Schizophrenia and Schizophrenia and Schizophrenia and - PowerPoint PPT Presentation

Schizophrenia and Schizophrenia and Schizophrenia and Schizophrenia and Schizophrenia and Schizophrenia and Schizophrenia and Schizophrenia and the lesser brain: the lesser brain: the lesser brain: the lesser brain: Promising new treatment target Promising new treatment target Promising new treatment target Promising new treatment target William P. William P. Hetrick Hetrick, Ph.D. , Ph.D. Department of Psychological & Brain Sciences Department of Psychological & Brain Sciences Department of Psychological & Brain Sciences Department of Psychological & Brain Sciences Program in Neuroscience Program in Neuroscience Indiana University, Bloomington Indiana University, Bloomington y y g g Supported by: Supported by: NARSAD Award to WPH NIMH R03 MH066149 to WPH NIMH R01 MH074983 to WPH

Collaborators Collaborators Collaborators Collaborators Brian O’Donnell Mandi Bolbecker, Joe Steinmetz, Sharlene Newman, & Patrick Skosnik Anantha Shekhar

Overview Overview Overview Overview Schizophrenia and the theoretical model Schizophrenia and the theoretical model 1. 1. under investigation under investigation Supporting evidence for this model Supporting evidence for this model 2. 2. Multi Multi- -method approach to functional studies method approach to functional studies 3. 3. of motor & cognitive of motor & cognitive dysmetria dysmetria in in schizophrenia schizophrenia hi hi h h i i Cerebellar- Cerebellar -mediated eye blink conditioning: mediated eye blink conditioning: Behavioral findings Behavioral findings Behavioral findings Behavioral findings Neuroimaging findings Neuroimaging findings Pharmacological studies Pharmacological studies

Schizo Schizo Schizophrenia Schizophrenia p hrenia hrenia Diagnostic & Diagnostic & Diagnostic & Statistical Diagnostic & Statistical Statistical Manual (DSM) Statistical Manual (DSM) Manual (DSM) Definition Manual (DSM) Definition Definition Definition Positive symptoms Positive symptoms (“excess” behaviors) (“excess” behaviors) – Psychotic dimension P P Psychotic dimension h ti di h ti di i i Delusions, Hallucinations Delusions, Hallucinations – Disorganization dimension Disorganization dimension Disorganized thought Disorganized thought – Loose associations Loose associations Disorganized speech Disorganized speech – Neologisms, Perseveration, Clanging, Blocking Neologisms, Perseveration, Clanging, Blocking Inappropriate affect Inappropriate affect Negative symptoms N N Negative symptoms (“deficit” behaviors) ti ti t t (“deficit” behaviors) (“d fi it” b h (“d fi it” b h i i ) ) – Restricted and flat affect Restricted and flat affect – Alogia Alogia – Avolition Avolition Avolition Avolition – Anhedonia Anhedonia Psychomotor symptoms Psychomotor symptoms – Catatonia Catatonia – Neurological soft signs (independent of localized pathological lesion) Neurological soft signs (independent of localized pathological lesion) integrative sensory function; motor coordination; and motor sequencing. integrative sensory function; motor coordination; and motor sequencing. Lifetime prevalence: ~1% Lifetime prevalence: ~1%

Eugen Eugen Bleuler’s Bleuler’s model of model of schizophrenia: schizophrenia: “Fragmented “Fragmented Phrene Fragmented Fragmented Phrene Phrene Phrene” (1857-1939) “Split mind” (1908) “Split mind” (1908) p p ( ( ) ) – "breaking of associative threads" between "breaking of associative threads" between ideas ideas Core deficit is a fundamental Core deficit is a fundamental associative associative disturbance disturbance d stu ba ce d stu ba ce

“Fragmented Phrene” “Fragmented Phrene” Fragmented Phrene Fragmented Phrene "the thousands of associations guiding our thought the thousands of associations guiding our thought are interrupted by the disease in an irregular way here and there, sometimes more, sometimes less. The thought processes, as a result become strange Th th ht lt b t and illogical, and the associations find new paths, though they may be irrelevant to the problem at hand” (Bleuler, 1911, p.14)

Theoretical Model Under Study Theoretical Model Under Study Schizophrenia is characterized by Schizophrenia is characterized by abnormalities in the temporal abnormalities in the temporal abnormalities in the temporal abnormalities in the temporal coordination of thoughts, perceptions, coordination of thoughts, perceptions, motor behavior, and emotions (i.e., motor behavior and emotions (i e motor behavior, and emotions (i.e., motor behavior and emotions (i e fragmented fragmented phrene phrene – cognitive cognitive cognitive dysmetria cognitive dysmetria dysmetria (Andreasen dysmetria (Andreasen Andreasen, 1998). Andreasen, 1998). , 1998). , 1998). The examination of temporal processing The examination of temporal processing The examination of temporal processing The examination of temporal processing and related neural substrates may shed and related neural substrates may shed light on mechanisms associated with light on mechanisms associated with g these abnormalities. these abnormalities.

Supporting evidence for this model Supporting evidence for this model Supporting evidence for this model Supporting evidence for this model Cortico Cortico-cerebellar loops Cortico Cortico cerebellar loops cerebellar loops subserve cerebellar loops subserve subserve motor & subserve motor & motor & motor & cognitive functions cognitive functions Pervasive motor abnormalities in Pervasive motor abnormalities in Pervasive motor abnormalities in Pervasive motor abnormalities in schizophrenia spectrum schizophrenia spectrum C C Cerebellar findings Cerebellar findings b ll b ll fi di fi di

Cortico Cortico- -cerebellar Loops cerebellar Loops Ramnani (2006) Nature Reviews Neuroscience: Theoretical Model of Motor Control: Theoretical organization of information processing streams that use forward processing streams that use forward models for motor control. Motor commands directed to systems that control movement are also copied to forward models that mimic input–output relationships exhibited by these systems.

Cortico Cortico- -cerebellar Loops cerebellar Loops Ramnani (2006) Nature Reviews Neuroscience: Anatomical of Motor Control Model:

Cortico Cortico- -cerebellar Loops cerebellar Loops Ramnani (2006) Nature Reviews Neuroscience: Model of Prefrontal Non-motor Control: Information arising in the prefrontal cortex is copied to the cerebellum in the same is copied to the cerebellum in the same way that motor commands are copied from the primary motor cortex to the spinal cord. In this scheme, cerebellar forward models mimic the input–output relationships of prefrontal targets. Forward models might therefore be able to mimic information processing that is intrinsic to the prefrontal processing that is intrinsic to the prefrontal cortex.

What Is The Role of Cerebellum in Cortico-cerebellar Circuits? Schmahmann & Sherman (1998)  Cerebellar Cognitive Affective Syndrome Cerebellar Cognitive Affective Syndrome  “a pattern of behavioral abnormalities…that includes impairments of executive function…, often with perseveration, distractibility or inattention; visual-spatial disorganization and impaired visual-spatial memory; personality change with blunting of affect or disinhibited and inappropriate behavior; and difficulties with language”  C C Cerebellum modulates neural circuits that link prefrontal, posterior parietal, Cerebellum modulates neural circuits that link prefrontal, posterior parietal, b ll b ll d l t d l t l i l i it th t li k it th t li k f f t l t l t t i i i t l i t l superior temporal and limbic cortices with the cerebellum. superior temporal and limbic cortices with the cerebellum.