Neuroimaging

Neuroimaging and Mental Illness

Brian Wells, MS3, MSM, MPH

Why neuroimaging?• The research agenda for DSM-V emphasizes a

need to translate basic and clinical neuroscience research findings into a new

classification system for all psychiatric disorders based upon pathophysiologic and etiological processes

• Etiologic and pathophysiologically-based diagnostic system v. symptomatologic and syndromic approach of DSM-III and DSM-IV

Philips, ML. The Emerging Role of Neuroimaging in Psychiatry: Characterizing Treatment-Relevant EndophenotypesAm J Psychiatry 164:697-699, May 2007

http://en.wikipedia.org/wiki/Am_J_Psychiatry


Why neuroimaging?• Although structural imaging

techniques are most useful for ruling out medical etiologies of mental status disturbances, functional neuroimaging techniques currently have an adjunctive role in the evaluation of dementia and seizure disorders and show promise for the evaluation of primary psychiatric disorders in the future.Rauch SL, Renshaw PF. Clinical neuroimaging in psychiatry.Harv Rev Psychiatry. 1995 Mar-Apr;2(6):297-312.

Why neuroimaging?• Potential for improved early diagnosis

and treatment– Antipsychotics are now the top-

selling class of medications in the United States, with prescription sales of $14.6 billion in 2009.

– Many clinicians worry these agents are being overprescribed and used inappropriately.

• IMS Health. (2010). IMS Health reports U.S. prescription sales grew 5.1% in 2009, to $300.3 billion.• Culpepper L et al. Are antipsychotics overprescribed? http://www.medscape.com/viewarticle/737587?src=mp&spon=17• Lieberman JA et al. Effectiveness of antipsychotic drugs in patients

with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223

Why neuroimaging?• We are surely now in a position

in psychiatry to fully embrace the potential of neuroimaging

and other basic and clinical neuroscience findings to help us

identify neural system abnormalities that are more accurate than traditional clinical measures in characterizing subgroups of individuals who will subsequently respond best to different treatment modalities.Philips, ML. The Emerging Role of Neuroimaging in Psychiatry: Characterizing Treatment-Relevant EndophenotypesAm J Psychiatry 164:697-699, May 2007



Neuroimaging Modalities

• CT• MRI• PET• SPECT• fMRI• MRS

Rauch SL, Renshaw PF. Clinical neuroimaging in psychiatry.Harv Rev Psychiatry. 1995 Mar-Apr;2(6):297-312.

*schizophrenics show over-activation of the cingulate gyrus, while controls seem to activate prefrontal cortex more than schizophrenics.

http://pnl.bwh.harvard.edu/index.html

Research Areas

• Schizotypal personality disorder• Schizophrenia• PTSD• Bipolar disorder• Multiple others

Schizotypal Personality Disorder• Cluster A: Odd/Eccentric• Cluster A patients tend to be detached and

distrustful• SPD involves social withdrawal and emotional

coldness but also includes oddities of thinking, perception, and communication, such as magical thinking, clairvoyance, ideas of reference, or paranoid ideation.

• These oddities suggest schizophrenia but are never severe enough to meet its criteria.

• People with schizotypal personality are believed to have a muted expression of the genes that cause schizophrenia.

http://www.merckmanuals.com/professional/sec15/ch201/ch201a.html?qt=schizotypal&alt=sh

Schizotypal personality disorder• STG is involved in the perception of emotions in

facial stimuli• Contains Brodmann areas 41, 42 (primary auditory)

and 22p (Wernicke’s)• Reduction of left STG gray matter volume in SPD

subjects when compared to normal controls.• Comparisons with chronic schizophrenics

previously studied showed the SPD group had a similarity of left STG gray matter volume reduction, but fewer medial temporal lobe abnormalities.

• This finding supports the hypothesis of the importance of STG involvement in the schizophrenia spectrum disorders.

• Possible that presence of medial temporal lobe abnormalities may help to differentiate who will develop schizophrenia and who will develop SPD

3D reconstruction of the cortex and superior temporal gyrus, shown in red.

Chandlee, CD et al. Schizotypal Personality Disorder and MRIAbnormalities of Temporal Lobe Gray Matter. Biol Psychiatry 1999;45:1393–1402

Imaging Summary• SPD - Reduction of left STG gray matter

volume; fewer medial temporal lobe abnormalities

Schizophrenia• A recent World Health Organization (WHO)

report estimates that nearly 1% of the population in the US is affected by schizophrenia.

• A growing body of evidence suggests that early detection and treatment of schizophrenia (and many other brain disorders) is critical in forming and predicting the course and outcome of the disorder.

McGlashan, T.: Early detection and intervention in schizophrenia: editors introduction.Schizophr Bull 22(2), 197–199 (1996)

Schizophrenia• Schizophrenia is characterized by psychosis (loss of

contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction.

• Although its specific cause is unknown, schizophrenia has a biologic basis, as evidenced by alterations in brain structure (eg, enlarged cerebral ventricles, decreased size of the anterior hippocampus and other brain regions) and by changes in neurotransmitters, especially altered activity of dopamine and glutamate.

• 5 Subtypes: Paranoid, Catatonic, Disorganized, Residual, Undifferentiated

Schizophrenia• No definitive test for schizophrenia exists• Diagnostic and Statistical Manual of Mental Disorders,

Fourth Edition Text Revision (DSM-IV-TR), the diagnosis requires both of the following:– ≥ 2 characteristic symptoms (delusions,

hallucinations, disorganized speech, disorganized behavior, negative symptoms) for a significant portion of a 1-mo period

– Prodromal or attenuated signs of illness with social, occupational, or self-care impairments evident for a 6-mo period that includes 1 mo of active symptoms

• Treatment is with antipsychotic drugs, psychotherapy and rehabilitation/community support http://www.merckmanuals.com/professional/sec15/ch202/ch202e.html

http://www.merckmanuals.com/professional/sec15/ch202/ch202e.html

http://www.merckmanuals.com/professional/sec15/ch202/ch202e.html

Schizophrenia• MRI has been useful in revealing subtle structural

brain abnormalities in schizophrenia patients, including ventricular enlargement, volume reduction in the frontal and parietal lobes, and gray matter reduction of medial temporal lobe structures

• It is unknown whether the brain abnormalities observed with MRI in schizophrenia are confounded by chronicity or whether there is a continual degenerative process.

• Chronic schizophrenia patients may demonstrate pathology secondary to chronic neuroleptic medication and long-term institutionalization.

Heschl's gyrus and planum temporale regions drawn on a coronal MR slice (left), and a 3D rendering shown overlayed on an axial MR slice.

Shenton, ME et al. A review of MRI findings in schizophreniaSchizophrenia Research 49 (2001) 1-52.

Schizophrenia• Heschl’s gyrus (AKA transverse temporal gyrus)

– Found in primary auditory cortex - Brodmann 41, 42

– First cortical structure to process incoming auditory information

– Active during auditory processing under fMRI for tone and semantic tasks.

• Planum temporale– Posterior to Heschl’s gyrus within Sylvian fissure– Most asymmetrical of all brain structures– Significant L/R asymmetry is normal– 5x larger on left in some individuals– Evolutionary ancestral origins shown in primates– Functions in sound location, language, music


Schizophrenia• Inferior fronto-occipital fasciculus

– The ability to suppress one's impulses and actions constitutes a fundamental mechanism of cognitive control, thought to be subserved by the right inferior frontal cortex (rIFC)

• Uncinate fasciculus– Function unknown but traditionally assigned to

the limbic system– links the forward portions of the temporal lobe

with the inferior frontal gyrus and the lower surfaces of the frontal lobe

• Tract integrity measured by fractional ansiotropy; higher values mean diffusion occurs along one axis

Forstmann, BU et al. Function and Structure of the Right Inferior Frontal Cortex Predict Individual Differences in Response Inhibition: A Model-Based Approach. The Journal of Neuroscience, 24 September 2008, 28(39): 9790-9796; doi: 10.1523/

FOF displayed in green

Schizophrenia• Examining first episode patients can thus obviate

chronicity-related confounders.• Findings suggest that within the first year changes are

observed in the superior temporal gyrus region of the temporal lobe, including Heschl's gyrus and planum temporale, brain regions important in primary and secondary auditory processing.

• Data suggests that first-episode schizophrenia might also be associated with disruptions in extensive portions of white matter fiber tracts, especially in the corpus callosum, uncinate fasciculus, inferior fronto-occipital fasciculus and internal capsule, and that negative symptoms are associated with white matter abnormalities related to the right inferior fronto-occipital fasciculus.


LaVenture A et al. Abnormalities in White Matter Integrity in First Episode Schizophrenia Using Atlas-Based Segmentation. Mysell Harvard Research Day, Psychiatry Annual Meeting 2010

Schizophrenia• Left-lateralized reductions in gray matter

volume in anterior hippocampus / amygdala, parahippocampal gyrus, and superior temporal gyrus

• Hallmark clinical symptom of thought disorder is associated with a specific reduction in the volume of left posterior superior temporal gyrus gray matter, which encompasses primary auditory cortex and association cortex, including planum temporale (neuroanatomical substrates of language)

Coronal MR scans from a chronic schizophrenic (right) and normal comparison subject (left). Note increase in CSF in left amygdala-hippocampal complex.

Coronal MR scans from a chronic schizophrenic (right) and normal comparison subject (left). Note increase in CSF in left amygdala-hippocampal complex (smaller amygdala on left)



• Schizophrenia - first year changes are observed in the superior temporal gyrus region of the temporal lobe, including Heschl's gyrus and planum temporale

• Schizophrenia – chronic changes - left-lateralized reductions in gray matter volume in anterior hippocampus / amygdala, parahippocampal gyrus, and superior temporal gyrus

Posttraumatic stress disorder• Posttraumatic stress disorder (PTSD) causes recurring,

intrusive recollections of an overwhelming traumatic incident that persist > 1 mo, as well as emotional numbing and hyperarousal.

• Traumatic events commonly associated with these disorders include assaults, sexual assaults, car accidents, dog attacks, and injuries (especially burns). In young children, domestic violence is the most common cause of PTSD.

• Treatment is with behavioral therapy, SSRIs, and antiadrenergic drugs.

• SSRIs often help reduce emotional numbing and reexperiencing of symptoms but are less effective for hyperarousal. Antiadrenergic drugs (clonidine, prazosine) may help relieve hyperarousal symptoms, but supportive data are preliminary.

Posttraumatic stress disorder• Studies in PTSD Vietnam combat veterans

revealed:– Reduced left and right hippocampal

volume– Volume reductions were associated

with severity of combat exposure, suggesting that the severe stress of military combat both damages the hippocampus

• A similar study was undertaken with Gulf war veterans in Israel, and these data are have shown similar findings

Boone, Omar et al. Longitudinal MRI Study of Hippocampal Volumein Trauma Survivors With PTSD. Am J Psychiatry 2001; 158:1248–1251

Hippocampus (green), Fornix (blue) and Mammilary Bodies (gray) are shown in 3D.

Posttraumatic stress disorder

• Smaller hippocampal volume is not a necessary risk factor for developing PTSD and does not occur within 6 months of expressing the disorder

• This brain abnormality might occur in individuals with chronic or complicated PTSD.

Boone, Omar et al. Longitudinal MRI Study of Hippocampal Volumein Trauma Survivors With PTSD. Am J Psychiatry 2001; 158:1248–1251

Posttraumatic stress disorder• A study reported in Nature-Neuroscience

evaluated MR brain morphometry of the hippocampus in monozygotic twins discordant for PTSD. The PTSD twin was diagnosed with PTSD as a result of combat exposure in the Vietnam War.

• The twin aspect of this study was important as it showed that individuals discordant for PTSD showed reduced hippocampal volume compared with twins where PTSD was present in neither twin.

• This finding suggests that there may be a predisposition or vulnerability factor involved in the genesis of PTSD

Gilberson, MW et al.Smaller hippocampal volumepredicts pathologic vulnerabilityto psychological trauma.Nature-Neuroscience, October 2002



• Schizophrenia - first year changes are observed in the superior temporal gyrus region of the temporal lobe, including Heschl's gyrus and planum temporale


• PTSD – reduced hippocampal volume past 6 months

Bipolar Disorder• Bipolar I disorder (BPI) affects at least 1% of

the population, is associated with increased mortality, and is among the top 10 most disabling illnesses worldwide.

• Bipolar disorders usually begin in the teens, 20s, or 30s.

• When one takes into account those with bipolar II and subthreshold bipolar disorder capturing those with briefer or only treatment-emergent hypomania, lifetime prevalence rates approach 5%.

Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2007;64:543–552.

Bipolar disorder• Diagnosis is based on

identification of symptoms of mania or hypomania plus a history of remission and relapse

• Thyroxine (T4) and thyroid-stimulating hormone levels to exclude hyperthyroidism

• Exclusion of stimulant drug abuse clinically or by urine testing

Bipolar disorder• Bipolar disorders are classified as

– Bipolar I disorder: Defined by the presence of at least one full-fledged (ie, disrupting normal social and occupational function) manic or mixed episode and usually depressive episodes

– Bipolar II disorder: Defined by the presence of major depressive episodes with at least one hypomanic episode but no full-fledged manic episodes

– Bipolar disorder not otherwise specified (NOS): Disorders with clear bipolar features that do not meet the specific criteria for other bipolar disorders

Bipolar disorder. Merck Manual – http://www.merckmanuals.com/professional/sec15/ch200/ch200c.html?qt=bipolar&alt=sh

Bipolar disorder• Treatment is with

– Mood stabilizers (eg lithium) and certain anticonvulsants (eg carbamazepine), 2nd generation antipsychotic (eg aripiprazole, risperidone) or both

– Support and psychotherapy– ECT for depression refractory to treatment

• Treatment in 3 phases– Acute – To stabilize and control the initial,

sometimes severe manifestations– Continuation – To attain full remission– Maintenance – To keep paients in

remission

Bipolar disorder• One major issue in diagnosing and treating

bipolar disorder is the high rate of misdiagnosis or late diagnosis

• In one community sample of diagnosed bipolar disorder patients, approximately 70% had a missed diagnosis. A total of 60% of those were diagnosed with major depressive disorder, with one third going 10 years or more without a correct diagnosis. In addition, these patients had on average 3.5 other diagnoses and saw on average four physicians before receiving the correct diagnosis.

Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161–174.

Bipolar disorder• Fewer than half of the people who were

previously diagnosed with bipolar disorder could be said to have the disorder when strict diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders-IV were applied.

• Dangers to overdiagnosis, chief among them unnecessary exposure to mood stabilizers and all their powerful side effects

• Role for neuroimaging

Reference Zimmerman. Journal of Clinical Psychiatry. May 2008http://www.webmd.com/bipolar-disorder/news/20080506/bipolar-disorder-overdiagnosed

Bipolar disorder• Identifying endophenotypic markers

for bipolar disorder at this time would seek to serve two main goals:1. To clarify diagnosis and discriminate the

depression in bipolar disorder from that of UPD to treat accordingly

2. To identify at-risk individuals for early diagnosis with the goal of intervening before illness onset.

Keener, MT et al. Neuroimaging in bipolar disorder: A criticalreview of current findings. Curr Psychiatry Rep. 2007 December; 9(6): 512–520

Two overlapping neural systems implicated in bipolar disorder. An anterior limbic subcortical system (left) is responsible for emotion processing. Lateral prefrontal cortical regions (right) are implicated in executive control. These two systems interact and overlap in ventral frontal areas such as the orbitofrontal cortex (OFC) that are responsible for decision making about emotional material and attentional control during emotional stimuli processing. Directional findings in bipolar disorder are represented by size of nodes and vertical arrows. DLFPC—dorsolateral prefrontal cortex; DMPFC—dorsomedial prefrontal cortex; Dorsal ACG—dorsal cingulate gyrus; VLPFC—ventrolateral prefrontal cortex; VMPFC—ventromedial prefrontal cortex.

Bipolar Disorder \Early Onset. Studies show markedly increased perfusion in bilateral frontal and posterior parietal lobes. There is also hypoperfusion of both orbito-frontal areas, anterior and mesial temporal areas.

Mena, Ismael. et al. Bipolar affective disorders: Assessment of functional brain changes by means of Tc99m HMPAO NeuroSPECT. Alasbimn Journal 6(23): January 2004. Article N° AJ23-2.

Bipolar disorder• PET studies in depressed BPI, bipolar II, and

manic individuals have shown increased amygdalar and ventral striatal limbic subcortical activity compared with healthy controls

• In adults, there are findings of enlarged (or shrunken) amygdalae, decreased dorsal and ventral prefrontal cortices, and smaller or no change in hippocampi.

Altshuler LL, Bartzokis G, Grieder T, et al. An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry. 2000;48:147–162.

Blumberg et al. 2003 "Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder". Arch Gen Psychiatry 60 (12): 1201–8.

Imaging Summary• SPD - Reduction of left STG gray matter volume; fewer

medial temporal lobe abnormalities• Schizophrenia - first year changes are observed in the

superior temporal gyrus region of the temporal lobe, including Heschl's gyrus and planum temporale


• PTSD – reduced hippocampal volume past 6 months• Bipolar - increased perfusion in bilateral frontal and

posterior parietal lobes. There is also hypoperfusion of both orbito-frontal areas, anterior and mesial temporal areas. Structure - Enlarged amygdalae, decreased dorsal and ventral prefrontal cortices, and smaller or no change in hippocampi.

Summary

• Neuroimaging of psychiatric illness is a rapidly developing field

• Helps explain biologic basis of mental illness

• Promises to aid diagnosis and identify early-onset and predisposition to disease

• Could enhance treatment and reduce misdiagnosis/overdiagnosis

Thank you!

Education

Neuroimaging