Chapter 025, Cingulate Cortex

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Carstensen, L. Socioemotional selectivity theory and the regulation of emotion in the second half of life.

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Endogenous and exogenous modulators of potentials evoked by a painful cutaneous laser (LEPs)

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Little is known about the specific functions of the human cortical structures receiving nociceptive input, their relationship to various dimensions of pain, and the modulation of these inputs by attention. We now review studies demonstrating the subdural potentials evoked by a cutaneous laser stimulus which produces a pure pain sensation by selective activation of cutaneous nociceptors LEPs.

LEP, lesion and imaging data define pain-related elements within each of these structures: insula and parietal operculum within PS, anterior and middle cingulate cortex, and possibly Brodman's areas 3a, 3b and 1 within SI. LEPs recorded over each of these areas is modulated with laser intensity and evoked pain. Attention to the painful laser produces an increase in the amplitude of LEPs over all three cortical areas and emergence of a late positive potential over ACC alone.

These studies provide clear evidence of human cortical structures receiving nociceptive input and the modulation of that input by exogenous e. Endogenous and exogenous modulators of potentials evoked by a painful cutaneous laser LEPs. T1 - Endogenous and exogenous modulators of potentials evoked by a painful cutaneous laser LEPs.

In addition to hypofunction, studies report structural abnormalities in the anterior cingulate, thalamus, and cerebellum in schizophrenia. Specifically, voxel based morphometry Mouchet-Mages et al. The presence of structural abnormalities in these structures supports abnormalities in the distributed cerebellar network. The cingulum bundle, including the anterior cingulate, has consistently shown abnormalities in schizophrenia White et al. Patients with schizophrenia have an overall reduction of gray matter in the anterior cingulate Brodmann Area 32 Glahn et al.

Post mortem studies revealed a reduction in laminar thickness in the anterior cingulate dorsal and subcullosal regions Fornito et al. Mitelman et al. Our data support this hypothesis, as our patients with larger anterior cingulate volumes reported greater psychotic symptom improvement overtime McCormick et al. In addition, functional and structural imaging data found convergent abnormalities in the medial frontal cortex including the anterior cingulate Fornito et al. Structural abnormalities have also been revealed in thalamic nuclei and their projections in schizophrenia Andreasen et al.

Specifically, the thalamus has been shown to be reduced in size in schizophrenia Andreasen et al. In addition, FA was decreased in the internal capsule connecting the thalamus to the anterior cingulate Oh et al. DTI reveals reduced FA in the white matter fiber tracts located between the thalamus and cerebellum in patients with schizophrenia compared to normal controls.

Specifically, there was reduced FA within the superior cerebellar peduncle but not along the tract from the cerebellum to the thalamus Magnotta et al. Little is known about whether the thalamus is essentially involved in schizophrenia or whether it is simply a convergence point and relay station for signals from other parts of the brain Saalmann and Kastner, However, medial thalamic nuclei have been shown to project to the anterior cingulate cortex and inactivating these projections impairs working memory Hsu and Shyu, ; Parnaudeau et al.

We have also reported that our schizophrenia patients have decreased overall cerebellar volume and, more specifically, decreased volume of the anterior lobe of the cerebellar vermis. Decreased cerebellar volume correlated with longer duration of psychotic and negative symptoms, and greater psychosocial impairment Nopoulos et al. Post mortem morphometric analyses of patients with schizophrenia confirm decreased anterior cerebellar vermis volume Weinberger et al. There may also be reduced FA in the vermis and middle cerebellar peduncles of schizophrenia patients Okugawa et al.

Human lesion studies provide support for cingulocerebellar involvement in cognition. Although cerebellar lesions predominantly reveal motor impairments Groiss and Ugawa, , patients also suffer from comorbid cognitive impairments Gottwald et al. These dysfunctions include impaired timing, attention, memory, and language, all of which classically rely on the frontal lobes Akshoomoff and Courchesne, ; Fiez et al. Inducing transient impairments using repetitive transcranial cerebellar stimulation has recently been shown to impair cognitive tasks such as language, emotion, learning, memory, perception, and timing Fierro et al.

Similar deficits are reported following lesions to the anterior cingulate Devinsky et al. Specifically, timing on the go-nogo task, which probes response inhibition, has been shown to be impaired Picton et al. Neuronal tract-tracing has made giant strides to link the cerebellum to prefrontal networks, but many have focused exclusively on the dorsal lateral prefrontal cortex, which rodents lack Uylings et al. Retrograde tracer infusions in the dorsolateral prefrontal cortex and DTI reveal projections back to the deep cerebellar nuclei and cerebellar cortex via the pontine nuclei PN; Middleton and Strick, ; Kamali et al.

These studies establish the potential for cerebellar-prefrontal interactions in primates but additional research is necessary Uylings et al. Figure 2. Fronto-ponto-cerebellar tractography reconstructed on a 3D T1- weighted image Kamali et al. As we have argued, the anterior cingulate cortex is essential for normal cognition and shows impairments in schizophrenia.

Although homogenous in rodents, nomenclature is inconsistent. The cerebellar afferent pathway in the cingulocerebellar circuit involves direct anterior cingulate projections to the PN Vilensky and Van Hoesen, ; Glickstein et al. Specifically, Vilensky et al. These corticopontine fibers form the middle cerebellar peduncle and project to the deep cerebellar nuclei and cerebellar cortex.

There is evidence for two efferent pathways through which deep cerebellar nuclei communicate with the anterior cingulate. The first efferent pathway involves a disynaptic connection between the deep cerebellar nuclei and contralateral thalamus Magnotta et al. Medial thalamic nuclei have been shown to project to the anterior cingulate cortex Hsu and Shyu, ; Parnaudeau et al.

Therefore, it is likely that cerebellar projections to the thalamus are capable of transmitting information to broad regions of the anterior cingulate cortex. These connections are highly topographic and the labeled neurons are highly dependent on the precise location of the tracer injection.

The second efferent pathway includes deep cerebellar nuclei fastigial projections to the VTA Snider et al. The VTA is known to supply dopaminergic input to the anterior cingulate and is able to affect neuronal activity when pharmacologically manipulated Williams and Goldman-Rakic, Studies have corroborated this efferent pathway by showing that electrically stimulating cerebellar dentate nuclei DN; Mittleman et al.

Conversely, electrically stimulating the medial prefrontal cortex elicited neuronal firing in cerebellar lobule VII which projects back to the deep nuclei Watson et al. One challenge of electrical stimulation in mapping these circuits is that the influence of fibers of passage and indirect stimulation of neighboring nuclei confounds the results.

Future studies using optogenetics may achieve greater specificity. Although these studies show connections exist, the precise projections remain elusive. Single synapse red prefrontal beads and green cerebellar tracer colocalized on left ventrolateral thalamic nuclei and on VTA neurons nuclei Figures 3A,B. Convergence of information in these networks provides two avenues through which the cerebellum may influence neurons in the anterior cingulate cortex. However, the cerebellum may influence cortical function indirectly through other thalamic inputs.

More analyses are needed to identify or rule out colocalization in other thalamic nuclei. Figure 3. Proposed efferent cingulocerellar circuitry. Two efferent pathways are thought to connect the cerebellum and prefrontal cortex 1 Cerebellar projections originating from dentate DN or fastigial nuclei FN to the contralateral thalamus and anterior cingulate cortex; and 2 Cerebellar projections originating from DN or FN to the contralateral ventral tegmental area VTA which send dopaminergic projections to the anterior cingulate cortex. The afferent pathways from the anterior cingulate back to the cerebellum via the pontine nuclei PN and inferior olive IO.

B Our tract tracing data following anterograde tracer green in the right dentate nuclei and retrograde tracer red in the contralateral left medial prefrontal cortex revealed tracer colocalization of both red and green beads on a single contralateral ventrolateral thalamic VLTh neuron B. This anatomical connection opens up an avenue for the cerebellum to modulate aberrant prefrontal networks in schizophrenia. We are currently analyzing longitudinal DTI and tractography data from patients at intake and throughout the disease course, which will allow us to choose regions of interest in the anterior cingulate and the deep cerebellar nuclei to more precisely document abnormalities in the cingulocerebellar circuit.

It is important to note that as deep cerebellar nuclei are the sole output of the cerebellum, abnormalities in any area of the cerebellum have the potential to influence frontal function through the cinglocerebellar circuit. It is through the convergence of cerebellar deep nuclei and anterior cingulate projections on thalamic neurons that we propose the cerebellum can be harnessed to rescue aberrant prefrontal circuits in schizophrenia. The implications of this efferent, disynaptic pathway are numerous.

Cerebellar stimulation may have the ability to restore prefrontal neuronal activity and firing patterns, allowing relief from some of the cognitive symptoms of schizophrenia. Several studies provide support for the efficacy of cerebellar stimulation in neuropsychiatry Grimaldi et al. A classic study electrically stimulated the cerebellum and reported improved cognition based on increased alertness, improvement in thinking, and fluency of speech in addition to many enriched emotional characteristics in patients with epilepsy Cooper et al.

Recently, cerebellar vermal TBS has been effective at relieving some cognitive symptoms in treatment-resistant schizophrenia patients Demirtas-Tatlidede et al. In addition, Schutter et al. The exact cerebellar circuitry needs to be explicitly mapped prior to pursuing translational research.

How the cerebellum normally influences the prefrontal cortex and anterior cingulate is an important question that can be investigated using neuronal ensemble recordings of these areas in animals exhibiting phenotypes of schizophrenia. The cingulocerebellar circuit is likely essential for a variety of cognitive tasks as is documented by the previously described neuroimaging results. Correlating neuronal recordings will provide clarity as to how the cerebellum and prefrontal cortex work in synchrony during cognitive tasks such as learning, timing, and attention.

Task-specific modulation will indicate if these areas are necessary. Several groups have made progress deciphering the role of nodes in the cingulocerebellar circuit using electrical stimulation Mittleman et al. However, results from these studies are limited due to the unwanted spread of electrical stimulation. To circumvent this issue, we propose using optogenetic stimulation of select, isolated pools of neurons in the cingulocerebellar circuit.

Optogenetic stimulation of Purkinje cells has been shown to be an effective way to modulate cerebellar output Tsubota et al. Using our tract-tracing results to target specific deep nuclear projections in the cingluocerebellar circuit, channelrhodopsin, a light-activated channel, can be infused into cerebellar neurons. Once expressed, these proteins render their projections photoexcitable. Optical fibers can be placed in the thalamus to selectively stimulate the cerebellar neuronal projections to the anterior cingulate while not affecting other cerebellar neuronal populations. Optogenetically stimulating cerebellar dentate projections in the thalamus could influence the prefrontal cortex Figure 4.

This optogenetic paradigm could be combined with neuronal ensemble recordings to probe the dynamic relationship between the prefrontal cortex and cerebellum while analyzing task-dependent modulation. Based on evidence from cerebellar stimulation studies, cerebellar optogenetic stimulation has the potential to enhance prefrontal neuronal modulation and show correlates of behavioral improvement.

Figure 4. Schematic representation of the cingulocerebellar pathways allowing the cerebellum access to the prefrontal cortex. We propose using optogenetic stimulation of cerebellar projection neurons in the thalamus to recover activity in aberrant prefrontal neuronal ensembles in schizophrenia. Channelrhodopsin, a light-activated channel, can be infused into cerebellar neurons rendering cerebellar projections photoexcitable.

Stimulating thalamic or VTA optical fibers can selectively stimulate the cerebellar neuronal projections to the anterior cingulate while not affecting other cerebellar neuronal populations. This optogenetic paradigm can be used in animals exhibiting phenotypes of schizophrenia and other neuropsychiatric illnesses in combination with elementary cognitive tasks impaired in schizophrenia to recover cognitive function and probe the cingluocerebellar circuit. Another way to investigate the cingulocerebellar circuit is to induce abnormalities similar to those reported during schizophrenia and attempt to rescue impairments using cerebellar stimulation.

Targeting neurotransmitter cascades such as dopamine Abi-Dargham et al. These manipulations may induce changes in neuronal activity that resemble abnormalities in schizophrenia and can be correlated with behavioral abnormalities. For example, frontal dopamine has been implicated in schizophrenia Abi-Dargham et al. The level of frontal dopamine determines the type and severity of associated symptoms Goldman-Rakic et al. Excess dopamine contributes to positive symptoms such as hallucinations and delusions, while depleted dopamine is responsible for negative symptoms such as anhedonia, avolition, and cognitive deficits such as impaired timing Andreasen and Olsen, ; Seeman, ; Kuepper et al.

We, and others, have shown that temporal processing depends on the cerebellum for short, sub-second intervals Ivry and Spencer, ; Buhusi and Meck, ; Bracha et al.

Original Research ARTICLE

In schizophrenia, the prefrontal cortex shows abnormal D1 dopamine Weinberger et al. In animals, it is possible to model these concepts by locally infusing pharmacological agents into the frontal cortex to disrupt prefrontal D1 dopamine signaling and mimic impaired timing Narayanan et al. If the cingulocerebellar circuit is necessary for temporal processing and is sensitive to levels of prefrontal dopamine, pharmacologically manipulating prefrontal dopamine will disrupt neuronal activity and impair timing.

Mittleman et al. Therefore, optogenetically stimulating cerebellar nuclei has the potential to rescue aberrant contralateral prefrontal neuronal ensembles, recovering elementary cognitive tasks Boyden et al.

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  5. An example of a task that has been used to probe the role of the cingulocerebellar circuit is eyeblink conditioning as it is abnormal in schizophrenia Brown et al. Specifically, trace eyeblink conditioning, where a conditioning stimulus and an unconditioned stimulus are separated by a trace interval, requires integration of the cerebellum and frontal cortex Weiss and Disterhoft, Siegel et al.

    They found direct projections to the ipsilateral rostral PN via the corticospinal pyramidal tract. It has also been reported that prefrontal neurons are consistently active in the trace interstimulus interval, likely encoding the elapsed time between the stimulus and providing the cerebellum with the timing information necessary to accurately execute the eyeblink response Siegel et al. It is possible to pharmacologically mimic psychiatric abnormalities by inactivating various areas of the prefrontal cortex to produce disruptions in trace eyeblink conditioning.

    Following expression of channelrhodopsin infusions in deep cerebellar nuclei, optogenetic stimulation of cerebellar projections to the thalamus have the potential to recover prefrontal neuronal activity and rescue eyeblink conditioning. Optogenetic stimulation of the cingulocerebellar pathway can also be explored in genetically modified animals exhibiting schizophrenia phenotypes. Each of these animals has cerebellar abnormalities similar to those consistently detected in schizophrenia making them ideal models to study the cingulocerebellar circuit Shevelkin et al.

    There are many additional aspects of this circuit that can be explored. Although we have focused on a very specific circuit involving the anterior cingulate and cerebellum, it is possible that a more widespread activity is sufficient for normal functioning. There are known connections throughout frontal lobes and normalized neuronal firing throughout the brain may prove essential rather than the firing patterns of one particular structure. This theory is supported by the more diffuse type of stimulation used by transcranial magnetic stimulation Grimaldi et al.

    Although schizophrenia is not considered to be a motor disease, many indicators of motor dysfunction are present, suggesting that the basic abnormality in the disorder could be a brain system that mediates both motor and cognitive functions. Kraepelin described a variety of motor abnormalities in schizophrenia in his classic textbook Slowed reaction time is one of the oldest and most robust tests showing differences between schizophrenic patients and normal controls. More recent studies of premorbid indicators and neurological soft signs also implicate the motor system Walker and Shaye, ; Gupta et al.

    These mild indicators of poor coordination provide a clue that the underlying mechanism may reflect an abnormality in a basic process that regulates the synchrony of both thought and motor activity. Therefore, schizophrenia may be conceptualized as a disease that is characterized by poor coordination, or dysmetria, in all domains of functioning, including movement and cognition.

    In addition to its role in cognition, the cerebellum has traditionally been associated with movement and gait. Therefore, the circuit between the prefrontal cortex and cerebellum may facilitate the smooth execution, or synchrony of both motor and cognitive function. As we have proposed optogenetic stimulation of cerebellar projections for the treatment of the cognitive symptoms of schizophrenia, the motor impairments may actually benefit as well.

    Cerebellar circuitry involves efferent connections with the basal ganglia which project back to the cerebellum via the PN similar to the anterior cingulate projections Bostan and Strick, ; Bostan et al. However, similar to schizophrenia, the role of the cerebellum in PD is unknown. Recently, Wu et al.

    They speculated that the cerebellum plays either a compensatory role or a pathological role Wu and Hallett, Using optogenetic stimulation of cerebellar projections in the striatum, it may be possible to modulate cerebellar activity and repair movement, gait, and cognition in PD patients. How cerebellar circuitry interacts with the anterior cingulate via the dopaminergic VTA projections should be pursued, as cerebellar stimulation could represent novel therapeutic opportunities for both the cognitive and motor impairments in PD.

    Courchesne et al. In addition to decrease in cerebellar vermal volume, there appears to be aberrancies in cerebellar-prefrontal interactions Carper and Courchesne, ; Pierce and Courchesne, ; Courchesne et al. Recently, Purkinje cell abnormalities have been linked to behavioral deficits similar to those exhibited in autism Sudarov, The middle cerebellar peduncle has also shown structural impairments in autism and as the output pathway for cerebellar projections, this altered microstructure could have dire consequences for cerebellar-frontal lobe communications Sivaswamy et al.

    More research needs to be done to understand the behavioral and cognitive symptoms in autism which depend on the cingulocerebellar pathway Heck and Howell, Using optogenetics, this circuit should be parsed out and pursued to repair brain circuitry in autism. There are currently several animal models that exhibit phenotypes of autism, which are ripe for investigation. The ideas described here have the potential to map the influence of cerebellar circuitry on the frontal cortex and lead to new insights about cingulocerebellar interactions.

    Through the cingulocerebellar circuit, cerebellar stimulation may recover aberrancies in the anterior cingulate cortex, rescuing cognition in schizophrenia. To our knowledge, this idea has not been proposed before, and we hope systematically applying the techniques described here to the many cognitive tasks impaired in schizophrenia such as attention and working memory, will encourage the development of new, targeted treatments for treatment-resistant patients. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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