Neurobio Structures Networks LECTURE

Lecture: 02/09

Hypofrontality

  • prefrontal cortex and frontal circuitry have been the long-standing focus of inquiry into the pathology of schizophrenia

  • hypofrontality - reduced activation of the frontal cortex in schizophrenia, most consistently observed during executive-function tasks

    • particularly the dorsolateral prefrontal cortex (DLPFC)

  • early neuroimagining evidence (1970’s - 1980’s)

    • regional cerebral blood flow (rCBF) studies suggested reduced frontal perfusion

    • PET studies later showed reduced frontal glucose metabolism

  • fMRI findings (1990’s onward)

    • many studies showed reduced DLPFC activation during working-memory tasks

    • however, some studies reported increased or inefficient PFC activation, depending on task demands and performance level

  • current interpretation

    • hypofrontality reflects inefficient recruitment of prefrontal control networks, rather than simply “less frontal activity”

  • why did the field move beyond the hypofrontality hypothesis?

    • these early brain imaging studies did not fully account for important confounds

      • early functional imaging methods has limited spatial andn temporal resolution and small sample sizes

      • task performance differences (attention, IQ, working-memory capacity)

      • negative symptoms and motivation

      • medication side effects (i.e., the effect of antipsychotic drugs on the vascular system)

      • abnormalities in non-frontal regions that influence frontal activity (e.g., parietal cortex functioning)

  • in summary:

    • people living with schizophrenia often show impaired performance on tasks engaging the prefrontal cortex, especially working memory and executive control

    • early reports of reduced frontal metabolism and blood flow were influential but later found to be context-dependent and methodologically confounded

    • current models emphasize prefrontal network dysfunction, rather than simple hypo- or hyperactivity


Hippocampal Abnormalities

  • early neuroimaging studies in the 1990’s reported increased resting cerebral blood flow and metabolism in the hippocampus in schizophrenia

  • later task-based fMRI studies also showed increased hippocampal activation, particularly during memory-related tasks

  • there findings contributed ot the idea that hippocampal hyperactivity may be a core feature of schizophrenia, in contrast to early models focused primarily on prefrontal dysfunction

  • schizophrenia is associated with impaired hippocampal habituation, meaning reduced ability to downregulate neural responses after repeated presentation of emotionally salient stimuli

  • during repeated viewing of facial expressions, individuals with schizophrenia show sustained hippocampal activation, whereas comparison participants show the expected decrease in activation over time (Holt et al., 2005)

  • post-mortem studies reveal:

    • normal total number of hippocampal neurons

    • selective reduction of inhibitory interneurons (e.g., PV+ interneurons)

  • MRI studies reveal:

    • reduced hippocampal volume


Hippocampal Structure

  • the majority of hippocampal neurons (~90%) are glutamatergic pyramidal cells, which provide long-range excitatory projections outside the hippocampus

  • a smaller population (~10%) consists of GABAergic interneurons

  • interneurons play a critical role in:

    • synchronizing pyramidal neuron firing

    • maintaining excitation-inhibition balance

    • regulate information flow through hippocampal circuits


Do structural changes in the hippocampus predict the onset of psychosis?

  • individuals at Clinical High Risk (CHR) for psychosis participated in a longitudinal MRI study

  • CHR participants includes individuals with

    • attenuated psychotic symptoms

    • brief intermittent psychotic symptoms

    • familial risk plus recent functional decline

  • participants were followed over time to determine who transitioned to psychosis

  • the key question: do hippocampal structural changes predict later conversion to psychosis?

  • participants were followed at monthly intervals to complete a structural clinical symptom rating scale for the first year, at 3 month intervals during the second , and the third year and annually thereafter until transition to frank psychosis or until end of follow-up period (5 years)

  • those who converted tro psychotic disorder were scanned again after conversion, those who did not convert were scanned at the end of the study period

  • all patients were antipsychotic naive at the time of baseline

  • total of 18 patients completed the study (8 converted to psychosis, 10 did not)

  • at the time of follow up scan, 5 of the converters were treated with antipsychotics

  • a significant main effect of time: hippocampal volume decreased over time in all subjects

  • no difference between converters and non-converters


Hippocampal abnormalities in schizophrenia

  • increased hippocampal activity in schizophrenia, possibly reflecting impaired habituation or regulation of hippocampal responses

  • no reduction in total hippocampal neuron number, but selective loss of GABAergic interneurons

  • reduced hippocampal volume is frequently observed, though not specific to schizophrenia and not predictive of psychosis onset

  • environmental risk factors are also at play

    • for instance, cannabis use is high in psychotic disorders

    • the early and heavy use of cannabis alters hippocampal structure (Cousijn et al., 2012)

  • dopamine hypothesis of schizophrenia has been linked to hippocampal hyperactivity


Effects of cannabis use on hippocampal volume

  • they found reduced hippocampal volumes in cannabis dependence, not in non-dependent cannabis users

    • THC use and cannabis dependence are associated with increased risk for psychosis, particularly in individuals with existing vulnerability

    • Findings suggest hippocampal circuitry may be especially vulnerable across multiple pathways linked to psychosis risk

    

Cerebellar abnormalities in schizophrenia

  • once thought to primarily support motor coordination, the cerebellum is now known to contribute to cognitive and emotional regulation

  • the cerebellum participates in distributed circuits linking cortex → cerebellum → thalamus → cortex (CCTCC)

  • post-mortem studies suggest reduced Purkinje cells desity in the cerebellum

  • neuroimaging studies show reduced cerebellar activation across multiple cognitive tasks

  • these findings contributed to Dr. Andreasen’s “cognitive dysmetria” hypothesis of schizophrenia

  • The hyper and hypo connectivity pattern of the thalamus with the cortex has recently been replicated for striato-cortical and cerebello-cortical connectivity in an MRI study of 159 chronic schizophrenia patients and 162 matched controls.

  • These results highlight that the cortico-cerebellar-thalamic-cortical circuit (CCTCC) is widely affected in schizophrenia

  • It’s brain wide alterations rather than exclusively focal functional disturbances that are altered in schizophrenia.


Thalamic abnormalities in schizophrenia

  • intrinsic brain networks revealed with resting-state functional connectivity MRI

  • thalamus → sensory-motor cortex hyperconnectivity

  • thalamus → prefrontal cortex hypoconnectivity

    • also observed in CHR & predicts conversion

  • Communication between the thalamus and the cortex is modulated by the thalamic reticular nucleus (TRN).

  • TRN is a very small structure that receives collaterals from thalamocortical and corticothalamic projections

  • TRN is made up almost entirely of GABAergic interneurons

  • Abnormal wiring of the thalamocortical circuitry in psychotic disorders.

  • It predicts conversion to psychosis in clinical high risk.

  • Not unique to schizophrenia.

  • Possibly due to loss of GABAergic interneurons in the thalamic reticular nucleus

Lecture: 2/11

Can E/I imbalance explain schizophrenia?

  • Global alteration of excitation inhibition balance in schizophrenia

  • BUT- the extend to which different brain functions are affected by schizophrenia vary greatly:

    • severe alterations of belief, thought, and higher-order executive cognitive function.

    • mild alterations in lower-level sensory and motor functions

  • If these neural changes are pervasive, how do we explain the presence of deficit “hotspots”?


Can brain abnormalities predict the emergence of psychosis?

  • An important goal in our field is to identify structural and functional changes in the brain that can reliably predict who will develop a psychotic disorder.

  • This is typically done by recruiting a large group of participants who are at heightened risk for developing psychosis and either:

    • obtain brain imaging data longitudinally (e.g. every 6 months) to identify progressive changes in brain structure and volume

    • Obtain brain images at a single time point but monitor participants clinically to determine diagnostic outcomes, then compare brain imaging at baseline between high-risk converters and high-risk non-converters

  • North American Prodrome Longitudinal Study (NAPLS3).

  • Determining whether brain grey matter structure changes prior to conversion to a psychotic disorder

  • Whether gray matter changes can elucidate illness-related neurobiological processes

  • If yes, can we target the prevention of these brain changes?

  • One possible target could be interventions that are geared towards protecting excitation/inhibition balance