Schizophrenia Research Forum - A Catalyst for Creative Thinking

Altered Connections Between Cortex and Striatum Mark Risk for Psychosis

September 17, 2013. Different signaling patterns between the cortex and striatum distinguish the brains of people with first-episode psychosis from those of control subjects, reports a study published online September 4 in JAMA Psychiatry. Moreover, the same circuit alterations are present in their healthy relatives.

Using resting-state functional magnetic resonance imaging (fMRI), Alex Fornito of Monash University in Melbourne, Australia, and colleagues at the University of Cambridge, U.K., examined patterns of co-activation between the striatum’s subregions and the cortical regions that target them. This revealed patterns of over- and under-coordination of activity in people with psychosis and those at genetic risk for it: In particular, dorsal regions of the striatum seemed decoupled from their cortical partners, whereas ventral regions showed overly tight connectivity with them, compared to healthy controls.

The striatum in focus
The findings suggest a vulnerability that may allow psychosis entry to the brain. Early on, prior to the development of full-blown psychosis, signs of aberrant brain signals can be detected in people at risk for psychosis (e.g., see SRF related news story). But it has been unclear whether this really indicates genetic risk or whether these abnormalities reflect the mild, intermittent psychotic experiences that put these people into the clinical at-risk category. In the new study, the researchers study people newly ill with psychosis, as well as their unaffected first-degree relatives; these people share some of the genetic risk for the disorder, but none of the psychosis. Anomalies detected in both groups, then, could reflect the risk state.

A recent study with this design implicates numerous brain networks (Khadka et al., 2013), and the new study focuses on the complicated connections between the striatum and cortex. The striatum has been seen as a locus of psychosis because its rich dopaminergic innervation makes it a candidate target of antipsychotic action. Previous work focused on the ventral parts of the striatum in psychosis, which receive inputs from limbic parts of the cortex as does the orbitofrontal cortex (OFC) involved in emotion and motivation. Recent studies, however, have suggested a role for the dorsal parts, also called the “associative” striatum, which receive inputs from cortical regions involved in cognition, such as the dorsolateral prefrontal cortex (DLPFC): Aberrant dopamine signaling localizes to the dorsal striatum in people showing mild signs of psychosis (see SRF related news story) and in people with schizophrenia (Kegeles et al., 2010; see also SRF Q&A with Anissa Abi-Dargham).

The new study examines the state of these dorsal and ventral striatal-cortical networks in psychosis and in people at genetic risk for psychosis. Using resting-state fMRI, the researchers measured the extent to which any two brain regions were simultaneously active while the study participant rested in the scanner: Regions that turn on and off in lockstep likely work together and are deemed to be functionally connected.

Seeds of psychosis
First author Alex Fornito and colleagues scanned 19 people with their first episode of psychosis, 25 of their unaffected first-degree relatives, and 26 healthy controls. The diagnoses of those with psychosis mainly consisted of schizophrenia or bipolar disorder. With the resulting images, the researchers selected six regions within the caudate and the putamen—the two main components of the striatum—spanning the dorsal and ventral parts. They then asked how activity in these predefined seed regions varied with activity in the rest of the brain.

To get at disease-related changes in how information flowed along the dorsal and ventral networks, the researchers compared those individuals with psychosis to controls. This revealed abnormally low functional connectivity in the dorsal network and abnormally high functional connectivity in the ventral network. Specifically, those with psychosis showed reduced connectivity between the dorsal caudate and DLPFC, but unusually heavy connectivity between the superior ventral caudate (sVC) and its limbic cortical partner, the OFC. The sVC also showed strong connectivity with the left DLPFC, a connection not seen at all in controls. This crossed connection suggests that the boundary between the ventral and dorsal systems is blurred in the brains of people who develop psychosis. A similar pattern held true for the dorsal and ventral parts of the putamen, and connectivity findings did not seem to vary with antipsychotic medication.

Risk regions
The unaffected relatives shared the same pattern of under-connectivity in the dorsal network and over-connectivity in the ventral network, suggesting this pattern marks a brain vulnerable to psychosis. Specifically, compared to controls, unaffected relatives showed weak functional connectivity between the dorsal caudate and DLPFC, and heavy connectivity between the sVC and the OFC. A similar gradient of connectivity was seen for the putamen regions. The magnitude of this over- and under-connectivity did not differ from that found in people with psychosis. Yet one key difference emerged: The unaffected relatives did not show a crossed connection between the ventral striatum and the DLPFC, which suggests that transitioning from risk to actual illness involves problems in additional circuits.

The researchers suggest that diminished dorsal connectivity triggers the ventral network problems; for example, enhanced dopamine signaling detected in dorsal striatum could promote noisy signals there, resulting in disjointed signaling between cortex and dorsal striatum, which could compromise top-down cognitive processes. This, in turn, may allow for runaway crosstalk between the ventral striatum and its cortical partners, which could lead to aberrant salience, a process that assigns importance to irrelevant stimuli and so could provide the grist for psychosis (Kapur, 2003).

Consistent with this, among people with psychosis, the weaker the connections between dorsal caudate and frontal cortical regions, the worse their psychotic symptoms, as measured by the positive symptom scores on the Brief Psychiatric Rating Scale (R = -0.53, p = 0.2). Although a positive correlation was also found between ventral corticostriatal network connectivity strength and positive symptom severity, this was not significant. The researchers also reported that lower connectivity between the dorsal caudate and the left DLPFC in particular correlated with worse negative symptom scores, which suggests this connection may be particularly relevant to schizophrenia.

Despite the tangle of connections between striatum and cortex, the research suggests some organization to the aberrant connectivity that appears in mental illness. This may stem from deviations in early brain development, which seems to follow a fairly basic blueprint (see SRF related news story). Future research will have to probe how genetic or environmental factors prod a vulnerable brain to full-blown illness.—Michele Solis.

Reference:
Fornito A, Harrison BJ, Goodby E, Dean A, Ooi C, Nathan PJ, Lennox BR, Jones PB, Suckling J, Bullmore ET. Functional Dysconnectivity of Corticostriatal Circuitry as a Risk Phenotype for Psychosis. JAMA Psychiatry. 2013 Sep 4. Abstract

Comments on Related News


Related News: High Dopamine Levels in People With Evidence of Prodromal Schizophrenia

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 28 January 2009
Posted 28 January 2009

This paper introduces new knowledge and at the same time replicates many of the themes that have emerged in the area of dopamine research and schizophrenia. The new knowledge is that DA dysregulation precedes onset, and is present in the same anatomical area and with a similar magnitude to that observed in schizophrenia. It shows once again that the dopamine dysregulation in schizophrenia is one of the most replicated and consistent findings in the field.

The area of pathology within the striatum is, as described in schizophrenia, the associative, rather than the limbic or sensorimotor striatum (Kegeles et al., 2006). This represents the main area of projection of the DLPFC. Furthermore, this part of the striatum receives input from other limbic cortical areas (Haber et al., 2006) and may play a role in integrating emotions and cognition. Alterations in this integrative function could lead to misattributions or mislabelings leading to paranoia or “inappropriate” affect, in addition to the cognitive deficits.

The relationship to baseline psychotic symptoms, present for the prodrome but not detected in schizophrenia, as we have previously shown, too (Laruelle et al., 1999), is worth commenting on. It suggests that dopamine may play an essential role in the genesis of psychotic symptoms. This role may be most predominant early on in the disease, rather than later in the course of the illness. Later, symptoms may perpetuate for other reasons. Alternatively, it may be that their partial improvement due to treatment prior to the scan may make the relationship more difficult to detect, and that relationship would be detected if studies included only drug naïve patients. Either way, the relationship to severity of symptoms in the prodromal stage suggests that dopamine dysregulation may be an early part of the pathogenetic pathway, and not a subsequent consequence of other events. This is strengthened by the relationship to deficits on a verbal fluency task, suggesting again a general role for dopamine in the genesis of all symptom domains.

The next questions that emerge from these data are, How early in life is the DA alteration present and what are its effects on the developing brain and the relevant circuitry? As D2 overexpression in the striatum during development resulted in long-lasting alterations in cortical dopamine and cortical function in mice (Kellendonk et al., 2006), it may be that early alterations of D2 signaling within the associative striatum have effects on other targets within the associative striatum and along the whole integrated cortico-striato-thalamocortical circuit that become obvious only at onset. Identifying and halting this process early on are needed in order to prevent long-lasting deficits. In this regard, the paper does not present evidence that increased dopamine predicts conversion, which would be needed if one should propose a test of striatal dopamine for therapeutic intervention. For this to happen, large-scale imaging studies showing sensitivity and specificity of [18F]-DOPA as a biomarker for conversion are needed, similarly to studies conducted now in the field of Alzheimer disease using PET and tracers to label β amyloid.

References:

Kegeles L, Frankle W, Gil R, et al. Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: implications for mechanisms of action of antipsychotic drugs. J Nucl Med. 2006(47):139P.

Haber SN, Kim KS, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J Neurosci. Aug 9 2006;26(32):8368-8376. Abstract

Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46(1):56-72. Abstract

Kellendonk C, Simpson EH, Polan HJ, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. Feb 16 2006;49(4):603-615. Abstract

View all comments by Anissa Abi-Dargham

Related News: Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

Comment by:  Thomas McGlashan
Submitted 21 January 2012
Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified "prodromal" subjects those who are most likely to become psychotic. That such diverse measures proved to be successful in identifying "true positives" can be regarded as a milestone in this line of investigation. It represents a quantitative leap forward in our ability to reduce the uncertainty of predicting psychosis, and hints at the day when tragedies such as the one occurring in Tucson, Arizona, become a thing of the past.

References:

Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

View all comments by Thomas McGlashan

Related News: Corticostriatal Connectivity Predicts Antipsychotic Response

Comment by:  Alexander Fornito
Submitted 18 November 2014
Posted 18 November 2014

A Focus on Dorsal Frontostriatal Circuitry as a Potential Neural Basis for Psychotic Symptoms

Since seminal reports that the clinical efficacy of antipsychotic drugs correlates strongly with their capacity for striatal D2 receptor antagonism (Creese et al., 1976; Seeman and Lee, 1975), the striatum has been thought to play a central role in the pathophysiology of psychotic illness. Accordingly, human positron emission tomography (PET) studies have revealed robust elevations of markers of presynaptic dopamine in this region of the brain (Howes et al., 2012), and recent evidence suggests that these changes may be specific to the dorsal, so-called associative, striatum (Howes et al., 2009). Importantly, these elevations are present before psychosis onset (Howes et al., 2009), correlate with the severity of prodromal symptoms (Howes et al., 2009), and predict which high-risk individuals transition to psychosis (Howes et al., 2011).

Building on evidence that striatal dopamine and prefrontal activity are strongly correlated (Fusar-Poli et al., 2010; Meyer-Lindenberg et al., 2002), we recently used resting-state functional MRI to probe the functional connectivity of distinct frontostriatal circuits in people with first-episode psychosis and their unaffected first-degree relatives (Fornito et al., 2013). We found evidence for a common connectivity reduction in both patients and relatives in a dorsal circuit linking the associative striatum with dorsolateral and medial prefrontal cortex (PFC). Moreover, the magnitude of these reductions correlated with the severity of psychotic symptoms. In a separate study, we found evidence for a similar functional connectivity reduction in people experiencing an at-risk mental state for psychosis (Dandash et al., 2014). In this case, the magnitude of the connectivity reduction correlated with the severity of prodromal symptoms related to perceptual abnormalities. Collectively, these findings suggest that reduced functional connectivity between the associative striatum and dorsolateral PFC represent a candidate risk biomarker for psychosis onset that is intimately related to striatal dopamine dysregulation.

The new study of first-episode psychosis patients by Sarpal and colleagues (Sarpal et al., 2014) adds important evidence in support of this hypothesis. Specifically, they find that improvement of psychotic symptoms following 12 weeks of treatment with either risperidone or aripiprazole is associated with increased functional connectivity between the dorsal caudate and dorsolateral PFC; dorsal caudate and medial PFC; ventral caudate and hippocampus; and ventro-rostral putamen and anterior cingulate and insula cortices. Thus, where other studies have demonstrated that lower functional connectivity of the dorsal caudate-dorsolateral PFC correlates with more severe symptoms, this study shows that clinical amelioration is coupled with increased functional connectivity of this system. There is, therefore, a tight association between dorsal frontostriatal functional connectivity and the emergence of psychotic symptoms. Although it is not yet possible to determine whether the neural changes cause symptom exacerbation or are merely an epiphenomenon, the fact that functional connectivity alterations are observed in symptom-free unaffected relatives (Fornito et al., 2013) points to a causal role for frontostriatal disconnectivity in the expression of psychotic illness.

Another important conclusion that can be drawn from the study by Sarpal et al. is that the ability of antipsychotic agents to effect symptom-related changes in corticostriatal functional connectivity clearly implicates dopamine as playing a central role in this circuit-level abnormality. This result is consistent with PET evidence for dopaminergic abnormalities in patients and high-risk populations being most prominent in the associative striatum (Howes et al., 2009). Indeed, our own work has suggested that dorsal circuit changes cannot be mimicked by acute NMDA antagonism in healthy volunteers via administration of ketamine (Dandash et al., 2014), further underscoring the central role of dopamine (rather than any putative upstream candidate pathophysiological mechanisms) in these changes.

Notably, Sarpal et al. did not find any baseline corticostriatal functional connectivity differences between their patient and healthy control groups, contrasting with our own work and others' reporting evidence for patient-related reductions in this circuit (Fornito et al., 2013; Dandash et al., 2014; Anticevic et al., 2014). The reasons for this discrepancy are unclear, but may be related to methodological differences. The schizophrenia research community would benefit by leveraging the recent emergence of online data-sharing initiatives (e.g., 1000 Functional Connectomes Project) that enable the rapid and open sharing of resting-state fMRI data in order to facilitate the replication of results and the identification of the most robust brain changes underlying the disorder.

References:

Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976 Apr 30; 192(4238):481-3. Abstract

Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975 Jun 20; 188(4194):1217-9. Abstract

Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012 Aug; 69(8):776-86. Abstract

Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009 Jan; 66(1):13-20. Abstract

Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D, Valmaggia L, Allen P, Murray R, McGuire P. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry. 2011 Sep; 16(9):885-6. Abstract

Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Grasby PM, McGuire PK. Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry. 2010 Jul; 67(7):683-91. Abstract

Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar; 5(3):267-71. Abstract

Fornito A, Harrison BJ, Goodby E, Dean A, Ooi C, Nathan PJ, Lennox BR, Jones PB, Suckling J, Bullmore ET. Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis. JAMA Psychiatry. 2013 Nov; 70(11):1143-51. Abstract

Dandash O, Fornito A, Lee J, Keefe RS, Chee MW, Adcock RA, Pantelis C, Wood SJ, Harrison BJ. Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis. Schizophr Bull. 2014 Jul; 40(4):904-13. Abstract

Sarpal DK, Robinson DG, Lencz T, Argyelan M, Ikuta T, Karlsgodt K, Gallego JA, Kane JM, Szeszko PR, Malhotra AK. Antipsychotic Treatment and Functional Connectivity of the Striatum in First-Episode Schizophrenia. JAMA Psychiatry. 2014 Nov 5. Abstract

Dandash O, Harrison BJ, Adapa R, Gaillard R, Giorlando F, Wood SJ, Fletcher PC, Fornito A. Selective Augmentation of Striatal Functional Connectivity Following NMDA Receptor Antagonism: Implications for Psychosis. Neuropsychopharmacology. 2014 Aug 21. Abstract

Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM, Savic A, Krystal JH, Pearlson GD, Glahn DC. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb Cortex. 2014 Dec; 24(12):3116-30. Abstract

View all comments by Alexander Fornito