.8-9, (April 15-May 1), pp. 602–609, ISSN 0006-3223

(September 2000), pp. 505–517, ISSN 0006-3223

(October 2005), pp. 900-19, ISSN 1359-4184

pp. 283-288, 0001-690X (b)

842–848, ISSN 0002-953X

ISSN 1294-8322

106, ISSN 0006-3223

1987), pp. 4-14, ISSN 0006-3223

Gruber O. (2008). Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder. *Acta Psychiatrica Scandinavica*, Vol.117, No.4, (April 2008),

Barta, P.E., Pearlson, G.D. (1994). Decreased regional cortical gray matter volume in schizophrenia. *The American Journal of Psychiatry,* Vol.151, No.6, (June 1994), pp.

Ventricular and sulcal measurements. *Biological Psychiatry*, Vol.22, No.1, (January

emotion and cognition in alcoholism: contributions from white matter fiber tractography. *Dialogues in Clinical Neuroscience*, Vol.12, No.4, (2010), pp. 554-560,

neuro-imaging studies. *Biological Psychiatry*, Vol.41, No.1, (January 1997), pp. 86–

Recent Findings, Implications for Classification, and Future Directions. *Biological* 

bipolar disorder: what have we learned? *Biological Psychiatry*, Vol.48, No.6,

magnetic resonance spectroscopy research*. Molecular Psychiatry*, Vol.10, No.10,

& Adler, C.M. (2002). Ventricular and periventricular structural volumes in firstversus multiple-episode bipolar disorder. *The American Journal of Psychiatry,*

Structural brain abnormalities in first-episode mania. *Biological Psychiatry*, Vol.33,

D1 dopamine receptor binding in mood disorders measured by positron emission tomography. *Psychopharmacology*, Vol.106, No.1, (1992), pp. 14-18, ISSN 0033-3158 Sullivan, G.M., Ogden, R.T., Oquendo, M.A., Kumar, J.S., Simpson, N., Huang, Y.Y., Mann,

J.J., & Parsey, R.V. (2009). Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. *Biological* 

Falkai, P., & Reith, W. (2004). MRI of the brainstem in patients with major depression, bipolar affective disorder and normal controls. *Psychiatry Research,*

J., Bastin, M.E., Johnstone, E.C., Lawrie, S.M., & McIntosh, A.M. (2009). White matter abnormalities in bipolar disorder and schizophrenia detected using

Sussmann, J.E., Lymer, G.K., McKirdy, J., Moorhead, T.W., Muñoz Maniega, S., Job, D., Hall,

diffusion tensor magnetic resonance imaging. *Bipolar Disorders*, Vol.11, No.1, (February 2009), pp. 11-18, ISSN 1398-5647


**14** 

*Ghent University* 

*Belgium* 

**Reinforcement Learning, High-Level** 

Reinforcement learning (RL) has a rich history tracing throughout the history of psychology. Already in the late 19th century Edward Thorndike proposed that if a stimulus is followed by a successful response, the stimulus-response bond will be strengthened. Consequently, the response will be emitted with greater likelihood upon later presentation of that same stimulus. This proposal already contains the two key principles of RL. The first principle concerns *associative learning*, the learning of associations between stimuli and responses. This theme was developed by John Watson. Building on the work of Ivan Pavlov, John Watson investigated the laws of classical conditioning, in particular, how a stimulus and a response become associated after repeated pairing. In the classical "Little Albert" experiment, Watson and Rayner (1920) repeatedly presented a rabbit together with a loud sound to the kid (little Albert); the rabbit initially evoked a neutral response, the loud sound initially evoked a fear response. After a while, also presentation of the rabbit alone evoked a fear response in the subject. In this same paper, the authors proposed that this principle of learning by association more generally is responsible for shaping (human) behavior. According to psychology handbooks John Watson hereby laid the foundation for behaviorism. The second principle is that *reinforcement* is key for human learning. Actions that are successful for the organism, will be strengthened and therefore repeated by the organism. This aspect was developed into a systematic research program by the second founder of behaviorism,

The importance of RL for explaining human behavior started to be debated from the late 1940s. Scientific criticism toward RL arrived from two main fronts. The first was internal, deriving from experimental findings and theoretical considerations within psychology itself. The second derived from external developments, in particular, advancements in information theory and control theory. These criticisms led to a disinterest for RL lasting several decades. However, in recent years, RL has been revived, leading to a remarkable interdiscplinary confluence between computer science, neurophysiology, and cognitive neuroscience. In the current chapter, we describe the relevant mid-20th century criticisms and developments, and how these were considered and integrated in current versions of RL. In particular we focus on how RL can be used as a model for understanding high-level

cognition. Finally, we link RL to the broader framework of neural Darwinism.

**1. Introduction** 

Burrhus Skinner (e.g., Skinner, 1938).

**Cognition, and the Human Brain** 

Massimo Silvetti and Tom Verguts

and amygdala in bipolar disorder. *Biological Psychiatry,* Vol.66, No.5, (September 2009), pp. 516-21,ISSN 0006-3223

